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The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis

The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis rheumatoid arthritis, psoriatic arthritis, psoriatic arthritis, ankylosing spondylitis, biologic, Anti-TNF, safety Introduction The use of biologic therapies has transformed the management of inflammatory arthritis (IA). In contrast to conventional systemic DMARDs (csDMARDs) traditionally used to treat inflammatory disease, these agents offer a targeted approach, and their widespread use has resulted in disease remission becoming an increasingly achievable goal. Biologic therapies are not without potential risk, and hence it is important that clinicians are aware of these risks and ensure that appropriate precautions are taken to minimize them. Information on the safety of biologic therapies continues to be collected through national registries, clinical and cohort studies and case series and reports. NICE has accredited the process used by the BSR to produce its guidance on the safety of biologic DMARDs in inflammatory arthritis. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. This guideline supersedes the previous BSR/BHPR anti-TNF [1], rituximab (RTX) [2] and tocilizumab (TCZ) [3] guidelines and has been developed in line with the BSR Guidelines Protocol. Scope and purpose Background and need for guideline In 2001, The British Society of Rheumatology published its first guidelines on the safety of anti-TNF agents in RA. This was subsequently updated in 2005 [4], and most recently in 2010 [1]. These guidelines covered the indications and precautions for the use of anti-TNF agents, and the action that should be taken in the case of an adverse event. The initial guidelines focused on the then-available first generation anti-TNF drugs (infliximab (INF), etanercept (ETN) and adalimumab (ADA)) in RA. This was then expanded in the 2010 guideline to include the newer anti-TNF agents, golimumab and certolizumab. Separate guidelines covering the use and safety of RTX [2] and TCZ [3] in RA were published in 2011 and 2014, respectively. The previous 2010 BSR/BHPR biologics safety guideline focused solely on anti-TNF inhibitors for RA. While most safety evidence, especially long-term observational data, exists for the first generation anti-TNF agents in RA, since the last guideline there has been significant new information from clinical studies regarding the safety of both anti-TNF agents and the newer non-TNF biologic DMARDs, both in RA and in other licensed IA indications. In light of this, the 2010 guideline working group lead, and a new guideline working group confirmed, the need for an updated guideline combining the wider spectrum of biological agents used at present across their multiple approved indications. Objectives of guideline The purpose of this guideline is to provide evidence-based recommendations for the safe use of biologic therapies in adults (aged >18 years). Although the majority of published safety data still concern the use of first-generation anti-TNF agents in RA, this guideline has been expanded from the previous to cover the safety aspects of all biologic therapies (approved by the National Institute for Health and Care Excellence (NICE) as of June 2016; Table 1) for the treatment of RA, PsA and axial spondyloarthritis (SpA) including AS [referred to as inflammatory arthritis (IA) henceforth]. Therapies approved by NICE after June 2016, such as secukinumab, sarilumab and the Janus kinase inhibitors, are not included. Table 1 Biologic therapies covered by this guideline Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Table 1 Biologic therapies covered by this guideline Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 This guideline highlights several specific safety areas including recommendations for baseline screening prior to initiation, recommendations for monitoring, the implications of co-morbid disease and ageing, vaccinations and the management of biologic therapies in specific situations such as infection, malignancy and the peri-operative window. Biologic therapies covered by this guideline (in alphabetical order) are shown in Table 1. Individual drug Summary of Product Characteristics (SPCs) are available online at www.medicines.org.uk, and can be used alongside this guideline. The following indications are covered by this guideline: RA, PsA and axial SpA, including AS. Target audience This guideline is aimed at secondary health care professionals who are involved in the management of patients with IA receiving biologic therapies. This may include rheumatologists, rheumatology specialist nurses and allied health professionals, specialist pharmacists, rheumatology speciality trainees and patients. General practitioners, physicians in other specialties and surgeons who manage patients treated with biologic therapies may also find this guideline useful. The areas the guideline does not cover This guideline does not cover specific indications for biologic therapy in IA; this has been described in national and international disease-specific recommendations, as well as NICE guidance (www.nice.org.uk). The guideline does not cover the safety aspects of csDMARDs. This has been recently updated in the BSR/BHPR non-biologic DMARD guidelines [5]. The guideline does not cover the use of biologic therapy for conditions other than RA, axial SpA including AS and PsA, nor safety in individuals aged <18 years. The safety of biologics in the context of pregnancy and breastfeeding is not covered here; this has recently been covered in the BSR/BHPR Prescribing Drugs in Pregnancy guidelines [6]. Finally, the guideline does not specifically cover the safety of biosimilar preparations of branded biologics; until further clinical data are available, the safety recommendations we propose for originator biologics can be applied to their biosimilar counterparts. Patients should be made aware of the potential switch to biosimilar preparations. The requirement for brand name prescribing and entry of patients into registries is essential to ensure ongoing pharmacovigilance including the collection of long-term observational safety data in this area. Stakeholder involvement This guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair, Dr Chris Holroyd, alongside representatives from relevant stakeholders (Table 2). In accordance with BSR policy, all members of the GWG made declarations of interest, which is available on the BSR website. Table 2 Names and affiliations of the Guideline working party Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Table 2 Names and affiliations of the Guideline working party Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Involvement and affiliations of stakeholder groups The GWG was composed of rheumatology consultants from various clinical backgrounds, rheumatology specialty trainees, rheumatology nurse specialists and a patient representative. All members contributed to the development of key questions on which to base the search strategy, guideline content, recommendations and strength of agreement (SOA). Rigour of development This guideline has been developed in line with BSR’s guideline protocol. A comprehensive literature search was undertaken by two reviewers, using MEDLINE, Cochrane, PubMed and EMBASE databases with specific search terms (Table 3). The reference lists of retrieved articles were manually searched for additional papers and these were included if appropriate. All searches were performed up to the end of June 2016. Abstracts from BSR, EULAR and ACR annual conferences up to and including EULAR 2016 were also included. Table 3 Search terms used for literature review Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Table 3 Search terms used for literature review Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Two thousand eight hundred and sixty-nine articles were identified from the literature search; after removal of duplicates, 560 were eligible for detailed review. Two reviewers independently extracted information from relevant papers using data extraction tables. Only articles in the English language containing information on the safety of biologic therapies were included. Two hundred and eighty-nine articles were finally included in the guideline. The guideline was developed and drafted via a series of telephone conference calls and face-to-face meetings, using the retrieved literature to underpin and facilitate discussions. Due to the breadth of the guideline, designated members of the GWG were divided into sub-groups to lead on specific sections of the guideline. One subgroup led the anti-TNF section, another the RTX and abatacept (ABA) section, and the third group led the TCZ and ustekinumab (UST) sections. Grading the evidence The GRADE method was used to assess the quality of evidence and the strength of recommendation [7]. Accompanying each recommendation in this guideline, in brackets, is the strength of recommendation, quality of evidence and SOA. Each subgroup produced GRADE scores for their sections, which was then distributed to and ratified by the entire GWG. Strength of recommendation Using GRADE, recommendations were categorized as either strong (denoted by 1) or weak (denoted by 2), according to the balance between benefits and risks. A strong recommendation was made when the benefits clearly outweigh the risks (or vice versa). A weak recommendation denotes that the benefits are more closely balanced with the risk or more uncertain. Quality of evidence Using the GRADE approach, the quality of evidence was determined as either high (A), moderate (B) or low/very low (C) reflecting the confidence in the estimates of benefits or harm. High quality (A): typically generated from well-conducted meta-analyses, randomized controlled trials (RCTs) or other overwhelming evidence (such as large, well-executed observational studies with a low risk of bias). Further research is very unlikely to change confidence in the estimate of effect. Moderate quality (B): usually from randomized controlled trails or observational studies with important limitations. Further research is likely to have an important impact on and may change the estimate of effect. Low quality (C): usually from observational studies, or randomized controlled trials with major limitations. Further research is very likely to have an important impact on the confidence in the effect estimate and is likely to change the estimate. Very low quality evidence is usually derived from observational studies with serious limitations or from non-systematic observations (such as case reports and case series). SOA Each draft recommendation was evaluated by all members of the GWG. Based on the strength of recommendation and level of evidence, each recommendation was subject to a vote by all members of the GWG; a scale of 1 (no agreement) to 10 (complete agreement) was used. Only recommendations with a mean SOA score of ⩾7 plus ⩾75% respondents scoring ⩾7 were included. The SOA is presented next to the GRADE score for each recommendation as a percentage (e.g. 100% would imply all responses were 10/10). Limitations of this guideline The literature search excluded any articles not available in English language and any non-human studies. In addition, there were a very small number of articles identified through the search strategy that we were unable to obtain through university library channels. Plan for review In line with BSR’s guideline protocol, this guideline will be updated in 3–4 years, but if there is a significant change in the evidence base then an earlier update may be undertaken. The guideline To date, most long-term observational studies have focused on the safety of first generation anti-TNF agents (INF, ETN and ADA) in RA. In some areas, there is an increasing body of evidence regarding the safety of non-TNF biologic agents; however, there remains a paucity to guide many clinical scenarios. Where appropriate the evidence underpinning our recommendations has been divided into two sections: anti-TNF biologics and non-anti-TNF biologics. Generic recommendations (i) The decision to initiate a biologic should be made in conjunction with the patient/carer and initiated by an expert in the management of rheumatic disease (grade 1C; SOA 99%). Biologic therapy for IA can be prescribed when patients meet the respective NICE recommendations. As NICE restrict eligibility and there are potential risks (as discussed through this document), as well as benefits from biologic therapies, decisions to initiate therapy should be made by a consultant rheumatologist. Following national initiatives and guidance, patients and/or their carers should be actively involved in the decision making processes. (ii) Patients should be provided with education about their treatment to promote self-management (grade 1B, SOA 99%). A Cochrane review in 2002 demonstrated that education had a positive effect in terms of both patient reported outcome and objective measures of clinical response; however, the benefits were not observed during a longer duration of follow-up [8]. The Department of Health has estimated that the average cost of education and self-management is £125/person and would save costs of £244/person on average [9]. Rheumatologists should therefore offer patients with IA the opportunity to discuss their condition and the risks and benefits of treatments both at diagnosis and throughout the course of their disease. Patients with IA should be offered verbal and written information to improve their understanding of their specific condition and its management. For those patients who would like further information, participation in existing educational activities including self-management programmes is recommended [10]. (iii) Patients should be assessed for co-morbidities as these may influence biologic choice, including evaluation for respiratory disease and screening for infection (grade 1C, SOA 99%). Comorbid conditions such as respiratory disease and underlying infection have significant implications for both csDMARD and biologic prescribing. Patients should be assessed for such comorbidities at baseline and reviewed regularly (at their annual review and upon changes in treatment as a minimum). Further information is detailed later in this document. (iv) Patients should have direct access to their specialist centre [e.g. via an advice line (Helpline)] for advice within one working day (grade 1C, SOA 98%). The NICE quality standard (QS33) for the management of RA states that patients experiencing flares in their condition or a drug-related side effect should be offered, and be able to obtain, direct advice from their rheumatology service [11]. Advice should be available within one working day and when required prompt action should be taken to ensure patients’ safety and optimize management of their RA. The principles behind this recommendation should also be applied to the other IA problems covered by this guideline. (v) Clinicians should be encouraged to recruit patients to the appropriate biologic therapy registry, with patient consent (grade 1C, SOA 98%). Although RCTs are considered the gold standard for the demonstration of biologic therapy efficacy, they are limited in their use for collecting safety data. There are several reasons for this—small patent numbers in RCTs make the detection of rare side effects difficult, short duration of follow-up leads to challenges in the detection of delayed side effects, homogeneous patient recruitment may not be representative of real life, exclusion criteria hamper recruitment of patients with important co-morbidities and RCTs are generally powered to detect efficacy outcomes, rather than significant safety signals. It is important that patients are recruited to the appropriate national biologic therapy registries [such as the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and the British Society for Rheumatology Biologics Register for AS (BSRBR-AS)], to enable long-term collection of real-life safety data on a large scale. For patients prior to treatment with a biologic Pre-treatment investigations Baseline assessment for all should include (grade 1C SOA 98%): laboratory evaluation of full blood count (FBC), creatinine/calculated glomerular filtration rate (GFR), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), albumin, tuberculin skin test (TST) or interferon-gamma release assay (IGRA) or both as appropriate, hepatitis B and C serology, and a chest radiograph. Baseline assessment in both csDMARD and biologic prescribing acts as a screening tool for underlying conditions such as lung, renal or hepatic disease and also provides a reference point for future comparison. While the pick-up rate of routine investigations in a healthy individual is low, there is an increased incidence of significant abnormalities in RA patients, due to their increased overall burden of comorbidities [12]. Screening for TB and hepatitis are discussed in more detail in the mycobacterium tuberculosis and hepatitis sections. Patients receiving RTX: baseline immunoglobulins (IgA, IgG and IgM) are recommended prior to initiation (grade 1A, SOA 98%). Few patients would be expected to have low Ig levels before the start of RTX therapy: ⩽2.2% in one study of 3595 patients [13]. However, several studies have found that a low level of immunoglobulins, especially IgG, is associated with a higher risk of neutropaenia and infection in patients receiving RTX [13–16]. Patients receiving TCZ: a baseline lipid profile is recommended prior to initiation. If abnormal, lipid lowering treatment should be initiated as per local guidance (grade 2A, SOA 99%). Blockade of the IL-6 receptor by TCZ is associated with an increase in lipid parameters compared with baseline. Despite the increase in low-density lipoprotein (LDL)-cholesterol, trial data seem to indicate that the ratio of total cholesterol: high-density lipoprotein (HDL)-cholesterol remains unchanged [17]. A post hoc retrospective pooled analysis [18] of 3986 patients who received TCZ found 0.34 independently adjudicated major adverse cardiovascular events (MACE) per 100 patient-years in 24 weeks of follow-up. The study found an association between baseline total cholesterol: HDL-cholesterol ratio and MACE, with poor RA disease control associated with a higher risk of future MACE. Pre-treatment management of and screening for co-morbidity Infection In general (recommendations for Mycobacterium tuberculosis, viral hepatitis and HIV are discussed separately): (i) Biologics should not be initiated in the presence of serious active infections (defined as requiring intravenous antibiotics or hospitalization (grade 1B, SOA 98%). Patients with RA, especially those with severe disease and extra-articular manifestations, have a higher risk of infection, estimated at double the risk of the general population [19]. Patients with severe disease, who already have a higher risk of infection, are more likely to receive biologic therapies; hence when evaluating the association between a drug and infection risk, it can be difficult to determine whether the infection risk is drug-related or is in keeping with that expected for the disease severity. The most recent Cochrane review of 106 controlled trials, including 42 330 patients with RA, found that patients receiving standard dose biologic therapies were at a 27% higher odds of serious infection compared with controls [20], findings consistent with the same author’s earlier Cochrane review [21]. Anti-TNF biologics Of all the studies evaluating the safety of biologic therapies, those investigating the association between anti-TNF agents and infection risk are the most numerous, the majority of which have focused on the use of the first generation anti-TNF's (INF, ETN and ADA) in RA. Although there have been some inconsistencies between the results from various analyses, the majority of studies have found a significant association between anti-TNF drugs in patients with RA and a higher risk of serious infection. Observational data from several national registries, including the BSRBR-RA [22], US Coronna registry [23] and the Spanish BIOBADASER 2.0 [24], have shown a significant positive association between anti-TNF agents and serious infection in RA. BSRBR-RA included data from 11 798 RA patients receiving ADA, ETN or INF, and 3598 csDMARD controls. The incidence of serious infection in the TNF group was 4.2/100 patient-years vs 3.2/100 patient-years in the DMARD group. The adjusted hazard ratio for serious infection in the TNF group was 1.2 (95% CI: 1.1–1.5) [22]; the highest risk of infection was in the first 6 months of treatment. This evidence has furthermore been supported by results from recent meta-analyses by Bernatsky et al. [25] and Michaud et al. [26], which both reported an approximate 1.4-fold increased risk of infection in RA patients treated with anti-TNF agents compared with csDMARD controls. There is a relative paucity of long-term observational data investigating the risk of infection in other types of IA, such as AS and PsA. A Cochrane review [27] and a meta-analysis of RCTs [28] in AS, and two meta-analyses of RCTs in PsA [29, 30] found no elevated risk of serious infection with anti-TNF therapy used in these conditions; however, the analyses included a low number of RCTs compared with the RA data (between 6 and 21 studies) and event rates of infection were low making the studies underpowered to show a significant association. Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. Non-anti-TNF biologics Comparatively fewer studies have examined the association between serious infection and non-anti-TNF biologic therapy. Longer term data on infection risk with these drugs is required, and until such information is available it would be prudent to take similar precautions with these drugs as with anti-TNF therapy. With regards to RTX, the most recent observational data, from the US Coronna registry [31], showed similar rates of infection in 265 patients receiving RTX compared with 739 patients receiving anti-TNF therapy (event rate of 37.7 vs 41 events per 100 person-years). However, a previous RCT meta-analysis of the risk of infection with RTX [32], which analysed data from three studies, did not show an increased risk of serious infection in patients receiving RTX compared with placebo. An observational French study found that the risk was highest in the first 6 months after commencing treatment [14]. Long-term safety after 9 and 11.5 years was assessed and was deemed no higher than MTX and placebo [13, 33]. TCZ has been shown to increase the risk of serious infection in patients with RA. The risk is likely to be similar to anti-TNF therapy although long-term comparative data are not available. In the ADACTA study [17], which was a double-blinded parallel arm trial comparing the efficacy and safety of ADA and TCZ as monotherapy, the rates of serious infection were similar in both groups (3%). A systematic review by Campbell et al. [34] showed a slightly increased risk of infection with TCZ 8 mg/kg compared with controls, but similar to rates of infection with other biologics. Infection risk with the lower dose of 4 mg/kg was lower. Yun et al. [35] conducted a retrospective cohort study using Medicare data including 23 784 patients on five anti-TNFs as well as ABA, RTX and TCZ, looking at incidence of hospitalized infection. The likelihood of being admitted to hospital with an infection on TCZ was lower than for INF, RTX and ETN, but higher than for ABA. A study that pooled data from the double-blind and open-label phases of five clinical trials of s.c. ABA reported an incidence rate (IR) of serious infections of 1.79 (95% CI: 1.42, 2.24), which did not significantly change over time (mean exposure 27.3 months) [36]. This is in keeping with previous data for i.v. ABA [37]. A 2009 meta-analysis suggested that the risk of serious infections during ABA treatment [odds ratio (OR) = 1.35, 95% CI: 0.78, 2.32 vs placebo) is not significantly increased [32]. At present there is a lack of long-term observational data concerning the risk of serious infection with UST. Given the theoretical risks with all biologics and the risk presented with the longer established treatments, the advice is that biologics should not be started in the presence of serious infection. (ii) Use biologics with caution in patients at high infection risk after discussing risks and benefits (grade 1B, SOA 99%). Several observational studies have identified factors that may increase an individual’s risk of infection with biologic therapies. This additional risk may be unacceptable to patients, and needs to be carefully weighed up against the perceived benefits when prescribing biologic therapies. Anti-TNF biologics Comorbidities such as chronic obstructive pulmonary disease (COPD) [24, 38], interstitial lung disease (ILD) [24] and renal failure [24] have been associated with higher rates of serious infection in RA patients receiving anti-TNF agents. Concomitant steroid use has also been repeatedly associated with higher infection risk [24, 38]; however, in many patients the introduction of biologic therapies will enable reduction or cessation of steroid exposure. Although some studies have identified older age as an independent risk factor for serious infection with anti-TNF drugs, two recent studies have been reassuring. Data from BSRBR-RA showed that while older patients (aged >75 years) had a higher absolute risk of infection, there was no increased relative risk of serious infection on anti-TNF agents [22]. Similarly, no significant difference in serious infection rate was observed in a Swiss cohort of RA patients receiving anti-TNF therapy when divided into those above or below 65 years of age [39]. There is a lack of data concerning risk factors for serious infection in patients with other types of IA treated with anti-TNF therapy. Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. Non-anti-TNF biologics The French AIR Registry, which analysed data from 1303 RTX-treated RA patients, found that rates of severe infection were significantly higher in those with chronic lung disease and/or cardiac insufficiency (OR = 3.0, 95% CI: 1.3, 7.3), extra-articular involvement (OR = 2.9, 95% CI: 1.3, 6.7) and low IgG level (<6 g/l) before initiation of RTX treatment (OR = 4.9, 95% CI: 1.6, 15.2) [14]. There is a lack of long-term observational data concerning risk factors for serious infection in patients with other types of IA treated with non-anti-TNF therapy; especially as UST is the only biologic within this category with a non-RA licence (for PsA). Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. (iii) Consider using ETN or ABA as a first-line biologic therapy in patients at high risk of infection (grade 2B, SOA 94%). Anti-TNF biologics There is some evidence from both RCTs and observational studies to suggest that the risk of serious infection may be lower with ETN compared with other anti-TNF agents. A meta-analysis of 44 RCTs found the odds of serious infection with anti-TNF agents to be lowest for ETN (pooled OR = 0.73, 95% CI: 0.45, 1.20 vs 1.42, 95% CI: 1.13, 178) for all anti-TNF agents combined) [26]. Several observational trials have also observed lower rates of serious infection with ETN, including a US claims database [40], BSRBR-RA [22], the Dutch DREAM registry [41], the Australian ARAD database [42] and the Italian GISEA registry [43]. Non-anti-TNF biologics A low incidence of serious infection with ABA has been reported in long-term observational studies [36, 37] and a meta-analysis [44]. In the AMPLE study [45], an RCT comparing the safety and efficacy of s.c. ABA vs ADA in patients with RA over 2 years, numerically lower rates of infection were observed in the ABA arm (3.8%) compared with ADA (5.8%); however, this study was not powered to detect a significant difference in infection rates. Mycobacterium tuberculosis   screening for TB before starting a biologic (i) All patients require screening for tuberculosis (TB) before starting a biologic (grade 1B, SOA 98%). Anti-TNF biologics The increased risk of active TB and reactivation of latent TB associated with anti-TNF treatment, as demonstrated in a number of studies, has led to a requirement to screen for active and latent TB in patients before anti-TNF treatment is given [46–54]. A 2014 meta-analysis of RCTs [55] confirmed an increased risk of mycobacterial infections in patients on biologics (OR = 3.73, 95% CI: 1.72, 8.13) and that the risk varied with different agents [see recommendation (iii) for latent and reactivated TB). Non-anti-TNF- biologics Relatively few large long-term studies have investigated the risk of TB reactivation with non-anti-TNF biologics. Although the results from studies appear reassuring for this group of drugs with regards to TB reactivation, until more data are available, the advice given for anti-TNF therapy should be considered. Data regarding the risk of reactivating TB with RTX look reassuring. The largest study to date, which combined data from clinical trials and long-term extension studies, reported only two cases of pulmonary TB among 3595 RA patients who had received RTX over a mean follow-up of 11 years [12]. A Taiwanese study of 56 patients (43 patients were presumed to be without latent TB infection, seven patients had latent TB and six patients had anti-TNF-associated TB) found that over a 1 year period of RTX therapy, no patient developed active TB [56]. A 2014 review [57] found no cases of active TB recorded in patients with RA and other rheumatic conditions treated with RTX and ABA, and in fact, argued against pre-screening for TB in patients receiving these two biologics. Koike et al. [58] published safety data from an all-patient post-marketing surveillance programme in Japan in 2011. Out of a total of 3881 patients treated with TCZ (1794 patient-years), four cases of active TB were identified (0.22/100 patient-years). Cantini et al. [57] observed eight cases of active TB in 21 trials of patients with RA receiving TCZ. Combined data derived from five RCTs of s.c. ABA in RA found that TB occurred rarely, with an IR of 0.09 (95% CI: 0.04, 0.25) among 1879 patients [36]; this is lower than that observed for other biologics [59]. Regarding UST, a safety analysis of 3117 patients from five phase III clinical trials across the USA, Europe and Asia identified 167 patients with latent TB. These patients received isoniazid prophylaxis prior to receiving treatment with UST. No cases of active TB resulted in the 12-week treatment period. However, cases of TB have been reported in patients on UST [60]. Screening for TB should include checking for previous TB exposure and treatment, performing a clinical examination, chest X-ray (CXR) and either a TST or an IGRA or both, as appropriate (grade 2C, SOA 98%). For patients on immunosuppressive therapy with a normal CXR, a TST is not helpful, as immunosuppression hinders interpretation (grade 2C, SOA 98%). Patients with an abnormal CXR, previous history of TB or TB treatment should be referred to a specialist with an interest in TB prior to commencing a biologic (grade 2C, SOA 99%). Immunocompromised patients screened for latent TB with an IGRA alone or together with a TST and found to have a positive result in either test should be considered for treatment prior to starting biologic therapy (grade 2C, SOA 96%). Investigations for latent TB infection in a person exposed to M. tuberculosis but without active signs of TB are based on the TST or IGRA. The TST involves an intradermal injection of purified protein derivative and measurement of skin erythema and induration, which corresponds to a delayed-type hypersensitivity reaction in patients with previous exposure to TB (including latent TB). Previous vaccination with BCG will also cause a skin reaction but of a lower magnitude than after exposure to TB. IFN-γ release assays [two commercially available: QuantiFERON-TB Gold In-Tube assay (QFT) and T-SPOT.TB] measure IFN-γ release by T cells in blood samples mixed with mycobacterium TB antigens. QFT measures the IFN-γ concentration (IU/ml) using ELISA technology, whereas T-SPOT.TB reports the number of T cells producing IFN-γ (spot forming cells). T-SPOT.TB is also known as the TB ELISPOT (enzyme-linked immunospot assay). The TST and IGRA measure the response of T cells to TB antigens. As a false-negative result occurs in 20–25% of patients with active pulmonary TB, these tests should not be used alone to exclude a diagnosis of active TB. Identifying latent TB in patients due to start biologic treatment has been problematic as the TST and, to a lesser extent, IGRA assays are thought to be less reliable in immunosuppressed patients [61, 62]. Most studies comparing TST with IGRA performance in immunosuppressed populations suggest sensitivity and specificity of IGRA is superior to TST [63–66] but not all studies support this [67, 68]. In addition, IGRA positivity has been shown to be more closely related to TB risk than positive TST results. A recent meta-analysis of the performance of the two available IGRA tests (QFT and T-SPOT.TB/ELISPOT) vs TST in patients with rheumatic disease before starting biologic therapy reported pooled concordances between the QFT assay and TST of 72% (65–78%) and between T-SPOT.TB and TST of 75% (67–83%). It also showed that IGRAs have a lower false-negative and false-positive rate, compared with TST, particularly in patients treated with corticosteroids and those with a history of BCG vaccination [69]. Although two IGRA tests are commercially available, based on the present data, there is no robust evidence to recommend a preference for one over the other. The true sensitivity or specificity of the TST or IGRA is uncertain because a gold standard test for the presence of latent TB is currently unavailable. However, a closer correlation has been found between IGRA and risk factors for latent TB infection, including personal history, TB contact history and a suggestive CXR [65, 70]. Some studies have suggested using only an IGRA when screening for latent TB because in immunosuppressed patients, it is more specific than the TST and may therefore reduce the proportion of patients needing chemoprophylaxis [71, 72]. However, observational studies suggest that, given the discordance between these two types of test, use of one test may miss some patients with latent TB who would be identified by an alternative test [70, 73, 74]. Observational studies support the use of combination testing [61, 75]. Current international guidelines support screening all patients for latent TB before starting biologic therapy. However, given the inconclusive evidence available, the optimum screening strategy is unclear, with disagreement on whether to use an IGRA or TST, or both. In the UK, the 2016 guidance from NICE [76, 77] recommends testing all immunocompromised patients for latent TB with an IGRA alone or together with a TST—a positive result in either test should prompt consideration for treatment. However, the WHO recommends using either test and the European Centre for Disease prevention and control recommends using both [78, 79]. Screening with TST or IGRA is unhelpful in patients who have had treatment for active or latent TB. In this situation a chest X-ray and sputum examination will be sufficient, with input from a TB specialist. Treatment of latent TB should be initiated after the possibility of TB disease has been excluded. The Centers for Disease Control and Prevention recommends treatment for latent TB in individuals with a positive IGRA result or a TST reaction of ⩾5 mm, in immunosuppressed individuals (e.g. those on >15 mg/day of prednisolone for 1 month or longer and taking anti-TNFs), HIV-infected individuals, patients with organ transplants and individuals with fibrotic changes on CXR consistent with prior TB (cdc.gov/tb). Treatment is also recommended in individuals with a positive IGRA or a TST reaction of ⩾10 mm, including recent immigrants (<5 years) from high-prevalence countries, injection drug users and residents and employees in high-risk settings (e.g.: nursing homes and hospitals). In addition, individuals with no known risk factors for TB may be considered for treatment of latent TB is they have a positive IGRA or a TST 15 mm or more. Targeted TB testing programmes are recommended among high-risk groups, with appropriate follow-up care. The four treatment regimens for latent TB infection use isoniazid, rifapentine or rifampicin, and consultation with a TB expert is advised if the known source TB infection has drug-resistant TB. TB drug treatment for the prevention of TB, also known as chemoprophylaxis, can reduce the risk of a first episode of active TB occurring in people with latent TB. Current evidence suggests that decisions about chemoprophylaxis should be based on the results of the TST and an IGRA. If either test is positive, it would be appropriate to treat with chemoprophylaxis while monitoring carefully for treatment-related side effects [76, 80, 81]. The majority of potential recipients of anti-TNF medication will have a normal CXR and will have been on immunosuppressive therapy thus hindering the interpretation of latent TB testing [82–84]. In these individuals, an individual risk–benefit calculation is recommended. If the annual risk of TB on anti-TNF treatment is higher than the risk of anti-TB therapy-induced hepatitis, then the risk–benefit analysis favours chemoprophylaxis; if lower, the risk–benefit calculation favours observation and investigation of symptoms [80]. The two chemoprophylaxis regimens commonly used in the UK are isoniazid for 6 months (6H) or rifampicin plus isoniazid for 3 months (3RH). Latent and reactivated TB (i) Patients should be treated with prophylactic anti-TB treatment prior to commencing a biologic (grade 1B, SOA 99%); therapy may be commenced after completing at least 1 month of anti-TB treatment and patients should be monitored every 3 months (grade 2C, SOA 91%). (ii) Patients who have had previous inadequate treatment for active TB should be investigated for active TB. In these individuals even when active disease has been excluded, the annual risk of TB (reactivation) is much higher than the general population rate, so the risk–benefit analysis favours chemoprophylaxis (grade 1C, SOA 98%). The above recommendation i and ii are based in part on expert opinion in the NICE guideline ‘Tuberculosis’ [76, 77] and the 2005 British Thoracic Society (BTS) guidelines [80]. While there is a consensus that all patients with latent TB should receive anti-TNF chemoprophylaxis prior to commencing a biologic, there is a lack of data regarding the point at which biologic therapy can then be started. The BTS guidelines suggest that a patient should receive a full course of anti-TB treatment before starting a biologic; however, while this is ideal, 3–6 months’ delay is likely to be unacceptable for the majority of patients due to the severity of their rheumatic disease. The BTS guidelines have not been updated since 2005, and since then clinical experience has developed. Current expert opinion suggests that biologic therapy can be started after competing at least 1 month of anti-TB therapy. This is primarily to ensure that anti-TB treatment is tolerated, especially in what is often a population over 55 years of age. Patients should be monitored every 3 months with close involvement with a TB specialist throughout. Chemoprophylaxis for TB itself carries a small risk, with drug-induced hepatitis being the main issue, increasing with age and associated with increased mortality. It is important to exclude active TB disease before chemoprophylaxis is given, as there are concerns that single agent chemoprophylaxis given when active disease is present could lead to the development of drug resistance [67]. Two preventative treatment regimens in common use in the UK are isoniazid for 6 months (6H), or rifampicin plus isoniazid (3RH) for 3 months. Rifampicin and pyrazinamide for 2 months (2RZ) was a regimen used in the USA [85], but it had a very high rate of hepatitis with a number of fatalities reported [86]. Consequently, the choice of regimen is between 6H, which has a lower hepatitis rate, and 3RH, which is of shorter duration and with which there is thought to be better adherence and also less risk of drug resistance developing if active disease is present [87]. (iii) As TB reactivation risk is higher with anti-TNF mAb drugs (notably ADA and INF) than for ETN, consider ETN in preference for those who require anti-TNF therapy and are at high risk of TB reactivation (grade 1B, SOA 99%). The risk of TB reactivation appears higher with the mAb INF and ADA than for ETN [45, 46, 48–51, 53], a finding confirmed with registry data [47, 52]. In the BSRBR-RA the rate of TB was higher with ADA (144 events/100 000 person-years) and INF (136 events/100 000 person-years) than with ETN (39 events/100 000 person-years) [47]. After adjustment, the incidence-rate ratio (IRR) compared with the ETN-treated patients was 3.1 (95% CI: 1.0, 9.5) for INF and 4.2 (95% CI: 1.4, 12.4) for ADA. In light of this, we suggest that ETN should be considered as a first-line anti-TNF treatment in patients at high risk of reactivation of latent TB. The incidence of TB for the newer anti-TNFs (certolizumab pegol (CZB) and golimumab (GOL)) is less well documented. Cantini et al. [57] assessed the safety data of both GOL and CZB in patients with rheumatic disease and identified 8 cases of active TB in 3387 patients with rheumatic disease treated with GOL (7 of the 8 TB cases occurred in TB-endemic countries, where the TB incidence is 50–299 cases per 100 000 inhabitants) and 10 cases of active TB in 3167 patients with RA treated with CZB. Active TB (i) Patients with evidence of active TB should be treated before starting a biologic (1C, SOA 99%); therapy may be commenced after completing at least 3 months of anti-TB treatment and there is evidence that the patient is improving with evidence of culture negativity (grade 2C, SOA 91%). Full compliance with anti-TB treatment should be supervised by a thoracic physician or infectious disease specialist, and ideally continued until the drug susceptibility profile of the organism in those with positive cultures is known. Furthermore, it would be preferable to delay anti-TNF treatment until completion of a full course of anti-TB treatment (this is based on the expert opinion from the BTS [80]). HBV and HCV (i) Patients should be screened for hepatitis B and C viral infection (grade 1C, SOA 98%). Hepatitis B and C are blood-borne infections of the liver that can result in chronic liver disease and hepatocellular carcinoma. NICE currently recommends that all people who are at increased risk of hepatitis B and C infection are offered testing and vaccination [NICE Public health guideline (PH43): Hepatitis B and C testing: people at risk of infection]. Examples of people at increased risk of hepatitis B and C infection are shown in Table 4. Table 4 Risk factors for hepatitis B and C infection People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders Table 4 Risk factors for hepatitis B and C infection People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders For hepatitis B in particular, additional groups at increased risk include people who may have been exposed to sexually acquired infection. For hepatitis C in particular, additional groups at increased risk include people who received a blood transfusion before 1991 or blood products before 1986, when screening of blood donors for hepatitis C infection and heat treatment for inactivation of viruses were introduced. Screening for HBV should include HBsAg and antibodies to hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs), followed by HBV DNA test if HBsAg or anti-HBc are positive. These results will dictate the level of monitoring and prophylaxis, which varies between occult HBV infection (i.e. HBsAg negative and anti-HBc positive or anti-HBs positive) and overt HBV infection (i.e. HBsAg positive). Screening for HCV infection is at present based on the detection of anti-HCV antibodies. If anti-HCV antibodies are detected, HCV RNA, or alternatively HCV core antigen if HCV RNA assays are not available, should be determined to identify patients with on-going infection. The prevalence of hepatitis B and C as comorbidities in patients with RA varies across the world, due to epidemiological variations in risk factors. In a French cohort of patients with early RA, the seroprevalence of HBV and HCV infection was reported as 0.12 and 0.86%, respectively [88]. A higher seroprevalence of 3% for HBV and 2% for HCV infection was recently reported in COMORA, an international cross-sectional study of comorbidities in RA [12]. Acknowledging that there are now effective therapies for viral hepatitis, there is a strong rationale for offering screening to all patients prior to commencing immunosuppression. (ii) In patients who are HBV positive, a risk–benefit assessment should be undertaken, as biologics may be safe if appropriate anti-viral treatment is given, working closely with a hepatologist (grade 1C, SOA 99%). Anti-TNF biologics There are a few medium-quality systematic reviews of observational studies evaluating the risk of reactivation of hepatitis B in patients with HBV infection treated with anti-TNF therapy in the context of an IA. A systematic review [89] included 536 patients with occult or overt HBV infection and an underlying rheumatological or dermatological condition treated with INF, ETN or ADA. The pooled estimate of HBV reactivation was 4.2% (95% CI: 1.4, 8.2%) for all patients. When the meta-analysis was restricted to patients with RA, the pooled prevalence of HBV reactivation was slightly lower at 3.3% (95% CI: 0.7, 7.5%). HBV reactivation rates were higher in the overt HBV group vs the occult HBV group (15.4 vs 3%). These reactivation rates were similar to those reported in two other systematic reviews [90, 91]. In a case–control study of RA patients with occult HBV infection [92], the use of anti-TNF therapy was more frequent in those with HBV reactivation than not (86 vs 36%) P = 0.008, hazard ratio (HR) = 10.9 (95% CI: 1.4, 87.7). Patients who are HBsAg negative and anti-HBc positive (or anti-HBs positive) are nonetheless deemed to have an occult infection as low-level HBV replication may persist, with detectable HBV DNA in the liver but generally not in the serum. The clinical relevance of this is unclear although immunosuppression may lead to HBV reactivation in these patients [93]. Therefore, where a decision is made to proceed with an anti-TNF agent on risk–benefit analysis, a rheumatologist should work closely with a hepatologist to ensure liver disease is fully assessed at baseline then monitored on treatment. Several international groups have recommended that patents with overt HBV receiving immunosuppressive medicines should receive anti-viral prophylaxis [93, 94]. Perez-Alvarez et al. [95] found that of the reported cases of overt HBV patients treated with anti-TNF agents, HBV reactivation was 2.5-fold higher in patients not receiving prophylaxis (64 vs 26%). Of the 82 patients with overt HBV treated with an anti-TNF, five had acute liver failure, one required a liver transplant and four died. The European Association for the Study of the Liver suggest overt HBV candidates for immuno-suppressive therapy should be tested for HBV DNA levels and should receive pre-emptive anti-viral treatment during therapy (regardless of HBV DNA levels) and for 12 months after cessation of therapy. Occult HBV patients with detectable serum HBV should be treated like overt HBV patients [93]. Non-anti-TNF biologics In patients receiving RTX, re-activation of HBV in patients with occult hepatitis B (HBsAg negative; anti-HBc positive) has been reported [96], with the authors suggesting that patients with sero-positivity for either occult or overt hepatitis B should be referred to a hepatologist. A systematic review by Campbell et al. [34] found no increased risk of hepatitis B reactivation with TCZ; however, the number of cases was low and further long-term data are required. There are no data concerning the use of ABA and HBV. There are very few published data on the use of UST in patients with chronic hepatitis B. In a small observational cohort of 14 with hepatitis B serology treated with UST, no increase in viral load was seen in patients who had received prophylaxis [97]. However, two out of seven patients (29%) who did not receive prophylactic anti-viral therapy were noted to have an increase in viral load. If clinically indicated, UST may be used in patients with hepatitis B following prophylactic anti-viral treatment. In conclusion, given the theoretical risks and lack of high-quality data, we recommend that the recommendations supported by evidence for anti-TNF therapy should be applied to the non-anti-TNF biologics. (iii) Studies to date suggest that though biologic therapy does not appear to have a detrimental effect on HCV infection, it should continue to be used only with caution in such patients, following a risk–benefit decision made with a hepatologist (grade 1C, SOA 96%). There are limited data assessing the effect of immunosuppression on hepatitis C. Anti-TNF biologics A prospective RCT of 29 patients receiving ETN, MTX or both found that AST, ALT and HCV viral load did not significantly change across all three arms up to 54 weeks [98]. Three case series totalling 26 patients with IA and chronic HCV treated with either ETN, ABA or INF followed up to 36 months, did not show any significant increase in HCV titre over a 36-month follow-up [99–101]. One patient with both HBV and HCV had breakthrough HCV requiring treatment [99]. Studies to date continue to show that that anti-TNF therapy does not have a detrimental effect on HCV infection. Despite absence of high-quality evidence, in an era of advances in therapeutic options the advice remains to aim for viral control before immunosuppression. Non-anti-TNF biologics There is some evidence that the viral load of hepatitis C is increased after RTX treatment compared with anti-TNF therapy, but this was from a small study [96]. There are insufficient data to recommend the use of TCZ, ABA and UST in patients with chronic hepatitis C infection. A systematic review by Campbell et al. [34] showed no increased risk of hepatitis C reactivation with TCZ; however, the number of cases was low and further long-term data are required. In a small observational cohort of four with hepatitis C serology treated with UST, no increase in viral load was seen in patients who had received prophylaxis [97]. HIV Risk factors for HIV infection should be documented prior to commencing a biologic and, if present, an HIV test should be performed (grade 2C, SOA 97%). If considering the use of biologic therapy in HIV positive patients, this should be discussed with an HIV specialist. It should be borne in mind that a reasonable benefit to risk ratio for HIV patients exists with anti-TNF therapy if HIV infection is controlled (CD4+ count >200 cells/mm3 and viral load undetectable) and anti-TNF is given in combination with highly active anti-retroviral therapy (grade 2C, SOA 99%). Individuals at risk of HIV are shown in Table 5. There is no evidence base to support the testing of all patients before commencing biologic therapy. The prevalence of HIV in most parts of the UK is low and the likelihood of a positive result in an individual without risk factors is very low. The recent NICE guideline NG60 [102] summarizes the groups in which an HIV test should be offered; it does not advise routine testing in all individuals prior to immunosuppressive agents, unless risk factors are present. Table 5 Risk factors for HIV infection Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Table 5 Risk factors for HIV infection Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Anti-TNF biologics The only evidence surrounding the use of anti-TNF therapies for IA in HIV-infected individuals comes from individual case reports and one case series. These reports suggest that they can be used to successfully treat IA in HIV positive patients and are generally well tolerated, provided that HIV treatment is well established prior to anti-TNF therapy initiation and CD4 count is >200 cells/mm3. The largest study to date is a retrospective case series of eight American HIV positive patients receiving either ETN, ADA and INF for rheumatic conditions [103]; five patients were receiving concomitant highly active anti-retroviral therapy (HAART). Anti-TNF therapy was restricted to those with CD4 cell count >200 cells/ml and viral loads of <60 000 copies/ml at the initiation of the therapy Over a mean follow-up of 28.1 (range 2.2–55) months, anti-TNF therapy achieved good efficacy with no clinical adverse events attributed to anti-TNF treatment and no deterioration in CD4 count or viral load. There have also been several individual case reports on the use of anti-TNF agents in HIV positive patients with co-existent rheumatic disease. Most patients receiving concomitant HAART had good clinical outcomes [104–106]; the sole exception is a case report of an HIV patient with PsA in whom ETN had to be stopped due to recurrent infections [107]. Although this patient was receiving HAART, his CD4 count was significantly lower than other cases (<50 cells/mm3), which may explain the negative outcome. Non-anti-TNF biologics There is insufficient evidence to recommend the use of RTX, TCZ, ABA or UST in patients with HIV infection. Malignancy Biologic therapies should not be commenced in patients with clinical signs of, or under investigation for, malignancy (basal cell carcinoma excluded) (grade 1C, SOA 96%). Patients should be advised that there is no conclusive evidence for an increased risk of solid tumours or lymphoproliferative disease linked with biologic therapy, but that ongoing vigilance is required (grade 1A, SOA 99%). Anti-TNF biologics: overall malignancy There has long been concern regarding the possible association between biologic therapies and malignancy, indeed a 2006 meta-analysis of nine randomized controlled trials [108] found a 3-fold increase in the rate of malignancy with INF and ADA. Recent results from several further meta-analyses of both RCTs [26, 109–115] and observational studies [116, 117] have been reassuring and have failed to find a significant association between anti-TNF use and overall malignancy in patients with RA. Most observational studies using national registry data have also been reassuring; recent studies from BSRBR-RA [118], BIOBADASER [119] and German RABBIT [120] registries have all failed to show a significant association between anti-TNF use in RA and overall malignancy, with up to 52 549 patient-years exposure. In contrast, studies using the Swedish ARTIS [121] and Danish DANBIO [122] registries have reported higher rates of invasive cervical cancer and colon cancer, respectively, in anti-TNF-treated RA individuals compared with those receiving csDMARD. Interestingly in the DANBIO study, when comparing the anti-TNF-treated RA group against the general population this association was no longer seen. Few studies have looked separately at the AS and PsA anti-TNF-treated population with regard to malignancies. A 2009 meta-analysis of RCTs that included five PsA RCTs and 10 AS RCTs found no significant association [109]. Likewise, a study from BSRBR, which analysed data from 596 patients with PsA receiving anti-TNF and compared them with RF negative controls (as PsA patients not receiving anti-TNF are not included within this registry) found that the rates of new malignancies were not significantly different between the two groups [123]. Anti-TNF biologics: lymphoma Patients with RA are known to be at an increased risk of lymphoma compared with the general population independent of treatment; reported risk ratios have varied from 1.9 to 2.7 compared with the general population [124, 125]. As this risk is likely to be highest in those patients with more severe disease, it is important that disease activity is considered as a confounder when assessing any relationship between anti-TNF use and lymphoma in this group. Current data do not suggest that PsA or AS are associated with an inherent increased risk of lymphoma [126–128]. Since the last published guideline in 2009, eight further studies have been identified, including one Cochrane meta-analysis [21], three further RCT meta-analyses [110, 115, 129], one meta-analysis of observational studies [116] and three cohort studies (using the French RATIO [130], Danish DANBIO [122] and Swedish ARTIS [131] registries). Although two of these studies found a higher risk of lymphoma in RA patients receiving anti-TNF agents compared with the general population [130, 131], reassuringly none of them found a significant difference between rates of lymphoma in RA patients receiving anti-TNF therapy compared with control RA patients. Mariette et al. [130], in a cohort study using the French RATIO registry, found no increased risk of lymphoma in SpA patients receiving anti-TNF compared with the general population. Non-anti-TNF biologics There is much less long-term observational evidence evaluating the risk of malignancy with the non-anti-TNF biologics; however, findings to date have been reassuring. To date, there have been no safety signals for RTX, TCZ, ABA or UST in malignancy. Although there is no direct evidence that RTX is safe in malignancy, most long-term data have not shown an increase in risk [13, 33]. Recent data from a pooled case analysis of 1246 patients receiving RTX for >5 years found no increase in the rates of malignancy compared with the general US population or compared with published data in adults with RA [13]. Similarly, data from a French cohort of 186 RA patients who had received at least one infusion of RTX did not show an increased risk of malignancy over 346 patient-years’ exposure [mean follow-up 22.3 (15.1) months] [132]. A meta-analysis of 4009 patients exposed to TCZ for a median of 4 years found no significant difference in the incidence of solid and lymphoproliferative malignancies compared with the general population [133]. Solomon et al. [134], in a US observational study of 408 patients receiving ABA for RA, found no increased risk of malignancy compared with patients receiving MTX (HR = 1.55, 95% CI: 0.40, 5.97]. In a retrospective analysis of 3117 patients who received UST for up to 5 years, the rate of malignancy (other than non-melanoma skin cancers) was found to be 0.59/100 patients-years (UST 45 mg) and 0.61/100 patient-years (UST 90 mg) [60]. The frequency was found to be no different from the general population. (iii) There is conflicting evidence regarding the risk of skin cancers with anti-TNF therapy; patients should be advised of the need for preventative skin care, skin surveillance and prompt reporting of new persistent skin lesions (grade 1B, SOA 96%). Anti-TNF biologics Although inconsistent, numerous studies have found a positive association between the use of anti-TNF agents in RA and the risk of malignant melanoma (MM). An observational study of US veterans with RA found a higher risk of MM in those exposed to anti-TNF agents compared with those receiving csDMARDs (HR = 1.5, 95% CI: 1.01, 2.24) [135]. An almost identical risk was observed in the Swedish ARTIS registry [136]. Other studies have also noted a positive association between anti-TNF agents and MM, but failed to reach statistical significance; these include the DANBIO registry [122] and a 2011 meta-analysis of observational studies [116]. The largest study to date combined data from 11 European registries including 48 304 RA anti-TNF-treated patients. One hundred and six invasive MM were observed in the anti-TNF group with a pooled standard incidence ratio of 1.2; however, this did not achieve statistical significance (95% CI: 0.99, 1.6; P = 0.062) [137]. Higher rates of MM were also observed in the TNF group compared with those receiving csDMARD; however, again statistical significance was not achieved (IRR = 1.14, 95% CI: 0.8, 1.6). There is also some evidence to suggest that there may be a positive association between anti-TNF use and non-melanoma skin cancer (NMSC). Two RCT meta-analyses of RA patients receiving anti-TNF from 2009 to 2012 failed to find a significant association between anti-TNF use and risk of NMSC, although the more recent and higher quality of the two meta-analyses did observe a non-significant trend towards more NMSC in anti-TNF-treated patients [112, 115]. A further meta-analysis of observational studies found that patients with RA receiving anti-TNF had a 45% higher risk of NMSC compared with csDMARD-treated patients [116]. Recent registry data have also been conflicting; The ARTIS cohort [138] found higher rates of squamous cell skin carcinoma in RA patients treated with anti-TNF therapy compared with those who had not received anti-TNF therapy. While BSRBR-RA [139] and DANBIO [122] registries both observed higher rates of NMSC in anti-TNF-treated RA patients compared with the national population, no difference was observed when compared against RA patients who had not received anti-TNF agents. Non-anti-TNF biologics There is less evidence regarding the risk of NMSC in patients receiving non-anti-TNF biologics, but at present there have not been any safety signals to suggest that these drugs increase the risk of NMSC; however, further studies are required. RTX and ABA were not associated with an increased risk of NMSC in a cohort of 6841 patients with RA receiving biologics in a Medicare cohort [140]. In a long-term safety analysis of 3117 patients with psoriasis receiving UST, the risk of developing NMSC was found to be 0.64 and 0.44/100 patient-years (UST 45 and 90 mg, respectively) [60], a similar rate to the general US population. However, we acknowledge that at a similar time point data in the anti-TNF cohorts were similarly inconclusive. As UST is a relatively new biologic drug, large-scale registry data are currently unavailable. We would therefore recommend that the same precautions outlined for anti-TNF agents be taken for UST. (iv) Anti-TNF therapy is relatively contraindicated in patients who have had prior treatment with >150 psoralen and ultraviolet A (PUVA) and/or >350 ultraviolet B (UVB) phototherapy. Such patients should be discussed with a dermatologist prior to commencing anti-TNF therapy (grade 2C, SOA 96%). Patients with a history of psoriasis may be at further increased risk of skin malignancy (in addition to that of anti-TNF therapy) due to previous phototherapy with UVB or PUVA [141]. Anti-TNF biologics Data directly comparing the rates of skin malignancy in anti-TNF-treated patients with psoriasis who have received phototherapy compared with those who have never received phototherapy are lacking. A recent Dutch study compared rates of NMSC in two cohorts of patients receiving anti-TNF agents for psoriasis (99% of whom had received phototherapy) against a cohort of anti-TNF-treated RA patients [142]. A significantly higher risk of NMSC was found in the psoriasis group (HR = 6.0, 95% CI: 1.6, 22.4) with a shorter time to first NMSC compared with the RA group. A low basal cell carcinoma (BCC) to squamous cell carcinoma (SCC) ratio was also observed suggesting that disease-related factors, such as phototherapy, may be important contributors to the risk of development of NMSC in psoriasis patients treated with anti-TNF. However, the mortality associated with the majority of skin cancers is very low, early detection significantly improves both morbidity and mortality, and most are completely cured with local, predominantly surgical, measures. Non-anti-TNF biologics The limited available data from only a few studies do not suggest that any of the non-anti-TNF biologics increase the risk of skin malignancy. We suggest that while prior PUVA or phototherapy exposure is not necessarily a contraindication for this group of drugs, patients should be discussed with a dermatology specialist and treatment decisions made on a case by case basis. (v) Caution should be exercised in the use of biologics in patients with previous malignancy (grade 1C, SOA 97%). The timing of commencement of biologic therapy post-malignancy is not fixed and will depend on type and stage of malignancy, risk of metastasis and patient views. RTX may be considered as a first-line biologic option in RA patients with previous malignancy (grade 2C, SOA 90%). There remains a paucity of data concerning the use of biologic therapies in patients with a past history of malignancy. As RCTs have, almost universally, excluded patients with a past history of malignancy, any relevant data have been collected from observational cohort studies. Results from studies published since the last guideline have been reassuring; however, caution should still be advised based on theoretical risk and the fact that patient numbers and further event rates in these studies have generally been low. Anti-TNF biologics Of the recent observational cohort studies, BSRBR-RA included the largest number of patients, with 243 RA patients with previous malignancy receiving anti-TNF and 159 receiving csDMARD (1.7% of the BSRBR-RA cohort); the mean interval between malignancy and anti-TNF commencement was long at 11.5 years [143]. Fifty-three new malignancies were identified in this cohort, with no significant difference in the rate of new malignancies between groups. This is in keeping with previous data from the ARTIS [144] and RABBIT [120] registries. Furthermore, a 2016 systematic review observed similar rates of cancer recurrence in anti-TNF-treated individuals (which consisted of patients with RA, psoriasis and IBD) compared with the control csDMARD population (28.8 vs 35.1 events/1000 person-years) [145]. Additionally, these rates were also not significantly different from those observed in patients receiving no immunosuppressive therapy. Two recent studies have looked specifically at the risk of recurrence of NMSC in patients receiving anti-TNF; results from these studies have been conflicting. BSRBR-RA found no increased risk of NMSC recurrence among 177 RA patients with a past history of NMSC receiving anti-TNF treatment compared with DMARD-treated patients, over a median follow-up of 4 years [139]. In contrast, a larger observational study of 6841 RA patients found that anti-TNF use increased the risk of a subsequent NMSC by 49% above that seen in RA patients treated with MTX alone [140]. There is a lack of data regarding the risk of malignancy recurrence in patients with PsA or AS treated with anti-TNF therapy. Non-anti-TNF biologics A small study from the BSRBR-RA followed up 23 patients with a prior malignancy who had received RTX as a first biologic for RA. Over a total follow-up time of 81 person-years, no increased rate of further malignancy was observed compared with csDMARD controls (unadjusted HR = 0.45, 95% CI: 0.11, 1.87). Similarly, RTX and ABA were not associated with an increased risk of a second NMSC in a Medicare cohort of 6841 patients with a history of NMSC receiving biologics for RA [140]. Data on the use of TCZ or UST in patients with a history of malignancy are lacking. Due to the theoretical risks, the advice substantiated by evidence for anti-TNF therapies should be applied to patients receiving these therapies. (vi) The effect of biologics on pre-malignant conditions remains unclear. Caution should be exercised in the use of biologics in such patients. RTX may be considered as a first-line biologic option is these patients (grade 2C, SOA 97%). Anti-TNF biologics There is little information concerning the risk of using anti-TNF therapy in patients with pre-malignant conditions. Two studies to date have examined the risk of malignancy in female patients with a past history of cervical dysplasia or carcinoma in situ (CIS) of the cervix, treated with anti-TNF. The BSRBR-RA compared 190 RA patients with a past history of CIS of the cervix who were receiving anti-TNF therapy (73% of whom started anti-TNF therapy within 10 years of CIS) against csDMARD controls [146]. Over 893 person-years of follow-up, two new genital cancers were observed in the csDMARD group vs no new genital cancers in the anti-TNF group. Due to the low number of new malignant events in the trial, this study was underpowered to draw firm conclusions. Similarly, the DANBIO registry found no new genital malignancies among 208 patients with RA, AS or PsA and a past history of cervical dysplasia or CIS, who had been treated with anti-TNF therapy [147]. Limitations of this study included its relatively short follow-up period of mean 3.5 years for the anti-TNF patients, and the fact that the mean interval between CIS or cervical dysplasia diagnosis and commencement of anti-TNF therapy was 17.7 years. To date, no studies have examined the risk in other pre-malignant conditions such as Barrett’s oesophagus or colonic polyps. Non-anti-TNF biologics To date, there are no data concerning the use of RTX, ABA, TCZ or UST in pre-malignant conditions. Overall, given the implications of malignancy and the relative lack of safety data in patients with an established or potential malignancy, biologics cannot be recommended at present. Cardiac problems (i) Although recent data are reassuring, biologics should be used with caution in patients with class III or IV cardiac failure, working closely with a cardiologist (grade 2C, SOA 96%). Anti-TNF biologics TNF-α levels are increased in the general population with heart failure [148] and experimental models have suggested that anti-TNF therapy may improve ventricular dysfunction [149]. However, early clinical trials of ETN and IFX used as a treatment of heart failure reported an increased risk of worsening chronic heart failure [150–152]. As a result the presence of a class III or IV heart failure was a contraindication to the use of anti-TNF therapy in RA (Table 6) [1]. Recently, an observational study compared 8656 patients starting treatment with traditional DMARDs with 11 587 starting an anti-TNF therapy and reported that anti-TNF therapy was not associated with an increased risk of hospital admissions due to cardiac failure compared with traditional csDMARDs [153]. Furthermore, in a recent systematic review and meta-analysis, no significant effect of treatment with TNF inhibitors on CF was observed in RA patients [154]. Interpretation of the results from these studies is hampered by issues relating to potential confounding by indication or contraindication and by lack of control for confounding conditions or severity of RA. Table 6 New York Heart Association classification of heart failure Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Table 6 New York Heart Association classification of heart failure Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Non-anti-TNF biologics At present, there are no safety signals to suggest that RTX is associated with deterioration of cardiac function. A pooled case analysis of 1246 patients receiving RTX for >5 years found no difference in cardiac events compared with the general RA population [13]. Studies have shown that IL-6 is associated with exacerbation of ischaemic heart disease and cardiomyopathy [155]. Suzuki et al. [156] used i.v. TCZ in a patient with severe RA, with triple vessel coronary artery disease and severely impaired left ventricular function, with no worsening of cardiac function but good results for RA control. There is currently no evidence to suggest that TCZ increases the risk of cardiac failure. However, as with all other biologic clinical trials, patients with moderate to severe heart failure were excluded from the studies and so the risk of biologic therapy in such patients has to be weighed against the potential risk of alternative therapies (such as steroids). There are no data to suggest that ABA or UST is associated with exacerbation of cardiac failure. (ii) Biological therapy may be used in patients with previous myocardial infarction or cardiovascular (CV) events (grade 2B, SOA 99%). Data thus far appear to be reassuring with a potential beneficial effect of anti-TNF therapy on the risk of MI. Recently, a cohort study linking the Swedish National Patient Register and the Swedish Biologics Register [157] compared 7704 RA patients receiving anti-TNF therapy to matched biologic-naïve RA patients at a 3:1 ratio (n = 23 112). There was a significantly lower risk for acute coronary syndrome among RA patients, who were exposed to anti-TNF therapy compared with the biologic naïve patients (HR = 0.82, 95% CI: 0.70, 0.95). This is consistent with the results of a systematic review and meta-analysis that found that anti-TNF therapy in patients with RA was significantly associated with a reduction in the risk of MI [154]. Data from the BSRBR-RA showed no significant difference in the incidence of first MI between RA patients taking TNF inhibitors and csDMARD-treated RA controls [158]. However, the subgroup of anti-TNF-treated patients with a good or moderate EULAR response at 6 months had a lower incidence of MI (3.5/1000 events in responders compared with 9.4/1000 events in non-responders). Similarly, there appears to be a potential beneficial effect of anti-TNF therapy on CV events but further data are required before firm conclusions can be drawn. Potential confounding by indication or contraindication and by lack of control for confounding conditions or severity of RA should be taken into account, but this would be compatible with the hypothesis that inflammation contributes to development of CV events. In a recent systematic review and meta-analysis, in RA TNF inhibitors were significantly associated with a reduction in the risk of all CV events (risk ratio (RR) = 0.70, 95% CI: 0.54, 0.90), as well as in myocardial infarctions (RR = 0.59, 95% CI: 0.36, 0.97), strokes (RR = 0.57, 95% CI: 0.35, 0.92) and major adverse cardiac events (RR = 0.3, 95% CI: 0.15, 0.57) [154]. There is a lack of data regarding the use of anti-TNF therapy in patients with PsA or AS in patients with previous myocardial infarction or CV events. Non-anti-TNF biologics No data exist to suggest that any of the non-anti-TNF biologics increase the risk of myocardial infarction or CV events. In view of the evidence from anti-TNF therapies and a lack of a mechanistic reason, we suggest that the recommendation be applied across biologic therapies. Respiratory disease Pre-existing ILD is not a specific contraindication to biologic therapy; however, caution is advised in patients with poor respiratory reserve (in whom a significant drop in lung function would be potentially life threatening); in this situation it is advised to work closely with a respiratory physician with a specialist interest in ILD (grade 2C, SOA 99%). RTX or ABA may be considered a first-line biologic in patients with ILD (grade 2C, SOA 84%). ILD is a common manifestation in patients with RA (prevalence 10–30%) and is generally associated with more severe disease [159, 160]. Uncertainty remains surrounding the natural history of RA-ILD and the effects of biologics (and csDMARDs) on this disease. Predominantly studies are centred on RA-ILD although there are pulmonary manifestations associated with other forms of IA, such as a prevalence of 0–30% for lung involvement in AS patients, most commonly upper lobe fibrosis. Anti-TNF biologics Since the 2010 guideline there have been several observational retrospective cohort studies assessing the relationship between ILD and anti-TNF therapy. The BSRBR-RA found no significant increase in mortality in 356 patients with RA-ILD treated with ETN, ADA or IFX, compared with those receiving csDMARD alone [161]. Selection bias could be an explanation for these results as this could have led to increased mortality in the traditional DMARD group and a favourable reduction in the mortality rate ratio for biologics use. The conclusion was that UK physicians were appropriately selecting patients suitable for anti-TNF therapy when underlying ILD was present. Where there is no pre-existing ILD, a US study found that anti-TNF therapy was not associated with a diagnosis of ILD among patients with RA over a mean follow-up of 3 years [162]; comparisons across anti-TNF agents found no differences in risk. The number of cases was limited in this study, with only 38 new ILD cases (23 on anti-TNF) among the 8417 persons included (0.4%). In terms of selection of patients, univariate analysis in a small Korean study suggested age at initiation of anti-TNF therapy was a risk factor for death when looking at a population of 24 RA-ILD patients on anti-TNF (76 vs 64 years old, P = 0.043) [163]. A Japanese study [164] found that over 1 year of follow-up of 58 RA patients with pre-existing ILD, 14 had ILD events and that the proportion was greater than the comparator arm without pre-existing ILD (24 vs 3%, P < 0.001). Pre-existing lung disease should not be considered an absolute contraindication to an anti-TNF. However, in patients with poor respiratory reserve (in whom a significant drop in lung function would be potentially life threatening), caution should be exercised when choosing an anti-TNF. Decisions should be made on an individualized basis in conjunction with a respiratory physician, and with full appreciation of the limited evidence base. Non-anti-TNF biologics There is little evidence on the impact of RTX, ABA, TCZ and UST on the occurrence or exacerbation of ILD, and this is often limited to case reports. A 2014 systematic review of case reports and series (from 1975 to 2013) of biologics causing ILD or worsening pre-existing ILD in RA patients found eight case reports for TCZ, three for RTX and one for ABA [165]. A US database study of 11 219 RA patients [166] found the lowest IR of ILD occurrence was with ABA (IR = 4.0/1000 person-years, 95% CI: 1.6, 8.2/1000 person-years); the highest being with INF (IR = 12.2/1000 person-years, 95% CI: 5.6, 23.2/1000 person-years); however, no significant differences in the incidence of ILD was found between the different biologic classes. No studies to date have examined the relationship between UST and ILD in PsA. Until further data are available concerning any causal relationship between non-anti-TNF biologics and ILD, we suggest that recommendations given for anti-TNF therapies should be followed. There is a weak evidence base to suggest that ABA and RTX might have less effect on ILD than other biologics [165–167]. Uveitis (i) ADA and INF can be considered for the treatment of uveitis, in preference to ETN, which appears to be associated with lower rates of treatment success and has been associated with the development of uveitis. The relative risks of these agents should be taken into account when selecting which treatment to use (grade 1 C, SOA 96%). Anti-TNF biologics A systematic review by Levy [168, 169] concluded that ADA and INF can be considered as second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy and scleritis in patients requiring immunomodulation who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. INF and ADA can be considered in these patients in preference to ETN, which appears to be associated with lower rates of treatment success. At present, ADA is the only anti-TNF agent licensed by the European Medicines Agency for the treatment of uveitis. While ADA and INF [168, 169] have successfully treated uveitis, there are several case reports of uveitis developing in patients treated with ETN [170, 171]. A registry-based study by Lim et al. [172] reported 43 cases of uveitis in patients who were receiving anti-TNF treatment over a period of 8 years. The number of patients taking ETN, INF or ADA in this group was 20, four and two, respectively; ETN therapy was associated with a significantly greater number of reported uveitis cases in comparison with INF (P < 0.001). This study was, however, limited by the information on the clinical diagnoses available to the authors. More data are required on uveitis associated with each of the anti-TNF agents before further conclusions can be drawn on the risks associated with these agents. Non-anti-TNF biologics There is a paucity of data concerning the safety of non-anti-TNF biologics in patients with a history of uveitis. There is one case report of a patient with RA treated with TCZ who developed acute anterior uveitis 5 weeks after stopping the therapy; however, causality is difficult to establish in this scenario [173]. Aside from that, there have not been any safety signals to suggest that there is concern about using these drugs in this patient cohort. There is some, mostly observational, data to suggest that non-anti-TNF biologics can successfully treat patients with refractory uveitis. A systematic review by Simonini et al. identified nine articles reporting data on the use of non-anti-TNF biologics to treat refractory uveitis (six retrospective chart reviews, two case series and one single-blind RCT of 16 patients) [174]. ABA, TOC and RTX all demonstrated efficacy in selected categories of chronic uveitis, refractory to previous DMARDs and anti-TNF agents; further randomized clinical trials in this area are needed. Demyelinating disease (i) Anti-TNF therapy should not be given when there is a personal history of multiple sclerosis or other demyelinating diseases. Consider using a non-anti-TNF biologic in this situation (grade 2B, SOA 97%). Anti-TNF biologics Studies have suggested an aetiological role for anti-TNF therapies in the development of neurological disorders; the disease is temporally associated with initiation of therapy, the symptomatology is suggestive of an antigen-mediated hypersensitivity process, and the disease improves or resolves after discontinuation of therapy and a positive rechallenge phenomenon is observed [175, 176]. Multiple sclerosis TNF blockade was shown to cause worsening of demyelinating disease in early studies of an anti-TNF therapy, in which patients with active multiple sclerosis (MS) documented an increase in MS flares on this therapy [177]. The prevalence of demyelinating disease induced by biologic therapies, reported in RCTs and post-marketing studies, has been estimated to range from 0.02 to 0.2% [178]. In a Canadian database of 105 000 RA patients there was a trend towards around a 30% increase in demyelinating events after exposure to anti-TNF agents, but this was not statistically significant [179]. A Danish registry study of almost 28 000 patients with IA found a significantly increased standardized incidence ratio of MS in men with RA or AS treated with anti-TNF therapy (SIR = 3.48, 95% CI: 1.45, 8.37), but not in women [180]. Optic neuritis Case reports of patients developing optic neuritis during anti-TNF treatment exist. A pooled case report study detailed 15 patients who developed optic neuritis while on anti-TNF therapy; eight of these patients had received IFX, five ETN and two ADA [181]. On stopping anti-TNF treatment, seven patients experienced either partial or complete resolution of their symptoms while four patients continued to have symptoms. Recently there has been a USA-based study of 61 000 individuals with inflammatory disease and new anti-TNF or non-biologic DMARD use. Among this cohort, three optic neuritis cases (two with IFX and one with ETN) were detected among anti-TNF new users, providing a crude IR of 10.4 (95% CI: 3.3, 32.2) cases per 100 000 person-years. No cases occurred in the csDMARD comparison group. However, in a secondary analysis of current and past users of csDMARDs and anti-TNF, optic neuritis rates were similar in the anti-TNF and comparison groups, respectively, leading the authors to conclude that anti-TNF therapy does not appear to promote the development of optic neuritis in patients who lacked a prior documented history of optic neuritis [182]. Demyelinating peripheral nervous system disease The association between anti-TNF treatment and various disorders of peripheral nerves such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and mononeuropathy multiplex has been highlighted in various case series and case reports [183]. Cases were reported for all three first generation anti-TNF agents with symptoms developing over a wide range of time intervals from starting anti-TNF treatment (8 h to 2 years) and lasting for varying time periods from 3 weeks to 35 months. Withdrawal of anti-TNF resulted in slow resolution of symptoms in many cases; however, additional treatment was required for others. A small minority of patients, however, never achieved symptom resolution. Prognosis following demyelinating disease or peripheral neuropathy In the BIOGEAS registry, 30% of patients with demyelinating disease (n = 44) had no resolution of symptoms. Eleven per cent of peripheral neuropathies had no resolution of symptoms on stopping therapy [175, 178]. Similarly, in a French registry, 22% of patients developing CNS demyelination on biologics went on to develop MS despite cessation of biologic therapy [184]. In light of these findings, individuals with a personal history of multiple sclerosis or other demyelinating diseases should not start anti-TNF therapy. Non-anti-TNF biologics There is no evidence to suggest that RTX, ABA or UST increases the risk of demyelinating diseases. Likewise, there is no consistent evidence to argue against the use of TCZ in demyelinating diseases; indeed there is ongoing interest in its use for the treatment of certain autoimmune neurological disorders such as neuromyelitis optica spectrum disorder [185]. Sato et al. [186] used TCZ in treating RA in a patient with multiple sclerosis for 5 years with no progression of her MS. In view of the above evidence, we suggest that a non-anti-TNF biologic is used in preference to anti-TNF therapy in patients with a personal history of demyelinating disorder. Diverticular disease (i) Exercise caution with TCZ in patients with diverticular disease, particularly when using concurrent NSAIDs and/or steroids (grade 2C, SOA 98%). Gastrointestinal perforation has been reported in patients treated with TCZ for RA. An occurrence of 2.8/1000 person-years was reported by Schiff et al. [187] in a pooled meta-analysis of five RCTs and two long-term extension studies, compared with 2.0/1000 person-years reported in the control group. Diverticulitis was present in 16 of the 18 patients who had a gastrointestinal (GI) perforation while receiving TCZ; most patients had also been treated with NSAIDs and/or steroids. A systematic review by Gout et al. [188] found that the risk of GI perforation with TCZ was lower than the risk with steroid and NSAID use, but higher than with anti-TNF therapy. A large study by Curtis et al. [189] looking at administrative data from a large US health plan showed that there was no increased risk of GI perforation with the use of non-TCZ biologics or MTX, but there was an increased risk with concomitant use of steroids and NSAIDs. The factor leading to the highest increase in risk was previous diverticulitis. Vaccinations (Also refer to vaccination recommendations while on biologic therapy). (i) HBV immunization should be considered for at risk patients (grade 2C, SOA 94%). Individuals with ongoing risk factors for hepatitis B infection [as outlined in recommendation (i) for active TB] should undergo immunization prior to starting anti-TNF treatment. Hepatitis B vaccines are inactivated vaccines and therefore do not contain live organisms and cannot cause hepatitis B in an immunosuppressed individual. There are limited data with regard to response to hepatitis B immunization in patients with rheumatic disease receiving biologic therapy. There is circumstantial evidence indicating that TNF blockade may directly modulate humoral responses [190], with one study suggesting that TNF blockade with ETN decreases responses to the hepatitis B vaccine; patients with RA who were treated with MTX had very good response rates, whereas those treated with an MTX–ETN combination or ETN alone had poor response rates [191]. Therefore, though it is safe to give hepatitis B vaccine to a patient on anti-TNF treatment, if possible, the first hepatitis B vaccine should be given prior to commencing anti-TNF therapy. Due to the risk of poor response, it is important that immunization against hepatitis B does not encourage relaxation of other measures to prevent exposure to the virus, such as condom use and needle exchange [192]. (ii) Patients >50 years should undergo vaccination against herpes zoster (HZ) assuming there are no contraindications (e.g. treatment within the past 3 months with >40 mg prednisolone per day for >1 week, >20 mg prednisolone per day for >14 days, MTX >25 mg/week, AZA >3.0 mg/kg/day). This should be administered preferably >14 days before starting biologic therapy (grade 2C, SOA 97%). The risk and severity of shingles (HZ infection) is considerably higher among immunosuppressed individuals, with evidence suggesting that people with rheumatic diseases have around double the incidence of shingles of the general population [193, 194]. A 2014 meta-analysis including ACR, EULAR and BSR registry data found that the pooled risk ratio for HZ in patients with IA on anti-TNF agents was 1.61 (95% CI: 1.16, 2.23). The proportions of severe HZ ranged from 2.0 to 5.5% with csDMARDS, compared with 4.9–20.9% with TNF-blockers [195]. According to Public Health England recommendations, eligible individuals anticipating immunosuppressive therapy should ideally be assessed for vaccine eligibility before starting treatment that may contra-indicate future vaccination [196]. Eligible individuals who have not received Zostavax should receive a single dose of vaccine at the earliest opportunity and at least 14 days before starting immunosuppressive therapy. HZ vaccine is now recommended in the UK for all individuals aged 70–79 and a national vaccination programme is underway. Zostavax reduces the risk of shingles by ∼50% in immunocompetent adults aged ⩾60 years [197]. Efficacy of the vaccine appears to wane within the years after vaccination, with studies suggesting efficacy of 39.6% for prevention of HZ and 60.1% for prevention of postherpetic neuralgia 4–7 years post-vaccination [198]. It is licensed for the use in individuals aged ⩾50 years, and therefore could not be recommended for patients younger than this [199]. Vaccination has been shown to be associated with reduced incidence of HZ in a study of over 460 000 patients aged ⩾60 years with autoimmune diseases [200]. As HZ vaccine is a live attenuated vaccine, it carries a small risk of infection, particularly in immunosuppressed individuals. However, in this study, among 633 patients with recent or current exposure to biologics at the time of vaccination, no case of HZ or varicella occurred. These data were, however, extracted from administrative claims from hospitals and cases of HZ and varicella were not confirmed with medical records review. Encouragingly, in two further studies, no increased incidence of HZ or varicella zoster was shown following vaccination in individuals with autoimmune disease receiving a variety of biologic therapies [201]. Nonetheless, Public Health England currently recommends that HZ vaccine should not be given to individuals already on biologic therapy or who, in the past three months have received >40 mg prednisolone per day for >1 week, >20 mg prednisolone per day for >14 days, non-biological oral immune modulating drugs (e.g. MTX >25 mg/week, AZA >3.0 mg/kg/day) [196, 202]. (iii) Patients who do not have a positive history of varicella zoster (chickenpox) infection should have a varicella zoster virus antibody test. If this is negative, and there are no contraindications (as listed in (ii)) varicella zoster vaccination should be offered prior to biologic commencement (grade 2C, SOA 98%). Varicella zoster virus, which causes chickenpox, is more common and serious in immunosuppressed individuals, as they are at risk of severe and potentially fatal disseminated varicella infections [203, 204]. It is the most frequent viral opportunistic infection (OI) seen in patients on MTX or anti-TNF agents [23]. The varicella vaccine is a live attenuated vaccine, and the two-dose vaccination schedule provides around 75% protection in adolescents and adults—mild breakthrough infections can occur in around 10% of adults [205]. For this reason it is not recommended for those already on immunosuppressive medication, such as AZA (>3.0 mg/kg/day), ciclosporin, MTX (>25 mg/week), CYC, LEF or equivalent 40 mg prednisolone/day); this group will cover a significant proportion of patients due to start anti-TNF therapy. In individuals due to start biologic therapy who are not in the above category, varicella zoster vaccination is recommended, in addition to vaccination of healthy susceptible close household contacts of immunocompromised patients (e.g. children of a patient due to start biologic therapy who have not had varicella zoster). Patients without a definite history of varicella zoster virus infection should undergo a varicella virus antibody test. If negative, and there is no contraindication, they should be offered vaccination on the two-dose schedule. Personal recall of varicella infection has been shown to be a good predictor of serological immunity [206, 207]. For patients receiving biologic therapy Monitoring on treatment (i) All patients should be reviewed for drug safety in a specialist department at least every 6 months. High risk patients (e.g. those at high risk of TB) should be reviewed every 3 months (grade 2C, SOA 94%). There is no evidence on the optimal monitoring requirements for patients receiving biologics. However, in view of the aforementioned potential risks associated with these treatments, and the NICE requirements to ensure a satisfactory clinical response to treatment, we suggest that patients are reviewed at least every 6 months by a rheumatology specialist. Higher risk patients may require more frequent review, as supported by NICE guidance. The 2011 NICE guideline cg117 [76] and the 2005 BTS guideline [208] recommend that high-risk TB patients should be monitored every 3 months (with a CXR and sputum cultures, if respiratory symptoms develop). (ii) Patients prescribed a biologic (other than TCZ) without concomitant csDMARD (or with csDMARDs that do not require blood test monitoring), should have monitoring blood tests (FBC, creatinine/calculated GFR, ALT and/or AST and albumin every 3–6 months (grade 2C, SOA 97%). Anti-TNF biologics Haematological abnormalities have been reported in patients treated with anti-TNF agents but in many cases there have been other co-prescribed medications that may have been responsible for these changes. One case series reported neutropaenia (<2.0 × 109/l) in 14.3% of 133 RA patients on anti-TNF therapy [209]. A history of previous neutropaenia on csDMARD therapy and a low baseline neutrophil count were shown to be predictors of neutropaenia. Two other studies have reported rates of anti-TNF-induced neutropaenia of 8 and 14% [210, 211]. The majority of reported cases of anti-TNF-induced neutropaenia were mild, did not result in any significant clinical complications and did not require modification in anti-TNF therapy. Reports of anti-TNF-associated pancytopenia and aplastic anaemia are rare but in some cases have been fatal [212]. More recently, a US cohort of 1322 patients receiving anti-TNF therapy had no increase in prevalence of anaemia, leucopenia or thrombocytopenia [213]. Other studies have shown resolution of anaemia of inflammation following treatment with anti-TNF agents. Niccoli et al. [214] monitored the FBC of 106 patients with AS over a 6-month period and found Hb, MCV, iron, ferritin, CRP and ESR improved, reaching statistical significance. However, this study is confounded by the simultaneous stopping of NSAIDs on commencement of anti-TNF, perhaps leading to a reduction in insidious GI bleeding. Liver function test derangement has also, albeit rarely, been associated with anti-TNF therapy. In an observational study of 6861 RA patients, over 6.5 years of follow-up, elevations in AST and ALT were found in 6.67% of patients [215]; however, only 0.77% had levels more than twice the upper limit of normal. IFX (as opposed to ADA or ETN) was associated with the highest frequency of elevations. Anti-TNF therapy is not known to affect renal function [216]; however, IA is associated with chronic kidney disease [217]. Hence in individuals already undergoing blood monitoring, an assessment of renal function may be useful to detect any deterioration in renal function and enable early investigation and treatment that may prevent further decline. Thus, in light of reports of pancytopenia and liver function test elevation with anti-TNF therapy, it is recommended that patients undergo blood monitoring on a regular basis (every 3–6 months). Non-anti-TNF biologics Late-onset neutropaenia is a recognized side effect of RTX therapy and, although it usually follows a benign course and is infrequent, can present with infection [214, 215]. A UK study of 108 patients receiving RTX for RA between October 2007 and July 2011 identified five patients (4.6%) who developed late-onset neutropaenia (LON; neutrophil count ⩽1.5 × 109 after a median of 151 days [70–181, 215]; two patients developed pneumonia. A similar rate of 6% (eight patients) was observed in a Norwegian single-centre case review analysis of 133 RA patients, and was more common in those with low IgM and IgG levels [12]. Fifty per cent of patients with LON had infection at the onset of neutropaenia; six patients were rechallenged with RTX without recurrence of LON. In this study it took a median of 6.5 days for recovery of LON. (iii) Patients receiving csDMARD may require more regular laboratory monitoring (as per BSR/BHPR non-biologic DMARD guidelines, 2017) (grade 2B, SOA 96%). Patients receiving biologic therapy alongside a csDMARD may require blood test monitoring more frequently than every 3 months, depending on which csDMARD they are receiving. Minimal monitoring requirements for the different csDMARDs and the blood results that require action are given in the 2017 BSR/BHBR non-biologics DMARD guidelines [5]. The blood results that require action are the same as those defined in the BSR 2017 csDMARD guideline [5]. (iv) Patients receiving RTX should have serum immunoglobulins (especially IgG and IgM) checked prior to each cycle of RTX. Clinicians and patients should be aware that the risk of infection increases as serum IgG levels fall below normal. Lower dose RTX may be considered in this situation (grade 2A, SOA 99%). Lower levels of IgG have been associated with an increased risk of infection in individuals receiving RTX [13]. Van Vollenhoven et al. [13] monitored Ig levels every 8–16 weeks in patients with RA receiving RTX and found that following RTX therapy ⩽3.9% had low IgA or total Ig levels at any time, while 14.8 and 37.9% had below normal IgG and IgM levels, respectively, any time. Over the first 5 years of treatment the proportion of patients with IgM but not IgG or IgA below the lower limit of normal continued to increase. Serious infection rates in those patients who developed low IgG levels were higher than the serious infection rates in patients who never developed low IgG; however, this study was limited by low numbers in the low IgG subgroup (143 patients). Although there is no evidence to suggest an absolute total Ig, IgM or IgG threshold where RTX should not be given, clinicians and patients should be aware that the risk of serious infection increases as serum IgG level falls. Lower dose RTX (such as 2 × 500 mg infusions) may be considered in this situation [13, 218]. (v) Patients receiving i.v. or s.c. TCZ, with or without MTX, should have laboratory monitoring every 4 weeks for neutrophils and ALT/AST (grade 2B). Blood tests should ideally be in the week before i.v. TCZ, and in the 3 days before every fourth s.c. injection. Any decision to halt treatment should be made in accordance with the guidance in the TCZ SPC (grade 2C, SOA 96%). TCZ has been found to cause a reduction in absolute neutrophil count (ANC) in a number of studies [219–221]. This is thought to be due to peripheral margination of neutrophils, but is not associated with an increased frequency of infection. Nishimoto et al. [220] found that 6% of patients on TCZ experienced neutropaenia grade 3 or 4, with a further 15% having grade 1 or 2. Interestingly, these events were not associated with infection. Nakamura et al. [219] found ANC to drop in the first 24 h after i.v. TCZ administration, but the ANC recovered by the next infusion 4 weeks later. Maini et al. [221] found ANC to reach a nadir at 2 weeks post-infusion, with recovery occurring within the following 2 weeks. More recently, a double blind, double dummy RCT [222] compared patients receiving TCZ vs MTX vs TCZ + MTX. No significant difference was seen between the groups in terms of infection or drop in ANC. A 97-week open label extension of a 24-week double blind study comparing i.v. and s.c. formulations of TCZ has shown that even at 97 weeks, a small number of patients still develop new grade 3 or 4 neutropaenia, with numbers similar in both i.v. and s.c. groups (0.81 and 0.76%, respectively) [223]. Rises in transaminases (ALT and AST) have been found with TCZ in a number of studies. Various studies have noted raised transaminases that spontaneously resolved without the need for TCZ dose change [224–228]. Dougados et al. [229], and others, found that 41–51% of patients on TCZ in combination with a conventional DMARD will have spontaneously resolving episodes of raised ALT up to three times the upper limit of normal [224, 225, 228, 229]. In a retrospective cohort study looking back over 45 months, Machado-Alba et al. [230] found 5/51 (9.8%) patients on TCZ developed a rise in ALT up to three times the upper limit of normal. The TCZ SPC has detailed guidance concerning when to stop or change therapy in the context of blood test abnormalities and should be referred to (http://www.medicines.org.uk/emc/medicine/22311/-SPC/RoActemra). (vi) Patients receiving TCZ should have their serum lipids checked at 3 months, and treated appropriately if abnormal; they may be checked again thereafter at physician’s discretion (grade 2A, SOA 99%). TCZ has been noted to cause an initial rise in serum lipids [187, 221, 231], but long-term extension studies have shown them to broadly stabilize within 3 months [232]. A post hoc analysis by Gabay et al. [233] of 324 patients in the ADACTA trial up to 24 weeks showed that compared with ADA, TCZ was associated with a slightly raised LDL cholesterol level, but the overall lipid profiles were similar. An increase in cardiac events has not been found, perhaps with the deleterious effect of higher lipids being offset by better control of inflammatory disease. Further work is required in this area. Co-morbidity management on treatment (i) Patients with significant co-morbidities who are also receiving biologic therapies, should have close involvement with specialists in that field (grade 1C, SOA 99%). Infection In general: (i) All biologics should be discontinued in the presence of serious infection, but can be recommenced once the infection has resolved (grade 1A, SOA 99%). Anti-TNF biologics No studies to date have assessed outcomes in patients with IA receiving anti-TNF therapy who did not stop treatment in the presence of severe infection; however, there are data, primarily from case reports, suggesting that infections may become more severe if patients continue with anti-TNF therapy [234]. Patients should be made aware of the increased risk of infection, and should be advised to stop therapy until the infection has resolved. Non-anti-TNF biologics As no studies have investigated the outcome in patients continuing with these drugs in the presence of active infection, caution is advised and it is suggested that non-anti-TNF biologics should also be stopped until infection has cleared. Further data in this area are required. Mycobacterium tuberculosis (i) Patients commenced on biologics should be closely monitored for TB while on treatment and for at least 6 months after stopping treatment (grade 2C, SOA 98%). This recommendation is largely based on expert opinion from NICE [76] and the BTS guidelines [208]. Any patient who develops symptoms consistent with TB, even if their pre-biologic TB screening was negative, should be investigated for active TB, initially with a chest X-ray and sputum examination. Up to a 19% risk of TB reactivation has been reported; however, this varies according to the local rates of a positive TST/IGRA and the local incidence of TB. Most cases of reactivation have occurred during the first year of anti-TNF treatment after completion of chemoprophylaxis [235]. (ii) Patients on biologics who develop symptoms suggestive of TB should receive full anti-TB treatment but may continue with their biologic if clinically indicated after risk/benefit analysis (grade 2C, SOA 96%). Patients who develop active TB while on biologic treatment should receive full anti-TB chemotherapy [236]. In these circumstances, treatment can be continued if clinically indicated because the patient would otherwise be prevented from receiving the continued clinical benefit to their underlying disease and may have a flare up or major clinical deterioration. While there is limited evidence in this area, it is reported that HIV positive individuals with reduced CD4 counts and clinical TB, who are even more immunosuppressed than those on anti-TNF treatment, respond equally well to TB treatment as those who are HIV negative [237]. Opportunistic infection (i) Health-care professionals should have a high index of suspicion for atypical/OIs, especially if current or recent steroid use. Biologic therapy should be promptly stopped in suspected cases. Patients should have rapid access to specialist health care for consideration of early treatment (grade 1B, SOA 99%). Anti-TNF biologics There have been a few observational cohort studies investigating the association between OIs and anti-TNF use. The largest of these studies, the US Safety Assessment of Biologic Therapy project, found a higher incidence of non-viral OIs compared with patients initiating non-biologic DMARDS [238]. Within the cohort of 33 324 new anti-TNF users over a 9 year period, 80 non-viral OIs were identified with pneumocystosis being the most common, accounting for 20% of OI cases (n = 16); histoplasmosis (n = 9) and cryptococcus (n = 3) were the next most frequently observed fungal OI. Nocardiosis (n = 12) had the highest incidence for opportunistic bacterial infection (n = 12), followed by salmonellosis [8] and listeriosis (n = 4). The overall crude rate of non-viral OI in the TNF group was 2.7 vs 1.7 per 1000 person-years in those receiving only csDMARD (adjusted HR = 1.6, 95% CI: 1, 2.6). Data collected from the US CORONNA registry found that anti-TNF drugs were an independent predictor of OI (bacterial and viral) [23]. One hundred and sixty-four OIs were observed in the TNF-treated group, with an IRR of 1.18 (95% CI: 1.08, 1.32) compared with MTX alone. The combination of MTX and anti-TNF did not appear to further increase the risk of OI above that of anti-TNF alone. In both studies, baseline steroid use was an independent risk factor for OI; however, to date there is insufficient evidence to support the use of primary prophylaxis in this group. Non-anti-TNF biologics The risk of non-TB atypical OIs does not seem to be increased with RTX, TCZ, ABA or TCZ compared with other biologics, but long-term data are lacking [59]. Vallabhaneni et al. [239] looked at 4000 patients who had received TCZ, and 11 of these (0.28%) developed invasive fungal infections, which is non-inferior to other biologics. There are no observational data regarding the long-term risk of UST and atypical OI. (ii) In patients exposed to primary varicella through a close household contact [and without a positive history of varicella zoster (chickenpox) infection or vaccination], post-exposure prophylaxis with varicella zoster immune globulin should be considered if the risks from infection are perceived to be significant. Shingles should be treated conventionally (grade 2C, SOA 94%). Anti-TNF biologics Several studies have found a significant association between anti-TNF therapy and risk of HZ. The most recent data comes from the Australian ARAD database of 2157 RA patients [42]. RA patients receiving IFX, ETN or ADA had a 37% higher risk of shingles (adjusted hazard ratio (aHR) 1.37, 95% CI: 1, 2.92) compared with csDMARD users. Data from BSRBR-RA showed that patients receiving first generation anti-TNF were found to have an up to 80% higher risk of shingles (aHR = 1.8, 95% CI: 1.2, 2.8; crude incidence of 1.6/100 person-years) [240]. This study, along with data from the RABBIT, BIOBADASER and CORRONA registries, was included in a 2014 meta-analysis, which found a pooled risk ratio for HZ with TNF inhibitors of 1.61 (95% CI: 1.16, 2.23) [195]. Relatively fewer studies have focused on varicella zoster (chickenpox) risk and anti-TNF therapy. Higher rates of hospitalized chickenpox and shingles compared with the general population have been observed in a study combining the BIOBADASER registry with the Spanish national hospital discharge database [241]. The IR for hospitalized shingles and chickenpox in patients receiving anti-TNF therapy was 44 and 26 per 100 000 person-years, compared with an expected IR of 3.4 and 1.9 per 100 000 person-years, respectively, in the general population. There remains little evidence on the effectiveness of varicella zoster immune globulin (VZIG) in preventing infection in immunosuppressed patients. A study of 81 immunosuppressed children who received VZIG following household exposure to varicella, found a moderate response to VZIG, although 49 children still developed varicella infection, including some who had serological evidence of past exposure [242]. Until more data are available, we feel that it is appropriate to recommend that VZIG is considered as a post-exposure prophylaxis for patients receiving biologic therapies who are exposed to varicella infection in whom the risks of infection are perceived to be high. VZIG is an intramuscular injection, and should be given as soon as possible—not later than 10 days after exposure; a second dose should be given if further exposure occurs >3 weeks after the first dose. Non-anti-TNF biologics There have been reports of higher than expected episodes of HZ in patients receiving RTX and ABA from cohort studies [35, 243]. Data are lacking on the risk of TCZ and UST and HZ. Until more data are available, we suggest that the recommendations for anti-TNF therapies be applied to all biologics. (iii) Clinicians should be vigilant for progressive multifocal leukoencephalopathy (PML), which has been primarily associated with RTX but has also been reported with anti-TNF therapy. Treatment should be stopped if PML develops. Rechallenge is not recommended (grade 1C, SOA 99%). PML has been reported in a few more patients than was reported on the previous guideline and to date there have been 11 cases in patients with RA [244]. The majority of case have been in association with RTX use, but rarely cases have been reported with other agents [245]. Considering how many more patients have been treated with RTX since the last guideline, this should be reassuring of the lack a major signal, but vigilance should still be maintained. The prognosis for PML is poor, with a high level of mortality at 1 year. Although there is no treatment for PML, stopping biologic therapy may slow progression. There are no data regarding PML receiving biologic therapies for non-RA IA. No cases of PML have been reported with TCZ, ABA or UST. Hepatitis B and C infection (i) Close monitoring of serum amino-transaminases and HBV DNA load is recommended in patients with occult or overt HBV infection treated with biologic therapy (grade 1C SOA 99%). Patients should be followed carefully by means of ALT and HBV DNA testing and treated with anti-viral therapy upon confirmation of HBV reactivation before ALT elevation. The frequency of monitoring can range from 1 to 3 months depending on the type of immunosuppressive therapy and comorbidities [93]. (ii) Close monitoring of serum amino-transaminases and HCV RNA during therapy should be considered in patients with HCV treated with a biologic (grade 1C, SOA 99%). Studies to date continue to show that biologic (especially anti-TNF) therapies do not have a detrimental effect on HCV infection [99, 101], but it would be prudent to work closely with a hepatologist and arrange monitoring. (iii) Patients with serological evidence of occult HBV infection may require concomitant anti-viral treatment if detrimental changes in monitoring tests develop (grade 1B, SOA 99%). Patients with previous occult HBV infection treated with biologic therapy who reactivate their HBV have generally good outcomes even if anti-viral treatment was required [90, 92, 246]. In these studies anti-viral treatment was generally given if HBV DNA level was >105 IU/ml, although we recommend that thresholds of treatment should be decided working with a hepatologist given that European Association for the Study of the Liver guidelines recommend treatment based on a combination of raised ALT, HBV DNA level >2000 IU/ml and severity of liver disease [93]. HIV (i) Patients with HIV receiving anti-TNF therapy require close monitoring of viral load and CD4 count. Treatment changes should be made in light of results, with guidance from an HIV specialist (grade 2C, SOA 99%). Refer to the earlier section on HIV. Malignancy Patients should be encouraged to comply with national cancer screening programmes (grade 1C, SOA 99%). Patients should be investigated for potential malignancy if clinically suspected and biologics should be stopped if non-BCC malignancy is confirmed (grade 1C, SOA 97%). There is an absence of evidence regarding the cessation of biologic therapy in the presence of proven malignancy; certainly no studies to date have investigated whether continuing or stopping biologic therapy in this situation has any effect on prognosis. Until any further evidence is available, it is suggested that all biologic therapies should be stopped if malignancy (excluding skin BCC) is confirmed, and any ongoing future treatment discussed with oncology specialists on a case by case basis. (iii) Biologic therapies may be continued in patients who develop a BCC that is fully excised, after careful discussion with the patient and a risk–benefit analysis (grade 2C, SOA 97%). There have been no studies to date assessing the outcome of biologic-treated patients who undergo complete excision of a NMSC and continue with biologic therapy. As described earlier, there is evidence to suggest that anti-TNF agents increase the risk of a future NMSC in individuals who have a past history of them [140], but conflicting results have also been reported in other studies [140]. Due to the low inherent risk of metastasis following the complete excision of a BCC, we suggest that in this situation biologic therapies may be continued after careful discussion with the patient and possible input from a dermatology specialist. Cardiac problems (i) If patients develop worsening cardiac failure while on anti-TNF, consideration should be given to stopping therapy if no other explanation for worsening cardiac failure is found following input from a cardiologist (grade 2C, SOA 99%). Although recent studies have reassuringly not found a significant effect of TNF inhibitors on cardiac failure [153, 154], early clinical trials did report a detrimental association [150–152]. There are numerous causes of cardiac failure including ischaemic heart disease, hypertension and valvular heart disease, all of which are more common than drug-induced causes. With this in mind, we suggest that consideration is given to stopping anti-TNF agents in individuals with worsening cardiac failure if this cannot be attributed to other pathologies after specialist input from a cardiologist. Respiratory disease (i) Patients with ILD receiving biologics should be regularly reviewed by a respiratory physician with a specialist interest in ILD, and ideally in a combined rheumatology/respiratory clinic. Pulmonary function tests (PFTs) should be performed as clinically indicated, usually every 4–6 months (grade 2C, SOA 99%). Most ILDs share a restrictive pattern, with reductions in lung volumes and a reduced diffusing capacity for carbon monoxide (DLCO). Low baseline forced vital capacity (FVC) and DLCO (e.g. FVC <60% and DLCO <40% of predicted values) are independent predictors of early death in patients with IPF. Serial PFTs add information on disease trajectory. Importantly, a short-term (6–12 month) decline in FVC of ⩾10%, or a decline in DLCO of ⩾15%, is associated with increased mortality in IPF [247]. In one systematic review, where ILD occurs subsequent to introduction of anti-TNF, ∼80% of cases were found in the first 20 weeks with a mean of 26 weeks [167]. Although there are no data to suggest the optimal frequency of pulmonary monitoring, we suggest that routine PFT monitoring should be performed as clinically indicated, usually every 4–6 months. (i) Consideration, in consultation with a respiratory physician with a specialist interest in ILD, should be given to stopping biologic therapy in patients with worsening or new features of ILD. RTX or ABA may be considered in patients with worsening or new ILD (grade 2C, SOA 90%). Anti-TNF biologics Patients demonstrating worsening respiratory symptoms or lung function should have the input of a respiratory physician with a specialist interest in ILD to consider the possible causes of the decline as the differential includes causes potentially related to biologic therapy such as infection, congestive heart failure, progression of RA-ILD, drug-induced pneumonitis or other causes not related to biologic therapy such as COPD or pulmonary emboli. Although it is difficult to establish causation of worsening or new features of ILD to anti-TNF, and in fact an observational study by Herrinton et al. [162] found that anti-TNF therapy was not associated with a diagnosis of ILD in RA patients over a mean follow-up of 3 years, we would still recommend consideration of discontinuation of anti-TNF in these circumstances until data from further, larger studies is available. Non-anti-TNF biologics Although it is difficult to establish causation of worsening or new features of ILD to any of the non-anti-TNF biologics, a decision to discontinue therapy should be taken in conjunction with respiratory specialist colleagues with the understanding that based on current levels of evidence, ILD is unlikely to be caused or exacerbated by RTX, ABA or TCZ. There are no data available regarding UST in this context. Uveitis If patients develop uveitis while on a biologic a trial of an alternative biologic could be considered, bearing in mind the latest reported relative risks (grade 1C, SOA 99%). Consider switching patients with uveitis currently taking ETN to INF or ADA (grade 2C, SOA 98%). Anti-TNF biologics Refer to the earlier section on uveitis. Non-anti-TNF biologics There has been one case report of a patient with RA treated with TCZ who developed acute anterior uveitis 5 weeks after stopping TCZ [248]. Causality is difficult to establish here and indeed TCZ has been used with moderate success in patients with uveitis [173]. There are no data concerning RTX, ABA or UST and the development of uveitis. Demyelinating disease (i) Anti-TNF should be withdrawn if demyelination occurs. Rechallenge with anti-TNF therapy is not recommended (grade 2B, SOA 99%). Any suspected cases of demyelination should be investigated and reported appropriately and referred urgently to a neurologist. The rationale behind this statement is covered in the earlier section on demyelinating disease. Sixteen cases of Guillain–Barré syndrome were identified from the FDA database following anti-TNF therapy [249]. Among the 13 patients for whom follow-up data were available, one patient experienced no resolution, nine patients had partial resolution and three patients had complete resolution of Guillain–Barré syndrome following therapy. There are some reports of successful rechallenge with anti-TNF without recurrence of neurological symptoms, but there are also reports of worsening symptoms or recurrence on rechallenge. Diverticular disease (i) TCZ should be withdrawn if bowel perforation occurs; reintroduction of TCZ in such patients is not recommended (grade 2C, SOA 99%). Refer to the earlier section on diverticular disease. CTD (i) If a lupus-like syndrome or other significant autoimmune disease develops while on anti-TNF therapy, treatment should be discontinued and appropriate interventions should be initiated. In such instances, a non-anti-TNF biologic should be considered. Rechallenging with an alternative anti-TNF agent should only be undertaken with caution (grade 1C, SOA 99%). Anti-TNF biologics There continue to be further case reports of lupus-like syndromes, vasculitis and other autoimmune conditions developing after the commencement of anti-TNF therapy that improve on cessation of the anti-TNF, but often requiring alternative immunosuppression in more severe cases. Full-blown anti-TNF induced lupus or vasculitis remains rare. In a study by Takase et al. [250], 18% of patients had ANA seroconversion (83 of 454) when monitoring ANA results while on an anti-TNF, with seroconversion after a median period of 11 months. Only three of these patients were classifiable as lupus, however. BSRBR-RA reported on 11 394 anti-TNF patients followed for a total of 26 927 person-years [251]. Forty anti-TNF-treated patients developed a new lupus event, compared with only one of the DMARD-treated patients (adjusted IRR = 3.17, 95% CI: 0.38, 26.26). The most common lupus symptom was skin rash; LN or neuropsychiatric symptoms were not reported. Ramos-Casals et al. [252] identified 379 patients affected by an autoimmune condition induced by an anti-TNF through a Medline search up to May 2008. SLE/lupus-like disease was found in 105 patients. SLE criteria met were most commonly ANA positive, anti-dsDNA positive, malar rash then arthritis, with <10% having renal or CNS involvement. Treatment was anti-TNF withdrawal in 93% of cases. Thirty-six patients needed steroid or immunosuppression. Mean follow-up was 10 months, and all improved. A retrospective review of Mayo clinic records 1998–2011 [253] looked at the clinical features, histopathological features and outcomes where diagnosis of vasculitis induced by anti-TNF had been made. Cutaneous small vessel vasculitis was the most common but systemic involvement including peripheral nerve and renal vasculitis was frequently observed; mean duration of anti-TNF prior to development of vasculitis was 34.5 months (2–72 month range). Follow-up after vasculitis was a mean 27.1 months (1–108). No recurrence was seen in these patients on stopping anti-TNF and there was a mean time of 6.9 months to resolution of vasculitis after stopping anti-TNF with all receiving adjuvant treatment. No patients were rechallenged with an anti-TNF agent. In conclusion there are reports to suggest a small number of patients are at risk of developing a lupus or vasculitis problem when treated with anti-TNF but it is rare to have major organ involvement and symptoms usually resolve on stopping anti-TNF. Although only small numbers of patients have been rechallenged with anti-TNF, when undertaken this led to recurrence in up to 75%, hence the recommendation to use caution if considering rechallenge [252, 254, 255]. Non-anti-TNF biologics There are no data to suggest an association between any of the non-anti-TNF biologics and induction of autoimmune CTD or vasculitis. Haematological disorders (i) Biologic therapies may be continued in patients at increased risk of, or with, venous thromboembolism (VTE) (grade 2C, SOA 99%). Anti-TNF biologics Although some studies have reported a potential increased risk of VTE in anti-TNF users [256], a retrospective cohort study using BSRBR-RA data compared the rates of VTE in RA treated with anti-TNF (n = 11881) with those treated with csDMARD (n = 3673) and found no difference in the rates of VTE between anti-TNF and csDMARDs [257]; the risk was similar across all anti-TNF agents. The study was, however, not powered to detect differences of small magnitude. It should be noted that the observational nature of the BSRBR-RA predisposes to channelling bias (patients with more severe disease are more likely to be enrolled into the anti-TNF cohort). Therefore, continuation of biologic therapies in patients at increased risk can be recommended, as, in addition, higher disease activity may predispose to a prothrombotic state [258]. Risk would also be increased if active disease caused immobility. Non-anti-TNF biologics There are no data to suggest that any of the non-anti-TNF biologics increase the risk of VTE. Psoriasis (i) If psoriasis develops in patients treated with anti-TNF, conventional psoriasis treatment should be started and consideration should be given to stopping anti-TNF if the skin lesions persist despite specialist dermatology input or are severe (grade 2B, SOA 99%). Anti-TNF biologics Several studies have suggested that anti-TNF agents may paradoxically increase an individual’s risk of developing psoriasis, despite these agents being licensed and approved by NICE for the treatment of psoriasis. BSRBR-RA compared 9826 RA patients receiving anti-TNF agents (either IFX, ETN or ABA) against 2880 csDMARD patients [259]. Over 520 person-years of follow-up, 25 cases of new onset psoriasis were observed in those receiving anti-TNF, 52% of which occurred within the first 6 months of therapy, compared with 0 cases in the csDMARD group; this equated to a crude IR of 1.04 (95% CI: 0.67, 1.54) vs 0 (95% CI: 0.71) per 1000 person-years. In this cohort, the highest rates of psoriasis were found with ADA compared with ETN and INF. A higher incidence of psoriasis has also been found in the BIOBADASER cohort [260]. Out of 4437 patients receiving first-generation anti-TNF agents, 32 cases of psoriasis were observed, with an IR of 2.31 (95% CI: 1.69, 3.15). In this cohort, the highest event rate was noted for INF, and the lowest for ETN. The majority of patients who develop psoriasis while receiving anti-TNF agents do not stop therapy, and are able to manage the condition with add-on therapy [258, 260, 261]. In the BSRBR-RA cohort, only 4 of the 13 patients who developed psoriasis in the first 6 months of anti-TNF therapy stopped treatment due to psoriasis; all reported improvement in psoriasis after stopping therapy [258]. Similarly, a retrospective review of the Mayo clinic experience identified 56 RA patients who developed psoriasis while receiving anti-TNF treatment [260]. Of these, 62% continued with therapy and were treated successfully with add-on medication, although higher rates of complete skin remission were observed in those that stopped treatment. The most common forms of psoriasis that occurred in this cohort were plaque psoriasis and palmopustular psoriasis. A literature review by Collamer and Battafarano [262] found that around 50% of patients who switch to an alternative ant-TNF agent due to psoriasis will not experience a recurrence of their lesions. Non-anti-TNF biologics There is no convincing data to suggest an association between any of the non-anti-TNF biologics and the development of psoriasis. Vaccinations (i) The Public Health England recommendations on the use of immunizations in patients on immunosuppressive therapy should be adhered to in patients on biologics. Live attenuated vaccines, such as the HZ vaccine, oral polio or rabies vaccine, should be avoided (grade 2C, SOA 99%). Public Health England recommend that live attenuated vaccines should not be routinely given to individuals who are immunosuppressed (including those receiving biologic therapy). Live attenuated organisms can replicate in an immunosuppressed individual and cause an extensive, serious infection. If the use of live vaccines is necessary, at least 2 weeks, but preferably 4 weeks should be allowed before anti-TNF therapy is commenced. In terms of travel advice, yellow fever is a live vaccine and must not be given, and therefore patients should be advised not to travel to countries requiring this (e.g. mid-African nations). An exemption statement may be given if a patient has to travel but the patient will be at risk. Measles, mumps and rubella are live vaccines, so should not be given to a patient on anti-TNF but the vaccine is not contraindicated in household contacts. Exposure to measles should be treated with immunoglobulin regardless of prior immunization [263]. BCG vaccine for TB is contraindicated in patients on anti-TNF treatment as it is also a live vaccine [264]. Polio vaccine is an inactivated vaccine so may be given to immunosuppressed individuals (live polio vaccine was used up until 2004 in the UK) [265]. (ii) Although there may be an attenuated response (particularly if MTX is co-prescribed), patients on biologics should receive influenza and pneumococcal immunizations unless there are contraindications (grade 1C, SOA 99%). Patients receiving immunosuppressive therapy are advised to have both influenza and pneumococcal immunization. A limited number of studies are available investigating the response to vaccination in rheumatoid patients, with assessments made on RA patients treated with either MTX alone or in combination with anti-TNF. Influenza immunization Anti-TNF biologics There is some evidence that there are differences in response to immunization between each of the first-generation anti-TNF agents. While ADA has been shown not to reduce responsiveness to immunization [266], some studies have suggested that ETN and INF administration is associated with decreased response rates [267, 268]. A study by Elkayam et al. [269] showed an adequate response overall to influenza vaccine in patients with RA on INF, but a slightly attenuated response in the group that were vaccinated 3 weeks after receiving INF rather than on the same day. However, numbers were small (38 patients on INF, seven given vaccine 3 weeks after INF) [269]. A review [267] of influenza studies has indicated that this immunization is well tolerated; however, a subset of patients may remain unprotected. Some patients may be concerned that the influenza vaccine may provoke a flare of their RA. However, reassuringly, a recent study published by Milanetti et al. [270] noted no increase in flares of RA in patients receiving influenza immunizations, but a slight increase in minor systemic and local side effects such as fever, injection site swelling, headaches and myalgia. Non-anti-TNF biologics The efficacy of the influenza vaccine in patients treated with RTX has been examined in several cohort studies. A meta-analysis by Hua et al. [271] has shown that some response occurs, but it is attenuated if the patient is on the drug. Response rates may improve if vaccination is given further away from the last RTX infusion; Westra et al. [272] found that the IgG response to vaccination was restored in patients who had received RTX 6–10 months prior to vaccination. IgM response, however, did not change. There is a small amount of evidence regarding the other non-anti-TNF biologics and their effect on response to influenza vaccine. A small Brazilian study of 11 RA patients receiving ABA found a reduced immune response to the influenza vaccine [273]. There are no data concerning TCZ and UST and the influenza vaccination. Although there are limited data and the suggestion that response to vaccination may be attenuated, because non-anti-TNF biologics are immunosuppressive medications, it is recommended that all patients receiving biologic therapies continue to have a yearly influenza vaccination. Pneumococcal immunization Anti-TNF biologics While MTX is associated with lower response rates to pneumococcal vaccines in most studies [274–277], some studies have suggested that ETN or INF in combination with MTX are not associated with a poor response [266, 274–276]. The reasons for these differences are unclear, but the theory that certain anti-TNF agents can lead to enhanced immune responses was put forward from one study [274], where patients with MTX had lowered responsiveness, but this does not explain why those with the combination of INF or ETN with MTX had even better response rates than the healthy controls. In the case of ADA, ADA alone has not been shown to affect the antibody titre response to pneumococcal immunization, but the combination of MTX and ADA was shown to be associated with decreased response rates when compared with MTX alone [266]. More recent evidence from a Swedish case–control study [278] in a group of 505 patients with RA or SpA showed adequate response rates to pneumococcal vaccine. Better antibody response ratios were seen in patients on anti-TNF monotherapy, compared with those treated with MTX or MTX plus anti-TNF. Ongoing MTX was predictive of reduced response. Overall, pneumococcal vaccine is recommended in patients receiving anti-TNF therapy, but clinicians should be aware that the response to vaccination may be attenuated if anti-TNF and MTX are used in combination. Non-anti-TNF biologics A small study by Crnkic Kapetanovic et al. [279] found that among 88 patients with RA, the antibody response to the pneumococcal vaccine was reduced most notably for RTX, but also with ABA; TCZ, on the other hand, was associated with a sufficient antibody response. There are no data regarding treatment with UST and response to the pneumococcal vaccine. (iii) In patients who are currently receiving biologics, human papillomavirus vaccine for cervical cancer risk in young women is recommended if they have already received part of the vaccination schedule, as per national guidelines (grade 2C, SOA 99%). There is a national human papillomavirus (HPV) childhood vaccination programme in place in the UK, introduced in 2008 for secondary-school-age girls of 12–13 years, although girls may receive their HPV vaccination programme up to their 18th birthday. There are no data for the two-dose schedule for immunocompromised patients, and therefore the three-dose schedule should be given if a girl has already started or is due to start anti-TNF therapy. National advice states that re-immunization should be considered after treatment has finished or recovery occurred, and specialist advice may be required [280]. Kumar et al. [281] described reduced immunogenicity in organ transplant recipients. Although most at-risk individuals will have received papillomavirus vaccine in childhood, there may be scenarios where young adults receiving biologics over the age of 18 have not received vaccination. We suggest that in these circumstances, vaccination should be offered, even though the individual is outside of the national vaccination programme age window. Peri-operative care The potential benefit of preventing post-operative infections by stopping biologics (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a peri-operative flare in disease activity (grade 2B, SOA 97%). For most biologics (exceptions: RTX and TCZ), consideration should be given to planning surgery when at least one dosing interval has elapsed for that specific drug; for higher risk procedures consider stopping 3–5 half-lives (if this is longer than one dosing interval) before surgery (grade 2B, SOA 97%). Biologics may be recommenced after surgery when there is good wound healing (typically around 14 days), all sutures and staples are out, and there is no evidence of infection (grade 1B, SOA 99%). For patients receiving RTX, treatment should ideally be stopped 3–6 months prior to elective surgery (grade 2B, SOA 94%). For patients receiving TCZ, i.v. TCZ should be stopped at least 4 weeks before surgery; s.c. TCZ should be stopped at least 2 weeks before surgery (grade 1C, SOA 96%). Anti-TNF biologics Current literature provides conflicting data with regard to the risk of infection peri-operatively in association with anti-TNF therapy. A Dutch retrospective study [282] of 1219 surgical procedures in RA patients found that peri-operative continuation of anti-TNF therapy did not seem to be an important risk factor for surgical site infection. This is supported by evidence from several smaller studies [283, 284]. Larger studies from Canada [285], Japan [286] and Germany [287] showed no significant differences in surgical site infection rates in patients on anti-TNF therapy compared with csDMARDS; however, biologic therapy was withheld peri-operatively in >80% of cases. Another Japanese study of orthopaedic surgery found no statistically significant increase in the incidence of delayed wound healing or superficial infection with anti-TNF agents [288]. There was no correlation between peri-operative disease activity, dose of ETN (25 vs 50 mg) or preoperative waiting period off biologics (<14 or >14 days) and likelihood of adverse events. Conversely, other studies have reported an increased risk of peri-operative infection rates with continued use of anti-TNF agents [289]. One report showed that the continuation of anti-TNF therapy was associated with an increased risk of peri-operative infections (OR = 4.4, 95% CI: 1.10, 18.41) in a series of 91 RA patients undergoing orthopaedic procedures [290]. Data from the BSRBR-RA [291] showed that the risk of serious post-operative infection was nearly 2-fold higher in patients who received anti-TNF therapy in the 28 days prior to surgery than in those who were not exposed. Two further Japanese studies have supported these findings, with suggestion of even greater increased risk of peri-operative infection on anti-TNF. A retrospective cohort study of 420 women with RA, Momohara et al. [292] found that anti-TNF agents (INF, ETN, ADA) increased the risk of surgical site infection 9-fold. A higher risk still was identified in a smaller case–control study of 64 patients [293]; INF and ETN were associated with an OR of 21.8 for surgical site infection (95% CI: 1.231, 386.1; P = 0.036). ETN was withheld for 2–4 weeks prior to the operation and INF for 4 weeks prior to the surgery. Critics have suggested that the cases of infection were overstated, however, as infections were counted ‘when surgeons diagnosed or suspected a surgical infection, and antibiotics were given prophylactically’. Surgeons were not blind regarding which patients had been exposed to anti-TNF therapy, and so could have had a higher index of suspicion for infection in patients on anti-TNF and hence be more likely to prescribe antibiotics [294]. Blinded, prospective studies are therefore needed before firm conclusions can be drawn about the infection risk associated with anti-TNF agents. In 2008, Pappas and Giles [295] identified six major studies investigating the peri-operative infection risk of anti-TNF therapy associated specifically with orthopaedic surgery. All studies assessed involved retrospective outcome data and the source populations differed greatly between studies making direct comparison difficult. Of the six published major studies, only one study [290] identified an increased risk associated with peri-operative anti-TNF exposure, but the authors recommended that anti-TNF therapy should be stopped for a duration of three to five times their half-lives pre-operatively and restarted once the wound healing is deemed satisfactory (10–14 days). The half-lives of biologic therapies are shown in Table 7. This may be manageable for those biologic agents with reasonably short half-lives, but with agents such as ADA and ABA, where five times the half-life equates to >2 months, cessation for this prolonged period of time is likely to lead to potentially significant (and possibly irreversible) declines in the disease control and major flare, often requiring steroid therapy (and the associated risks, which may be higher than biologic therapy). Table 7 Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Table 7 Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Pragmatically we suggest that surgery should be arranged for the week after the next scheduled dose of anti-TNF, and longer still (preferably five half-lives) if the surgery is deemed to be of especially high infection risk by the surgical team. With INF, five half-lives of the drug (45 days) may actually be shorter than the dosing interval, for example, patients receiving INF every 8 weeks. In this situation, ensuring that one dosing interval has elapsed before surgery should be sufficient even with procedures deemed to have a higher risk of infection. The idea behind this dosing principle is that the nadir of the drug’s effect would be at the end of its dosing interval. This is in line with advice from a recently published systematic review by the ACR and American Association of Hip and Knee Surgeons [296]. Non-anti-TNF biologics There is a paucity of data specific to non-anti-TNF biologics and peri-operative care. A retrospective study using the French AIR registry [297] identified 133 patients who had received RTX prior to a surgical procedure. Eight (6.7%) of the patients experienced a post-operative complication, including eight site infections and one deaths due to septic shock. Post-operative complications were higher in orthopaedic than abdominal surgery; however, only a significant association was seen with spinal surgery (P = 0.048). All patients had stopped RTX prior to surgery a mean of 6.4 months beforehand (interquartile range 4.3–8.7 months). There was no difference in event rates according to length of time off therapy prior to surgery. Unfortunately the study could not differentiate between acute and elective procedures, but 68% of procedures were orthopaedic. The number of complications was small and whether the time from infusion to complication of surgery is a major factor was difficult to interpret. TCZ is a very potent suppressor of acute phase response. A retrospective study looking at 161 patients on TCZ for RA undergoing orthopaedic surgery found 20 patients with wound healing delay, and three post-operative infections, two of which were superficial [292]. This study had no comparator, so conclusions are difficult to draw. Another study comparing patients undergoing surgery on TCZ and csDMARDS found those on TCZ did not mount as high a fever or as significant a rise in CRP as the csDMARD group. Following an infusion of i.v. TCZ, CRP and other markers of acute phase response reach a nadir between 1 and 3 weeks and then gradually return to normal. Although data are lacking, monitoring for post-operative infections in the first 4 weeks following a TCZ infusion is likely to be significantly hampered by a blunted acute phase response. Patients having i.v. or s.c. TCZ might need close monitoring in the post-operative period as the conventional indicators of sepsis (fever and acute phase response) might not be reliable. There are no data regarding ABA and UST in the peri-operative period. Until further evidence is available, and considering the balance between the potential risk of peri-operative complications vs the potential for disease flare if patients are without therapy for a prolonged period of time, we suggest that RTX is stopped at least 3–6 months prior to elective surgery; i.v. TCZ should be stopped at least 4 weeks prior to and s.c. TCZ at least 2 weeks prior to surgery. For all other non-anti-TNF biologics we suggest that surgery should be arranged for the week after the next scheduled dose of anti-TNF, and longer still (preferably five half-lives) if the surgery is deemed to be of especially high infection risk by the surgical team. Applicability and utility Clinician responsibility These guidelines represent a framework upon which clinical practice should be based. However, as with any guideline, individual patient circumstances can have important influences on clinical decision-making, and clinicians should continue to work alongside patients to make shared decisions about care. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. Potential organizational barriers to the guideline Biological therapy initiation should only take place under the supervision of an expert in the management of rheumatic disease (i.e. a consultant rheumatologist)—a recommendation supported across the NICE guidelines across the rheumatic disease areas. An important consideration regarding biologic therapy monitoring is the impact of frequent blood monitoring on health care services. Effective biologic therapy monitoring requires systems in place not only to ensure patients have regular blood tests, but also that the results of tests are reviewed and acted upon appropriately within a timely manner. The guideline makes three specific recommendations that will increase monitoring burden, as described below. All patients to be reviewed for drug safety in a specialist rheumatology department at least every 6 months. High risk patients (e.g. those at high risk of TB) should be reviewed every 3 months. Patients prescribed a biologic (other than TCZ) without concomitant csDMARD or with csDMARDs that do not require blood monitoring should have monitoring blood tests (FBC, renal and liver function) every 3–6 months. Patients prescribed i.v. or s.c. TCZ, with our without MTX, should have monitoring blood tests (FBC, liver function) every 4 weeks. Audit tool A model audit tool template is available for biologic therapy imitation and monitoring. The audit tool can be accessed via the BSR website. Overall summary and conclusions Biologic therapies represent a major advance in the treatment of IA, and appropriately their use continues to increase. Information on the longer term safety of these drugs continues to be collected both at a local level and through national registries across the world. Data remain scarce for the second-generation TNF inhibitors (CZB and GOL) and some of the newer non-anti-TNF biologic therapies (such as TCZ, ABA and UST). Similarly, there is a paucity of longer term observational safety data for any of the biosimilar therapies recently licensed and in increasing use worldwide. As questions in many commonly encountered clinical scenarios remain unanswered, it is essential that data on the safety of these products continue to be captured and reported, to inform further updates of this guideline. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: C.R.H. has been sponsored to attend meetings by AbbVie, Pfizer, Bristol-Myers Squibb and UCB and has received honoraria for speaking and attended advisory boards with AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Janssen and Novartis. R.S. has received sponsorship to attend the national BSR conference from Pfizer and has received honoraria to speak at regional educational meetings by AbbVie and Eli Lilly. M.B. has been sponsored to attend regional, national and international meetings by UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Janssen, Bristol-Myers Squibb, Novartis and Eli Lilly and received honoraria for speaking and attended advisory boards with Bristol-Myers Squibb, UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi aventis, Eli Lilly, Janssen and Novartis. A.M. has received honoraria for sponsored presentations from MSD, Bristol-Myers Squibb and Roche and received an honorarium from Pfizer for professional services. C.H. has received sponsorship to attend a national meeting by Pfizer. E.C. has received sponsorship to attend meetings by Pfizer and UCB and received honoraria for speaking for Eli Lilly. C.C. has received sponsorship to attend a national meeting by Pfizer. A.L. has received sponsorship to attend meetings and courses by AbbVie, Roche and UCB and has received honoraria for speaking by Roche/Chugai. J.T. has received honoraria from Hospira. S.B. has received sponsorship to attend a national meeting by Pfizer. All other authors have declared no conflicts of interest. Acknowledgements The GWG acknowledges the contribution from the following advisors: HIV section: Professor Karen Walker-Bone, MRC Lifecourse Epidemiology Unit, University of Southampton; TB section: Dr Ben Marshall, Consultant Respiratory Physician and Honorary Senior Lecturer, University Hospital Southampton. We would also like to acknowledge the contribution of the previous anti-TNF safety GWG. References 1 Ding T , Ledingham J , Luqmani R et al. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies . Rheumatology 2010 ; 49 : 2217 – 9 . Google Scholar Crossref Search ADS PubMed 2 Bukhari M , Abernethy R , Deighton C et al. BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis . Rheumatology 2011 ; 50 : 2311 – 3 . 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The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis

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Publisher
Oxford University Press
ISSN
1462-0324
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1462-0332
DOI
10.1093/rheumatology/key208
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Abstract

rheumatoid arthritis, psoriatic arthritis, psoriatic arthritis, ankylosing spondylitis, biologic, Anti-TNF, safety Introduction The use of biologic therapies has transformed the management of inflammatory arthritis (IA). In contrast to conventional systemic DMARDs (csDMARDs) traditionally used to treat inflammatory disease, these agents offer a targeted approach, and their widespread use has resulted in disease remission becoming an increasingly achievable goal. Biologic therapies are not without potential risk, and hence it is important that clinicians are aware of these risks and ensure that appropriate precautions are taken to minimize them. Information on the safety of biologic therapies continues to be collected through national registries, clinical and cohort studies and case series and reports. NICE has accredited the process used by the BSR to produce its guidance on the safety of biologic DMARDs in inflammatory arthritis. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. This guideline supersedes the previous BSR/BHPR anti-TNF [1], rituximab (RTX) [2] and tocilizumab (TCZ) [3] guidelines and has been developed in line with the BSR Guidelines Protocol. Scope and purpose Background and need for guideline In 2001, The British Society of Rheumatology published its first guidelines on the safety of anti-TNF agents in RA. This was subsequently updated in 2005 [4], and most recently in 2010 [1]. These guidelines covered the indications and precautions for the use of anti-TNF agents, and the action that should be taken in the case of an adverse event. The initial guidelines focused on the then-available first generation anti-TNF drugs (infliximab (INF), etanercept (ETN) and adalimumab (ADA)) in RA. This was then expanded in the 2010 guideline to include the newer anti-TNF agents, golimumab and certolizumab. Separate guidelines covering the use and safety of RTX [2] and TCZ [3] in RA were published in 2011 and 2014, respectively. The previous 2010 BSR/BHPR biologics safety guideline focused solely on anti-TNF inhibitors for RA. While most safety evidence, especially long-term observational data, exists for the first generation anti-TNF agents in RA, since the last guideline there has been significant new information from clinical studies regarding the safety of both anti-TNF agents and the newer non-TNF biologic DMARDs, both in RA and in other licensed IA indications. In light of this, the 2010 guideline working group lead, and a new guideline working group confirmed, the need for an updated guideline combining the wider spectrum of biological agents used at present across their multiple approved indications. Objectives of guideline The purpose of this guideline is to provide evidence-based recommendations for the safe use of biologic therapies in adults (aged >18 years). Although the majority of published safety data still concern the use of first-generation anti-TNF agents in RA, this guideline has been expanded from the previous to cover the safety aspects of all biologic therapies (approved by the National Institute for Health and Care Excellence (NICE) as of June 2016; Table 1) for the treatment of RA, PsA and axial spondyloarthritis (SpA) including AS [referred to as inflammatory arthritis (IA) henceforth]. Therapies approved by NICE after June 2016, such as secukinumab, sarilumab and the Janus kinase inhibitors, are not included. Table 1 Biologic therapies covered by this guideline Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Table 1 Biologic therapies covered by this guideline Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 Biological therapy Abbreviation Mechanism of action Abatacept ABA CTLA4-Ig Adalimumab ADA Anti-TNF α Certolizumab pegol CZB Anti-TNF α Etanercept ETN Anti-TNF α Golimumab GOL Anti-TNF α Infliximab INF Anti-TNF α Rituximab RTX Anti-CD20 Tocilizumab TCZ Anti-IL-6 receptor Ustekinumab UST Anti-IL-12/IL-23 This guideline highlights several specific safety areas including recommendations for baseline screening prior to initiation, recommendations for monitoring, the implications of co-morbid disease and ageing, vaccinations and the management of biologic therapies in specific situations such as infection, malignancy and the peri-operative window. Biologic therapies covered by this guideline (in alphabetical order) are shown in Table 1. Individual drug Summary of Product Characteristics (SPCs) are available online at www.medicines.org.uk, and can be used alongside this guideline. The following indications are covered by this guideline: RA, PsA and axial SpA, including AS. Target audience This guideline is aimed at secondary health care professionals who are involved in the management of patients with IA receiving biologic therapies. This may include rheumatologists, rheumatology specialist nurses and allied health professionals, specialist pharmacists, rheumatology speciality trainees and patients. General practitioners, physicians in other specialties and surgeons who manage patients treated with biologic therapies may also find this guideline useful. The areas the guideline does not cover This guideline does not cover specific indications for biologic therapy in IA; this has been described in national and international disease-specific recommendations, as well as NICE guidance (www.nice.org.uk). The guideline does not cover the safety aspects of csDMARDs. This has been recently updated in the BSR/BHPR non-biologic DMARD guidelines [5]. The guideline does not cover the use of biologic therapy for conditions other than RA, axial SpA including AS and PsA, nor safety in individuals aged <18 years. The safety of biologics in the context of pregnancy and breastfeeding is not covered here; this has recently been covered in the BSR/BHPR Prescribing Drugs in Pregnancy guidelines [6]. Finally, the guideline does not specifically cover the safety of biosimilar preparations of branded biologics; until further clinical data are available, the safety recommendations we propose for originator biologics can be applied to their biosimilar counterparts. Patients should be made aware of the potential switch to biosimilar preparations. The requirement for brand name prescribing and entry of patients into registries is essential to ensure ongoing pharmacovigilance including the collection of long-term observational safety data in this area. Stakeholder involvement This guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair, Dr Chris Holroyd, alongside representatives from relevant stakeholders (Table 2). In accordance with BSR policy, all members of the GWG made declarations of interest, which is available on the BSR website. Table 2 Names and affiliations of the Guideline working party Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Table 2 Names and affiliations of the Guideline working party Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Name Role Affiliation Christopher Holroyd Chair Biologics GWG University Hospital Southampton Rakhi Seth Consultant Rheumatologist University Hospital Southampton Marwan Bukhari Consultant Rheumatologist University Hospitals of Morecambe Bay NHS Foundation trust Anshuman Malaviya Consultant Rheumatologist Mid Essex Hospitals NHS Trust Claire Holmes Specialty trainee University Hospital Southampton Elizabeth Curtis Clinical Research Fellow MRC Lifecourse epidemiology Unit, University of Southampton Christopher Chan Specialty trainee University Hospital Southampton Mohammed A Yusuf Specialty trainee Mid Essex Hospitals NHS Trust Anna Litwic Consultant Rheumatologist Salisbury District Hospital Susan Smolen Rheumatology research nurse Mid Essex Hospitals NHS Trust Joanne Topliffe Rheumatology research nurse Mid Essex Hospitals NHS Trust Sarah Bennett Rheumatology nurse specialist University Hospital Southampton Jennifer Humphreys NIHR Academic Clinical Lecturer in Rheumatology Arthritis Research UK Centre for Epidemiology, University of Manchester Muriel Green Patient Representative Jo Ledingham Consultant Rheumatologist Queen Alexandra Hospital, Portsmouth Involvement and affiliations of stakeholder groups The GWG was composed of rheumatology consultants from various clinical backgrounds, rheumatology specialty trainees, rheumatology nurse specialists and a patient representative. All members contributed to the development of key questions on which to base the search strategy, guideline content, recommendations and strength of agreement (SOA). Rigour of development This guideline has been developed in line with BSR’s guideline protocol. A comprehensive literature search was undertaken by two reviewers, using MEDLINE, Cochrane, PubMed and EMBASE databases with specific search terms (Table 3). The reference lists of retrieved articles were manually searched for additional papers and these were included if appropriate. All searches were performed up to the end of June 2016. Abstracts from BSR, EULAR and ACR annual conferences up to and including EULAR 2016 were also included. Table 3 Search terms used for literature review Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Table 3 Search terms used for literature review Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Topic Search terms used in addition to either: ‘Rheumatoid + arthritis’, ‘Ankylosing spondylitis’, ‘Seronegative + arthritis’, ‘Psoriatic arthritis’, ‘Seronegative + spondyloarthropathy’, ‘Spondyloarthropathy’ AND one of Abatacept Adalimumab Certolizumab Etanercept Golimumab Inflximab Rituximab Tocilizumab Ustekinumab TNF TNF inhibitor TNF agent Anti-TNF Non-anti-TNF Biologic* Bacterial infection Infec* Sepsis Septic Bacteria* Listeria Salmonella Campylobacter Escherichia coli E. Coli Bacillus cereus Staphylococc* Streptococc* Brucella Clostridium Pneumocystis PCP Mycobacterial infection Mycobacteri* Tuberculosis Mycobacterium MTB TB HIV infection HIV infect* AIDS Kaposi sarcoma Retroviral positive Hepatitis Hepatitis Viral infection Varicella Herpes EBV CMV HPV Cytomegalovirus Epstein Barr Virus HSV VZV Varicella Zoster Fungal infection Fung* Histoplasmos* Aspergillus Coccidiomycosis Malignancy Malignancy Pre-malignant Cancer Lymphoma Lung cancer Bowel cancer Non-melanoma skin cancer Tumour Tumor Carcinoma in situ OR CIS Cervical* OR CIN Barrett* Heart failure Heart failure Cardiac failure Ischaemic heart disease Ischaemic heart disease Ischemic heart disease Myocardial infarct* Coronary artery bypass graft NSTEMI STEMI Acute coronary syndrome Respiratory disease Interstitial lung disease Fibrosis Pulmonary fibrosis Uveitis Uveitis Drug induced uveitis Demyelinating disease Demyelinat* Neuro* Optic neuritis Multiple sclerosis Diverticular disease Diverticul* Vaccinations Vaccin* Vaccine Pneumococcal vacc* Influenza vacc* Singles vacc* Hepattiis vac* Monitoring Monitor* Test* Connective tissue disease Drug induced vasculitis Drug AND induced AND lupus Drug induced lupus Haematological disorders Anaemia Neutropenia Pancytopenia Aplastic anaemia Lymphopeni* Thrombocytopeni* Psoriasis Drug induced psoriasis Peri-operative period Postoperative infection Surgery + infection Other terms Elderly Geriatric* Care of the elderly Mortality Safety Two thousand eight hundred and sixty-nine articles were identified from the literature search; after removal of duplicates, 560 were eligible for detailed review. Two reviewers independently extracted information from relevant papers using data extraction tables. Only articles in the English language containing information on the safety of biologic therapies were included. Two hundred and eighty-nine articles were finally included in the guideline. The guideline was developed and drafted via a series of telephone conference calls and face-to-face meetings, using the retrieved literature to underpin and facilitate discussions. Due to the breadth of the guideline, designated members of the GWG were divided into sub-groups to lead on specific sections of the guideline. One subgroup led the anti-TNF section, another the RTX and abatacept (ABA) section, and the third group led the TCZ and ustekinumab (UST) sections. Grading the evidence The GRADE method was used to assess the quality of evidence and the strength of recommendation [7]. Accompanying each recommendation in this guideline, in brackets, is the strength of recommendation, quality of evidence and SOA. Each subgroup produced GRADE scores for their sections, which was then distributed to and ratified by the entire GWG. Strength of recommendation Using GRADE, recommendations were categorized as either strong (denoted by 1) or weak (denoted by 2), according to the balance between benefits and risks. A strong recommendation was made when the benefits clearly outweigh the risks (or vice versa). A weak recommendation denotes that the benefits are more closely balanced with the risk or more uncertain. Quality of evidence Using the GRADE approach, the quality of evidence was determined as either high (A), moderate (B) or low/very low (C) reflecting the confidence in the estimates of benefits or harm. High quality (A): typically generated from well-conducted meta-analyses, randomized controlled trials (RCTs) or other overwhelming evidence (such as large, well-executed observational studies with a low risk of bias). Further research is very unlikely to change confidence in the estimate of effect. Moderate quality (B): usually from randomized controlled trails or observational studies with important limitations. Further research is likely to have an important impact on and may change the estimate of effect. Low quality (C): usually from observational studies, or randomized controlled trials with major limitations. Further research is very likely to have an important impact on the confidence in the effect estimate and is likely to change the estimate. Very low quality evidence is usually derived from observational studies with serious limitations or from non-systematic observations (such as case reports and case series). SOA Each draft recommendation was evaluated by all members of the GWG. Based on the strength of recommendation and level of evidence, each recommendation was subject to a vote by all members of the GWG; a scale of 1 (no agreement) to 10 (complete agreement) was used. Only recommendations with a mean SOA score of ⩾7 plus ⩾75% respondents scoring ⩾7 were included. The SOA is presented next to the GRADE score for each recommendation as a percentage (e.g. 100% would imply all responses were 10/10). Limitations of this guideline The literature search excluded any articles not available in English language and any non-human studies. In addition, there were a very small number of articles identified through the search strategy that we were unable to obtain through university library channels. Plan for review In line with BSR’s guideline protocol, this guideline will be updated in 3–4 years, but if there is a significant change in the evidence base then an earlier update may be undertaken. The guideline To date, most long-term observational studies have focused on the safety of first generation anti-TNF agents (INF, ETN and ADA) in RA. In some areas, there is an increasing body of evidence regarding the safety of non-TNF biologic agents; however, there remains a paucity to guide many clinical scenarios. Where appropriate the evidence underpinning our recommendations has been divided into two sections: anti-TNF biologics and non-anti-TNF biologics. Generic recommendations (i) The decision to initiate a biologic should be made in conjunction with the patient/carer and initiated by an expert in the management of rheumatic disease (grade 1C; SOA 99%). Biologic therapy for IA can be prescribed when patients meet the respective NICE recommendations. As NICE restrict eligibility and there are potential risks (as discussed through this document), as well as benefits from biologic therapies, decisions to initiate therapy should be made by a consultant rheumatologist. Following national initiatives and guidance, patients and/or their carers should be actively involved in the decision making processes. (ii) Patients should be provided with education about their treatment to promote self-management (grade 1B, SOA 99%). A Cochrane review in 2002 demonstrated that education had a positive effect in terms of both patient reported outcome and objective measures of clinical response; however, the benefits were not observed during a longer duration of follow-up [8]. The Department of Health has estimated that the average cost of education and self-management is £125/person and would save costs of £244/person on average [9]. Rheumatologists should therefore offer patients with IA the opportunity to discuss their condition and the risks and benefits of treatments both at diagnosis and throughout the course of their disease. Patients with IA should be offered verbal and written information to improve their understanding of their specific condition and its management. For those patients who would like further information, participation in existing educational activities including self-management programmes is recommended [10]. (iii) Patients should be assessed for co-morbidities as these may influence biologic choice, including evaluation for respiratory disease and screening for infection (grade 1C, SOA 99%). Comorbid conditions such as respiratory disease and underlying infection have significant implications for both csDMARD and biologic prescribing. Patients should be assessed for such comorbidities at baseline and reviewed regularly (at their annual review and upon changes in treatment as a minimum). Further information is detailed later in this document. (iv) Patients should have direct access to their specialist centre [e.g. via an advice line (Helpline)] for advice within one working day (grade 1C, SOA 98%). The NICE quality standard (QS33) for the management of RA states that patients experiencing flares in their condition or a drug-related side effect should be offered, and be able to obtain, direct advice from their rheumatology service [11]. Advice should be available within one working day and when required prompt action should be taken to ensure patients’ safety and optimize management of their RA. The principles behind this recommendation should also be applied to the other IA problems covered by this guideline. (v) Clinicians should be encouraged to recruit patients to the appropriate biologic therapy registry, with patient consent (grade 1C, SOA 98%). Although RCTs are considered the gold standard for the demonstration of biologic therapy efficacy, they are limited in their use for collecting safety data. There are several reasons for this—small patent numbers in RCTs make the detection of rare side effects difficult, short duration of follow-up leads to challenges in the detection of delayed side effects, homogeneous patient recruitment may not be representative of real life, exclusion criteria hamper recruitment of patients with important co-morbidities and RCTs are generally powered to detect efficacy outcomes, rather than significant safety signals. It is important that patients are recruited to the appropriate national biologic therapy registries [such as the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and the British Society for Rheumatology Biologics Register for AS (BSRBR-AS)], to enable long-term collection of real-life safety data on a large scale. For patients prior to treatment with a biologic Pre-treatment investigations Baseline assessment for all should include (grade 1C SOA 98%): laboratory evaluation of full blood count (FBC), creatinine/calculated glomerular filtration rate (GFR), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), albumin, tuberculin skin test (TST) or interferon-gamma release assay (IGRA) or both as appropriate, hepatitis B and C serology, and a chest radiograph. Baseline assessment in both csDMARD and biologic prescribing acts as a screening tool for underlying conditions such as lung, renal or hepatic disease and also provides a reference point for future comparison. While the pick-up rate of routine investigations in a healthy individual is low, there is an increased incidence of significant abnormalities in RA patients, due to their increased overall burden of comorbidities [12]. Screening for TB and hepatitis are discussed in more detail in the mycobacterium tuberculosis and hepatitis sections. Patients receiving RTX: baseline immunoglobulins (IgA, IgG and IgM) are recommended prior to initiation (grade 1A, SOA 98%). Few patients would be expected to have low Ig levels before the start of RTX therapy: ⩽2.2% in one study of 3595 patients [13]. However, several studies have found that a low level of immunoglobulins, especially IgG, is associated with a higher risk of neutropaenia and infection in patients receiving RTX [13–16]. Patients receiving TCZ: a baseline lipid profile is recommended prior to initiation. If abnormal, lipid lowering treatment should be initiated as per local guidance (grade 2A, SOA 99%). Blockade of the IL-6 receptor by TCZ is associated with an increase in lipid parameters compared with baseline. Despite the increase in low-density lipoprotein (LDL)-cholesterol, trial data seem to indicate that the ratio of total cholesterol: high-density lipoprotein (HDL)-cholesterol remains unchanged [17]. A post hoc retrospective pooled analysis [18] of 3986 patients who received TCZ found 0.34 independently adjudicated major adverse cardiovascular events (MACE) per 100 patient-years in 24 weeks of follow-up. The study found an association between baseline total cholesterol: HDL-cholesterol ratio and MACE, with poor RA disease control associated with a higher risk of future MACE. Pre-treatment management of and screening for co-morbidity Infection In general (recommendations for Mycobacterium tuberculosis, viral hepatitis and HIV are discussed separately): (i) Biologics should not be initiated in the presence of serious active infections (defined as requiring intravenous antibiotics or hospitalization (grade 1B, SOA 98%). Patients with RA, especially those with severe disease and extra-articular manifestations, have a higher risk of infection, estimated at double the risk of the general population [19]. Patients with severe disease, who already have a higher risk of infection, are more likely to receive biologic therapies; hence when evaluating the association between a drug and infection risk, it can be difficult to determine whether the infection risk is drug-related or is in keeping with that expected for the disease severity. The most recent Cochrane review of 106 controlled trials, including 42 330 patients with RA, found that patients receiving standard dose biologic therapies were at a 27% higher odds of serious infection compared with controls [20], findings consistent with the same author’s earlier Cochrane review [21]. Anti-TNF biologics Of all the studies evaluating the safety of biologic therapies, those investigating the association between anti-TNF agents and infection risk are the most numerous, the majority of which have focused on the use of the first generation anti-TNF's (INF, ETN and ADA) in RA. Although there have been some inconsistencies between the results from various analyses, the majority of studies have found a significant association between anti-TNF drugs in patients with RA and a higher risk of serious infection. Observational data from several national registries, including the BSRBR-RA [22], US Coronna registry [23] and the Spanish BIOBADASER 2.0 [24], have shown a significant positive association between anti-TNF agents and serious infection in RA. BSRBR-RA included data from 11 798 RA patients receiving ADA, ETN or INF, and 3598 csDMARD controls. The incidence of serious infection in the TNF group was 4.2/100 patient-years vs 3.2/100 patient-years in the DMARD group. The adjusted hazard ratio for serious infection in the TNF group was 1.2 (95% CI: 1.1–1.5) [22]; the highest risk of infection was in the first 6 months of treatment. This evidence has furthermore been supported by results from recent meta-analyses by Bernatsky et al. [25] and Michaud et al. [26], which both reported an approximate 1.4-fold increased risk of infection in RA patients treated with anti-TNF agents compared with csDMARD controls. There is a relative paucity of long-term observational data investigating the risk of infection in other types of IA, such as AS and PsA. A Cochrane review [27] and a meta-analysis of RCTs [28] in AS, and two meta-analyses of RCTs in PsA [29, 30] found no elevated risk of serious infection with anti-TNF therapy used in these conditions; however, the analyses included a low number of RCTs compared with the RA data (between 6 and 21 studies) and event rates of infection were low making the studies underpowered to show a significant association. Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. Non-anti-TNF biologics Comparatively fewer studies have examined the association between serious infection and non-anti-TNF biologic therapy. Longer term data on infection risk with these drugs is required, and until such information is available it would be prudent to take similar precautions with these drugs as with anti-TNF therapy. With regards to RTX, the most recent observational data, from the US Coronna registry [31], showed similar rates of infection in 265 patients receiving RTX compared with 739 patients receiving anti-TNF therapy (event rate of 37.7 vs 41 events per 100 person-years). However, a previous RCT meta-analysis of the risk of infection with RTX [32], which analysed data from three studies, did not show an increased risk of serious infection in patients receiving RTX compared with placebo. An observational French study found that the risk was highest in the first 6 months after commencing treatment [14]. Long-term safety after 9 and 11.5 years was assessed and was deemed no higher than MTX and placebo [13, 33]. TCZ has been shown to increase the risk of serious infection in patients with RA. The risk is likely to be similar to anti-TNF therapy although long-term comparative data are not available. In the ADACTA study [17], which was a double-blinded parallel arm trial comparing the efficacy and safety of ADA and TCZ as monotherapy, the rates of serious infection were similar in both groups (3%). A systematic review by Campbell et al. [34] showed a slightly increased risk of infection with TCZ 8 mg/kg compared with controls, but similar to rates of infection with other biologics. Infection risk with the lower dose of 4 mg/kg was lower. Yun et al. [35] conducted a retrospective cohort study using Medicare data including 23 784 patients on five anti-TNFs as well as ABA, RTX and TCZ, looking at incidence of hospitalized infection. The likelihood of being admitted to hospital with an infection on TCZ was lower than for INF, RTX and ETN, but higher than for ABA. A study that pooled data from the double-blind and open-label phases of five clinical trials of s.c. ABA reported an incidence rate (IR) of serious infections of 1.79 (95% CI: 1.42, 2.24), which did not significantly change over time (mean exposure 27.3 months) [36]. This is in keeping with previous data for i.v. ABA [37]. A 2009 meta-analysis suggested that the risk of serious infections during ABA treatment [odds ratio (OR) = 1.35, 95% CI: 0.78, 2.32 vs placebo) is not significantly increased [32]. At present there is a lack of long-term observational data concerning the risk of serious infection with UST. Given the theoretical risks with all biologics and the risk presented with the longer established treatments, the advice is that biologics should not be started in the presence of serious infection. (ii) Use biologics with caution in patients at high infection risk after discussing risks and benefits (grade 1B, SOA 99%). Several observational studies have identified factors that may increase an individual’s risk of infection with biologic therapies. This additional risk may be unacceptable to patients, and needs to be carefully weighed up against the perceived benefits when prescribing biologic therapies. Anti-TNF biologics Comorbidities such as chronic obstructive pulmonary disease (COPD) [24, 38], interstitial lung disease (ILD) [24] and renal failure [24] have been associated with higher rates of serious infection in RA patients receiving anti-TNF agents. Concomitant steroid use has also been repeatedly associated with higher infection risk [24, 38]; however, in many patients the introduction of biologic therapies will enable reduction or cessation of steroid exposure. Although some studies have identified older age as an independent risk factor for serious infection with anti-TNF drugs, two recent studies have been reassuring. Data from BSRBR-RA showed that while older patients (aged >75 years) had a higher absolute risk of infection, there was no increased relative risk of serious infection on anti-TNF agents [22]. Similarly, no significant difference in serious infection rate was observed in a Swiss cohort of RA patients receiving anti-TNF therapy when divided into those above or below 65 years of age [39]. There is a lack of data concerning risk factors for serious infection in patients with other types of IA treated with anti-TNF therapy. Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. Non-anti-TNF biologics The French AIR Registry, which analysed data from 1303 RTX-treated RA patients, found that rates of severe infection were significantly higher in those with chronic lung disease and/or cardiac insufficiency (OR = 3.0, 95% CI: 1.3, 7.3), extra-articular involvement (OR = 2.9, 95% CI: 1.3, 6.7) and low IgG level (<6 g/l) before initiation of RTX treatment (OR = 4.9, 95% CI: 1.6, 15.2) [14]. There is a lack of long-term observational data concerning risk factors for serious infection in patients with other types of IA treated with non-anti-TNF therapy; especially as UST is the only biologic within this category with a non-RA licence (for PsA). Given the theoretical risks, the advice substantiated by evidence for RA should be applied to patients with other IA problems. (iii) Consider using ETN or ABA as a first-line biologic therapy in patients at high risk of infection (grade 2B, SOA 94%). Anti-TNF biologics There is some evidence from both RCTs and observational studies to suggest that the risk of serious infection may be lower with ETN compared with other anti-TNF agents. A meta-analysis of 44 RCTs found the odds of serious infection with anti-TNF agents to be lowest for ETN (pooled OR = 0.73, 95% CI: 0.45, 1.20 vs 1.42, 95% CI: 1.13, 178) for all anti-TNF agents combined) [26]. Several observational trials have also observed lower rates of serious infection with ETN, including a US claims database [40], BSRBR-RA [22], the Dutch DREAM registry [41], the Australian ARAD database [42] and the Italian GISEA registry [43]. Non-anti-TNF biologics A low incidence of serious infection with ABA has been reported in long-term observational studies [36, 37] and a meta-analysis [44]. In the AMPLE study [45], an RCT comparing the safety and efficacy of s.c. ABA vs ADA in patients with RA over 2 years, numerically lower rates of infection were observed in the ABA arm (3.8%) compared with ADA (5.8%); however, this study was not powered to detect a significant difference in infection rates. Mycobacterium tuberculosis   screening for TB before starting a biologic (i) All patients require screening for tuberculosis (TB) before starting a biologic (grade 1B, SOA 98%). Anti-TNF biologics The increased risk of active TB and reactivation of latent TB associated with anti-TNF treatment, as demonstrated in a number of studies, has led to a requirement to screen for active and latent TB in patients before anti-TNF treatment is given [46–54]. A 2014 meta-analysis of RCTs [55] confirmed an increased risk of mycobacterial infections in patients on biologics (OR = 3.73, 95% CI: 1.72, 8.13) and that the risk varied with different agents [see recommendation (iii) for latent and reactivated TB). Non-anti-TNF- biologics Relatively few large long-term studies have investigated the risk of TB reactivation with non-anti-TNF biologics. Although the results from studies appear reassuring for this group of drugs with regards to TB reactivation, until more data are available, the advice given for anti-TNF therapy should be considered. Data regarding the risk of reactivating TB with RTX look reassuring. The largest study to date, which combined data from clinical trials and long-term extension studies, reported only two cases of pulmonary TB among 3595 RA patients who had received RTX over a mean follow-up of 11 years [12]. A Taiwanese study of 56 patients (43 patients were presumed to be without latent TB infection, seven patients had latent TB and six patients had anti-TNF-associated TB) found that over a 1 year period of RTX therapy, no patient developed active TB [56]. A 2014 review [57] found no cases of active TB recorded in patients with RA and other rheumatic conditions treated with RTX and ABA, and in fact, argued against pre-screening for TB in patients receiving these two biologics. Koike et al. [58] published safety data from an all-patient post-marketing surveillance programme in Japan in 2011. Out of a total of 3881 patients treated with TCZ (1794 patient-years), four cases of active TB were identified (0.22/100 patient-years). Cantini et al. [57] observed eight cases of active TB in 21 trials of patients with RA receiving TCZ. Combined data derived from five RCTs of s.c. ABA in RA found that TB occurred rarely, with an IR of 0.09 (95% CI: 0.04, 0.25) among 1879 patients [36]; this is lower than that observed for other biologics [59]. Regarding UST, a safety analysis of 3117 patients from five phase III clinical trials across the USA, Europe and Asia identified 167 patients with latent TB. These patients received isoniazid prophylaxis prior to receiving treatment with UST. No cases of active TB resulted in the 12-week treatment period. However, cases of TB have been reported in patients on UST [60]. Screening for TB should include checking for previous TB exposure and treatment, performing a clinical examination, chest X-ray (CXR) and either a TST or an IGRA or both, as appropriate (grade 2C, SOA 98%). For patients on immunosuppressive therapy with a normal CXR, a TST is not helpful, as immunosuppression hinders interpretation (grade 2C, SOA 98%). Patients with an abnormal CXR, previous history of TB or TB treatment should be referred to a specialist with an interest in TB prior to commencing a biologic (grade 2C, SOA 99%). Immunocompromised patients screened for latent TB with an IGRA alone or together with a TST and found to have a positive result in either test should be considered for treatment prior to starting biologic therapy (grade 2C, SOA 96%). Investigations for latent TB infection in a person exposed to M. tuberculosis but without active signs of TB are based on the TST or IGRA. The TST involves an intradermal injection of purified protein derivative and measurement of skin erythema and induration, which corresponds to a delayed-type hypersensitivity reaction in patients with previous exposure to TB (including latent TB). Previous vaccination with BCG will also cause a skin reaction but of a lower magnitude than after exposure to TB. IFN-γ release assays [two commercially available: QuantiFERON-TB Gold In-Tube assay (QFT) and T-SPOT.TB] measure IFN-γ release by T cells in blood samples mixed with mycobacterium TB antigens. QFT measures the IFN-γ concentration (IU/ml) using ELISA technology, whereas T-SPOT.TB reports the number of T cells producing IFN-γ (spot forming cells). T-SPOT.TB is also known as the TB ELISPOT (enzyme-linked immunospot assay). The TST and IGRA measure the response of T cells to TB antigens. As a false-negative result occurs in 20–25% of patients with active pulmonary TB, these tests should not be used alone to exclude a diagnosis of active TB. Identifying latent TB in patients due to start biologic treatment has been problematic as the TST and, to a lesser extent, IGRA assays are thought to be less reliable in immunosuppressed patients [61, 62]. Most studies comparing TST with IGRA performance in immunosuppressed populations suggest sensitivity and specificity of IGRA is superior to TST [63–66] but not all studies support this [67, 68]. In addition, IGRA positivity has been shown to be more closely related to TB risk than positive TST results. A recent meta-analysis of the performance of the two available IGRA tests (QFT and T-SPOT.TB/ELISPOT) vs TST in patients with rheumatic disease before starting biologic therapy reported pooled concordances between the QFT assay and TST of 72% (65–78%) and between T-SPOT.TB and TST of 75% (67–83%). It also showed that IGRAs have a lower false-negative and false-positive rate, compared with TST, particularly in patients treated with corticosteroids and those with a history of BCG vaccination [69]. Although two IGRA tests are commercially available, based on the present data, there is no robust evidence to recommend a preference for one over the other. The true sensitivity or specificity of the TST or IGRA is uncertain because a gold standard test for the presence of latent TB is currently unavailable. However, a closer correlation has been found between IGRA and risk factors for latent TB infection, including personal history, TB contact history and a suggestive CXR [65, 70]. Some studies have suggested using only an IGRA when screening for latent TB because in immunosuppressed patients, it is more specific than the TST and may therefore reduce the proportion of patients needing chemoprophylaxis [71, 72]. However, observational studies suggest that, given the discordance between these two types of test, use of one test may miss some patients with latent TB who would be identified by an alternative test [70, 73, 74]. Observational studies support the use of combination testing [61, 75]. Current international guidelines support screening all patients for latent TB before starting biologic therapy. However, given the inconclusive evidence available, the optimum screening strategy is unclear, with disagreement on whether to use an IGRA or TST, or both. In the UK, the 2016 guidance from NICE [76, 77] recommends testing all immunocompromised patients for latent TB with an IGRA alone or together with a TST—a positive result in either test should prompt consideration for treatment. However, the WHO recommends using either test and the European Centre for Disease prevention and control recommends using both [78, 79]. Screening with TST or IGRA is unhelpful in patients who have had treatment for active or latent TB. In this situation a chest X-ray and sputum examination will be sufficient, with input from a TB specialist. Treatment of latent TB should be initiated after the possibility of TB disease has been excluded. The Centers for Disease Control and Prevention recommends treatment for latent TB in individuals with a positive IGRA result or a TST reaction of ⩾5 mm, in immunosuppressed individuals (e.g. those on >15 mg/day of prednisolone for 1 month or longer and taking anti-TNFs), HIV-infected individuals, patients with organ transplants and individuals with fibrotic changes on CXR consistent with prior TB (cdc.gov/tb). Treatment is also recommended in individuals with a positive IGRA or a TST reaction of ⩾10 mm, including recent immigrants (<5 years) from high-prevalence countries, injection drug users and residents and employees in high-risk settings (e.g.: nursing homes and hospitals). In addition, individuals with no known risk factors for TB may be considered for treatment of latent TB is they have a positive IGRA or a TST 15 mm or more. Targeted TB testing programmes are recommended among high-risk groups, with appropriate follow-up care. The four treatment regimens for latent TB infection use isoniazid, rifapentine or rifampicin, and consultation with a TB expert is advised if the known source TB infection has drug-resistant TB. TB drug treatment for the prevention of TB, also known as chemoprophylaxis, can reduce the risk of a first episode of active TB occurring in people with latent TB. Current evidence suggests that decisions about chemoprophylaxis should be based on the results of the TST and an IGRA. If either test is positive, it would be appropriate to treat with chemoprophylaxis while monitoring carefully for treatment-related side effects [76, 80, 81]. The majority of potential recipients of anti-TNF medication will have a normal CXR and will have been on immunosuppressive therapy thus hindering the interpretation of latent TB testing [82–84]. In these individuals, an individual risk–benefit calculation is recommended. If the annual risk of TB on anti-TNF treatment is higher than the risk of anti-TB therapy-induced hepatitis, then the risk–benefit analysis favours chemoprophylaxis; if lower, the risk–benefit calculation favours observation and investigation of symptoms [80]. The two chemoprophylaxis regimens commonly used in the UK are isoniazid for 6 months (6H) or rifampicin plus isoniazid for 3 months (3RH). Latent and reactivated TB (i) Patients should be treated with prophylactic anti-TB treatment prior to commencing a biologic (grade 1B, SOA 99%); therapy may be commenced after completing at least 1 month of anti-TB treatment and patients should be monitored every 3 months (grade 2C, SOA 91%). (ii) Patients who have had previous inadequate treatment for active TB should be investigated for active TB. In these individuals even when active disease has been excluded, the annual risk of TB (reactivation) is much higher than the general population rate, so the risk–benefit analysis favours chemoprophylaxis (grade 1C, SOA 98%). The above recommendation i and ii are based in part on expert opinion in the NICE guideline ‘Tuberculosis’ [76, 77] and the 2005 British Thoracic Society (BTS) guidelines [80]. While there is a consensus that all patients with latent TB should receive anti-TNF chemoprophylaxis prior to commencing a biologic, there is a lack of data regarding the point at which biologic therapy can then be started. The BTS guidelines suggest that a patient should receive a full course of anti-TB treatment before starting a biologic; however, while this is ideal, 3–6 months’ delay is likely to be unacceptable for the majority of patients due to the severity of their rheumatic disease. The BTS guidelines have not been updated since 2005, and since then clinical experience has developed. Current expert opinion suggests that biologic therapy can be started after competing at least 1 month of anti-TB therapy. This is primarily to ensure that anti-TB treatment is tolerated, especially in what is often a population over 55 years of age. Patients should be monitored every 3 months with close involvement with a TB specialist throughout. Chemoprophylaxis for TB itself carries a small risk, with drug-induced hepatitis being the main issue, increasing with age and associated with increased mortality. It is important to exclude active TB disease before chemoprophylaxis is given, as there are concerns that single agent chemoprophylaxis given when active disease is present could lead to the development of drug resistance [67]. Two preventative treatment regimens in common use in the UK are isoniazid for 6 months (6H), or rifampicin plus isoniazid (3RH) for 3 months. Rifampicin and pyrazinamide for 2 months (2RZ) was a regimen used in the USA [85], but it had a very high rate of hepatitis with a number of fatalities reported [86]. Consequently, the choice of regimen is between 6H, which has a lower hepatitis rate, and 3RH, which is of shorter duration and with which there is thought to be better adherence and also less risk of drug resistance developing if active disease is present [87]. (iii) As TB reactivation risk is higher with anti-TNF mAb drugs (notably ADA and INF) than for ETN, consider ETN in preference for those who require anti-TNF therapy and are at high risk of TB reactivation (grade 1B, SOA 99%). The risk of TB reactivation appears higher with the mAb INF and ADA than for ETN [45, 46, 48–51, 53], a finding confirmed with registry data [47, 52]. In the BSRBR-RA the rate of TB was higher with ADA (144 events/100 000 person-years) and INF (136 events/100 000 person-years) than with ETN (39 events/100 000 person-years) [47]. After adjustment, the incidence-rate ratio (IRR) compared with the ETN-treated patients was 3.1 (95% CI: 1.0, 9.5) for INF and 4.2 (95% CI: 1.4, 12.4) for ADA. In light of this, we suggest that ETN should be considered as a first-line anti-TNF treatment in patients at high risk of reactivation of latent TB. The incidence of TB for the newer anti-TNFs (certolizumab pegol (CZB) and golimumab (GOL)) is less well documented. Cantini et al. [57] assessed the safety data of both GOL and CZB in patients with rheumatic disease and identified 8 cases of active TB in 3387 patients with rheumatic disease treated with GOL (7 of the 8 TB cases occurred in TB-endemic countries, where the TB incidence is 50–299 cases per 100 000 inhabitants) and 10 cases of active TB in 3167 patients with RA treated with CZB. Active TB (i) Patients with evidence of active TB should be treated before starting a biologic (1C, SOA 99%); therapy may be commenced after completing at least 3 months of anti-TB treatment and there is evidence that the patient is improving with evidence of culture negativity (grade 2C, SOA 91%). Full compliance with anti-TB treatment should be supervised by a thoracic physician or infectious disease specialist, and ideally continued until the drug susceptibility profile of the organism in those with positive cultures is known. Furthermore, it would be preferable to delay anti-TNF treatment until completion of a full course of anti-TB treatment (this is based on the expert opinion from the BTS [80]). HBV and HCV (i) Patients should be screened for hepatitis B and C viral infection (grade 1C, SOA 98%). Hepatitis B and C are blood-borne infections of the liver that can result in chronic liver disease and hepatocellular carcinoma. NICE currently recommends that all people who are at increased risk of hepatitis B and C infection are offered testing and vaccination [NICE Public health guideline (PH43): Hepatitis B and C testing: people at risk of infection]. Examples of people at increased risk of hepatitis B and C infection are shown in Table 4. Table 4 Risk factors for hepatitis B and C infection People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders Table 4 Risk factors for hepatitis B and C infection People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders People at higher risk of hepatitis B and C infection People born or brought up in a country with an intermediate or high prevalence of chronic hepatitis B or C. This includes all countries in Africa, Asia, the Caribbean, Central and South America, eastern and southern Europe, the Middle East and the Pacific islands People who have ever injected drugs Men who have sex with men (particularly, HIV-positive men who have sex with men are at a greater risk of hepatitis C) People in close contact with someone known to be chronically infected with hepatitis B or C Prisoners, including young offenders For hepatitis B in particular, additional groups at increased risk include people who may have been exposed to sexually acquired infection. For hepatitis C in particular, additional groups at increased risk include people who received a blood transfusion before 1991 or blood products before 1986, when screening of blood donors for hepatitis C infection and heat treatment for inactivation of viruses were introduced. Screening for HBV should include HBsAg and antibodies to hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs), followed by HBV DNA test if HBsAg or anti-HBc are positive. These results will dictate the level of monitoring and prophylaxis, which varies between occult HBV infection (i.e. HBsAg negative and anti-HBc positive or anti-HBs positive) and overt HBV infection (i.e. HBsAg positive). Screening for HCV infection is at present based on the detection of anti-HCV antibodies. If anti-HCV antibodies are detected, HCV RNA, or alternatively HCV core antigen if HCV RNA assays are not available, should be determined to identify patients with on-going infection. The prevalence of hepatitis B and C as comorbidities in patients with RA varies across the world, due to epidemiological variations in risk factors. In a French cohort of patients with early RA, the seroprevalence of HBV and HCV infection was reported as 0.12 and 0.86%, respectively [88]. A higher seroprevalence of 3% for HBV and 2% for HCV infection was recently reported in COMORA, an international cross-sectional study of comorbidities in RA [12]. Acknowledging that there are now effective therapies for viral hepatitis, there is a strong rationale for offering screening to all patients prior to commencing immunosuppression. (ii) In patients who are HBV positive, a risk–benefit assessment should be undertaken, as biologics may be safe if appropriate anti-viral treatment is given, working closely with a hepatologist (grade 1C, SOA 99%). Anti-TNF biologics There are a few medium-quality systematic reviews of observational studies evaluating the risk of reactivation of hepatitis B in patients with HBV infection treated with anti-TNF therapy in the context of an IA. A systematic review [89] included 536 patients with occult or overt HBV infection and an underlying rheumatological or dermatological condition treated with INF, ETN or ADA. The pooled estimate of HBV reactivation was 4.2% (95% CI: 1.4, 8.2%) for all patients. When the meta-analysis was restricted to patients with RA, the pooled prevalence of HBV reactivation was slightly lower at 3.3% (95% CI: 0.7, 7.5%). HBV reactivation rates were higher in the overt HBV group vs the occult HBV group (15.4 vs 3%). These reactivation rates were similar to those reported in two other systematic reviews [90, 91]. In a case–control study of RA patients with occult HBV infection [92], the use of anti-TNF therapy was more frequent in those with HBV reactivation than not (86 vs 36%) P = 0.008, hazard ratio (HR) = 10.9 (95% CI: 1.4, 87.7). Patients who are HBsAg negative and anti-HBc positive (or anti-HBs positive) are nonetheless deemed to have an occult infection as low-level HBV replication may persist, with detectable HBV DNA in the liver but generally not in the serum. The clinical relevance of this is unclear although immunosuppression may lead to HBV reactivation in these patients [93]. Therefore, where a decision is made to proceed with an anti-TNF agent on risk–benefit analysis, a rheumatologist should work closely with a hepatologist to ensure liver disease is fully assessed at baseline then monitored on treatment. Several international groups have recommended that patents with overt HBV receiving immunosuppressive medicines should receive anti-viral prophylaxis [93, 94]. Perez-Alvarez et al. [95] found that of the reported cases of overt HBV patients treated with anti-TNF agents, HBV reactivation was 2.5-fold higher in patients not receiving prophylaxis (64 vs 26%). Of the 82 patients with overt HBV treated with an anti-TNF, five had acute liver failure, one required a liver transplant and four died. The European Association for the Study of the Liver suggest overt HBV candidates for immuno-suppressive therapy should be tested for HBV DNA levels and should receive pre-emptive anti-viral treatment during therapy (regardless of HBV DNA levels) and for 12 months after cessation of therapy. Occult HBV patients with detectable serum HBV should be treated like overt HBV patients [93]. Non-anti-TNF biologics In patients receiving RTX, re-activation of HBV in patients with occult hepatitis B (HBsAg negative; anti-HBc positive) has been reported [96], with the authors suggesting that patients with sero-positivity for either occult or overt hepatitis B should be referred to a hepatologist. A systematic review by Campbell et al. [34] found no increased risk of hepatitis B reactivation with TCZ; however, the number of cases was low and further long-term data are required. There are no data concerning the use of ABA and HBV. There are very few published data on the use of UST in patients with chronic hepatitis B. In a small observational cohort of 14 with hepatitis B serology treated with UST, no increase in viral load was seen in patients who had received prophylaxis [97]. However, two out of seven patients (29%) who did not receive prophylactic anti-viral therapy were noted to have an increase in viral load. If clinically indicated, UST may be used in patients with hepatitis B following prophylactic anti-viral treatment. In conclusion, given the theoretical risks and lack of high-quality data, we recommend that the recommendations supported by evidence for anti-TNF therapy should be applied to the non-anti-TNF biologics. (iii) Studies to date suggest that though biologic therapy does not appear to have a detrimental effect on HCV infection, it should continue to be used only with caution in such patients, following a risk–benefit decision made with a hepatologist (grade 1C, SOA 96%). There are limited data assessing the effect of immunosuppression on hepatitis C. Anti-TNF biologics A prospective RCT of 29 patients receiving ETN, MTX or both found that AST, ALT and HCV viral load did not significantly change across all three arms up to 54 weeks [98]. Three case series totalling 26 patients with IA and chronic HCV treated with either ETN, ABA or INF followed up to 36 months, did not show any significant increase in HCV titre over a 36-month follow-up [99–101]. One patient with both HBV and HCV had breakthrough HCV requiring treatment [99]. Studies to date continue to show that that anti-TNF therapy does not have a detrimental effect on HCV infection. Despite absence of high-quality evidence, in an era of advances in therapeutic options the advice remains to aim for viral control before immunosuppression. Non-anti-TNF biologics There is some evidence that the viral load of hepatitis C is increased after RTX treatment compared with anti-TNF therapy, but this was from a small study [96]. There are insufficient data to recommend the use of TCZ, ABA and UST in patients with chronic hepatitis C infection. A systematic review by Campbell et al. [34] showed no increased risk of hepatitis C reactivation with TCZ; however, the number of cases was low and further long-term data are required. In a small observational cohort of four with hepatitis C serology treated with UST, no increase in viral load was seen in patients who had received prophylaxis [97]. HIV Risk factors for HIV infection should be documented prior to commencing a biologic and, if present, an HIV test should be performed (grade 2C, SOA 97%). If considering the use of biologic therapy in HIV positive patients, this should be discussed with an HIV specialist. It should be borne in mind that a reasonable benefit to risk ratio for HIV patients exists with anti-TNF therapy if HIV infection is controlled (CD4+ count >200 cells/mm3 and viral load undetectable) and anti-TNF is given in combination with highly active anti-retroviral therapy (grade 2C, SOA 99%). Individuals at risk of HIV are shown in Table 5. There is no evidence base to support the testing of all patients before commencing biologic therapy. The prevalence of HIV in most parts of the UK is low and the likelihood of a positive result in an individual without risk factors is very low. The recent NICE guideline NG60 [102] summarizes the groups in which an HIV test should be offered; it does not advise routine testing in all individuals prior to immunosuppressive agents, unless risk factors are present. Table 5 Risk factors for HIV infection Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Table 5 Risk factors for HIV infection Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Individuals at higher risk for HIV infection Individuals from a country or group with a high rate of HIV infection Men who disclose that they have sex with men, or are known to have sex with men, and have not had an HIV test in the previous year Trans women who have sex with men and have not had an HIV test in the previous year Individuals who report sexual contact (either abroad or in the UK) with someone from a country with a high rate of HIV Individuals who disclose high-risk sexual practices Individuals diagnosed with, or requests testing for, a sexually transmitted infection Individuals who report a history of injecting drug use Individuals who disclose that they are the sexual partner of someone known to be HIV positive or of someone at high risk of HIV (e.g. female sexual contacts of men who have sex with men) Anti-TNF biologics The only evidence surrounding the use of anti-TNF therapies for IA in HIV-infected individuals comes from individual case reports and one case series. These reports suggest that they can be used to successfully treat IA in HIV positive patients and are generally well tolerated, provided that HIV treatment is well established prior to anti-TNF therapy initiation and CD4 count is >200 cells/mm3. The largest study to date is a retrospective case series of eight American HIV positive patients receiving either ETN, ADA and INF for rheumatic conditions [103]; five patients were receiving concomitant highly active anti-retroviral therapy (HAART). Anti-TNF therapy was restricted to those with CD4 cell count >200 cells/ml and viral loads of <60 000 copies/ml at the initiation of the therapy Over a mean follow-up of 28.1 (range 2.2–55) months, anti-TNF therapy achieved good efficacy with no clinical adverse events attributed to anti-TNF treatment and no deterioration in CD4 count or viral load. There have also been several individual case reports on the use of anti-TNF agents in HIV positive patients with co-existent rheumatic disease. Most patients receiving concomitant HAART had good clinical outcomes [104–106]; the sole exception is a case report of an HIV patient with PsA in whom ETN had to be stopped due to recurrent infections [107]. Although this patient was receiving HAART, his CD4 count was significantly lower than other cases (<50 cells/mm3), which may explain the negative outcome. Non-anti-TNF biologics There is insufficient evidence to recommend the use of RTX, TCZ, ABA or UST in patients with HIV infection. Malignancy Biologic therapies should not be commenced in patients with clinical signs of, or under investigation for, malignancy (basal cell carcinoma excluded) (grade 1C, SOA 96%). Patients should be advised that there is no conclusive evidence for an increased risk of solid tumours or lymphoproliferative disease linked with biologic therapy, but that ongoing vigilance is required (grade 1A, SOA 99%). Anti-TNF biologics: overall malignancy There has long been concern regarding the possible association between biologic therapies and malignancy, indeed a 2006 meta-analysis of nine randomized controlled trials [108] found a 3-fold increase in the rate of malignancy with INF and ADA. Recent results from several further meta-analyses of both RCTs [26, 109–115] and observational studies [116, 117] have been reassuring and have failed to find a significant association between anti-TNF use and overall malignancy in patients with RA. Most observational studies using national registry data have also been reassuring; recent studies from BSRBR-RA [118], BIOBADASER [119] and German RABBIT [120] registries have all failed to show a significant association between anti-TNF use in RA and overall malignancy, with up to 52 549 patient-years exposure. In contrast, studies using the Swedish ARTIS [121] and Danish DANBIO [122] registries have reported higher rates of invasive cervical cancer and colon cancer, respectively, in anti-TNF-treated RA individuals compared with those receiving csDMARD. Interestingly in the DANBIO study, when comparing the anti-TNF-treated RA group against the general population this association was no longer seen. Few studies have looked separately at the AS and PsA anti-TNF-treated population with regard to malignancies. A 2009 meta-analysis of RCTs that included five PsA RCTs and 10 AS RCTs found no significant association [109]. Likewise, a study from BSRBR, which analysed data from 596 patients with PsA receiving anti-TNF and compared them with RF negative controls (as PsA patients not receiving anti-TNF are not included within this registry) found that the rates of new malignancies were not significantly different between the two groups [123]. Anti-TNF biologics: lymphoma Patients with RA are known to be at an increased risk of lymphoma compared with the general population independent of treatment; reported risk ratios have varied from 1.9 to 2.7 compared with the general population [124, 125]. As this risk is likely to be highest in those patients with more severe disease, it is important that disease activity is considered as a confounder when assessing any relationship between anti-TNF use and lymphoma in this group. Current data do not suggest that PsA or AS are associated with an inherent increased risk of lymphoma [126–128]. Since the last published guideline in 2009, eight further studies have been identified, including one Cochrane meta-analysis [21], three further RCT meta-analyses [110, 115, 129], one meta-analysis of observational studies [116] and three cohort studies (using the French RATIO [130], Danish DANBIO [122] and Swedish ARTIS [131] registries). Although two of these studies found a higher risk of lymphoma in RA patients receiving anti-TNF agents compared with the general population [130, 131], reassuringly none of them found a significant difference between rates of lymphoma in RA patients receiving anti-TNF therapy compared with control RA patients. Mariette et al. [130], in a cohort study using the French RATIO registry, found no increased risk of lymphoma in SpA patients receiving anti-TNF compared with the general population. Non-anti-TNF biologics There is much less long-term observational evidence evaluating the risk of malignancy with the non-anti-TNF biologics; however, findings to date have been reassuring. To date, there have been no safety signals for RTX, TCZ, ABA or UST in malignancy. Although there is no direct evidence that RTX is safe in malignancy, most long-term data have not shown an increase in risk [13, 33]. Recent data from a pooled case analysis of 1246 patients receiving RTX for >5 years found no increase in the rates of malignancy compared with the general US population or compared with published data in adults with RA [13]. Similarly, data from a French cohort of 186 RA patients who had received at least one infusion of RTX did not show an increased risk of malignancy over 346 patient-years’ exposure [mean follow-up 22.3 (15.1) months] [132]. A meta-analysis of 4009 patients exposed to TCZ for a median of 4 years found no significant difference in the incidence of solid and lymphoproliferative malignancies compared with the general population [133]. Solomon et al. [134], in a US observational study of 408 patients receiving ABA for RA, found no increased risk of malignancy compared with patients receiving MTX (HR = 1.55, 95% CI: 0.40, 5.97]. In a retrospective analysis of 3117 patients who received UST for up to 5 years, the rate of malignancy (other than non-melanoma skin cancers) was found to be 0.59/100 patients-years (UST 45 mg) and 0.61/100 patient-years (UST 90 mg) [60]. The frequency was found to be no different from the general population. (iii) There is conflicting evidence regarding the risk of skin cancers with anti-TNF therapy; patients should be advised of the need for preventative skin care, skin surveillance and prompt reporting of new persistent skin lesions (grade 1B, SOA 96%). Anti-TNF biologics Although inconsistent, numerous studies have found a positive association between the use of anti-TNF agents in RA and the risk of malignant melanoma (MM). An observational study of US veterans with RA found a higher risk of MM in those exposed to anti-TNF agents compared with those receiving csDMARDs (HR = 1.5, 95% CI: 1.01, 2.24) [135]. An almost identical risk was observed in the Swedish ARTIS registry [136]. Other studies have also noted a positive association between anti-TNF agents and MM, but failed to reach statistical significance; these include the DANBIO registry [122] and a 2011 meta-analysis of observational studies [116]. The largest study to date combined data from 11 European registries including 48 304 RA anti-TNF-treated patients. One hundred and six invasive MM were observed in the anti-TNF group with a pooled standard incidence ratio of 1.2; however, this did not achieve statistical significance (95% CI: 0.99, 1.6; P = 0.062) [137]. Higher rates of MM were also observed in the TNF group compared with those receiving csDMARD; however, again statistical significance was not achieved (IRR = 1.14, 95% CI: 0.8, 1.6). There is also some evidence to suggest that there may be a positive association between anti-TNF use and non-melanoma skin cancer (NMSC). Two RCT meta-analyses of RA patients receiving anti-TNF from 2009 to 2012 failed to find a significant association between anti-TNF use and risk of NMSC, although the more recent and higher quality of the two meta-analyses did observe a non-significant trend towards more NMSC in anti-TNF-treated patients [112, 115]. A further meta-analysis of observational studies found that patients with RA receiving anti-TNF had a 45% higher risk of NMSC compared with csDMARD-treated patients [116]. Recent registry data have also been conflicting; The ARTIS cohort [138] found higher rates of squamous cell skin carcinoma in RA patients treated with anti-TNF therapy compared with those who had not received anti-TNF therapy. While BSRBR-RA [139] and DANBIO [122] registries both observed higher rates of NMSC in anti-TNF-treated RA patients compared with the national population, no difference was observed when compared against RA patients who had not received anti-TNF agents. Non-anti-TNF biologics There is less evidence regarding the risk of NMSC in patients receiving non-anti-TNF biologics, but at present there have not been any safety signals to suggest that these drugs increase the risk of NMSC; however, further studies are required. RTX and ABA were not associated with an increased risk of NMSC in a cohort of 6841 patients with RA receiving biologics in a Medicare cohort [140]. In a long-term safety analysis of 3117 patients with psoriasis receiving UST, the risk of developing NMSC was found to be 0.64 and 0.44/100 patient-years (UST 45 and 90 mg, respectively) [60], a similar rate to the general US population. However, we acknowledge that at a similar time point data in the anti-TNF cohorts were similarly inconclusive. As UST is a relatively new biologic drug, large-scale registry data are currently unavailable. We would therefore recommend that the same precautions outlined for anti-TNF agents be taken for UST. (iv) Anti-TNF therapy is relatively contraindicated in patients who have had prior treatment with >150 psoralen and ultraviolet A (PUVA) and/or >350 ultraviolet B (UVB) phototherapy. Such patients should be discussed with a dermatologist prior to commencing anti-TNF therapy (grade 2C, SOA 96%). Patients with a history of psoriasis may be at further increased risk of skin malignancy (in addition to that of anti-TNF therapy) due to previous phototherapy with UVB or PUVA [141]. Anti-TNF biologics Data directly comparing the rates of skin malignancy in anti-TNF-treated patients with psoriasis who have received phototherapy compared with those who have never received phototherapy are lacking. A recent Dutch study compared rates of NMSC in two cohorts of patients receiving anti-TNF agents for psoriasis (99% of whom had received phototherapy) against a cohort of anti-TNF-treated RA patients [142]. A significantly higher risk of NMSC was found in the psoriasis group (HR = 6.0, 95% CI: 1.6, 22.4) with a shorter time to first NMSC compared with the RA group. A low basal cell carcinoma (BCC) to squamous cell carcinoma (SCC) ratio was also observed suggesting that disease-related factors, such as phototherapy, may be important contributors to the risk of development of NMSC in psoriasis patients treated with anti-TNF. However, the mortality associated with the majority of skin cancers is very low, early detection significantly improves both morbidity and mortality, and most are completely cured with local, predominantly surgical, measures. Non-anti-TNF biologics The limited available data from only a few studies do not suggest that any of the non-anti-TNF biologics increase the risk of skin malignancy. We suggest that while prior PUVA or phototherapy exposure is not necessarily a contraindication for this group of drugs, patients should be discussed with a dermatology specialist and treatment decisions made on a case by case basis. (v) Caution should be exercised in the use of biologics in patients with previous malignancy (grade 1C, SOA 97%). The timing of commencement of biologic therapy post-malignancy is not fixed and will depend on type and stage of malignancy, risk of metastasis and patient views. RTX may be considered as a first-line biologic option in RA patients with previous malignancy (grade 2C, SOA 90%). There remains a paucity of data concerning the use of biologic therapies in patients with a past history of malignancy. As RCTs have, almost universally, excluded patients with a past history of malignancy, any relevant data have been collected from observational cohort studies. Results from studies published since the last guideline have been reassuring; however, caution should still be advised based on theoretical risk and the fact that patient numbers and further event rates in these studies have generally been low. Anti-TNF biologics Of the recent observational cohort studies, BSRBR-RA included the largest number of patients, with 243 RA patients with previous malignancy receiving anti-TNF and 159 receiving csDMARD (1.7% of the BSRBR-RA cohort); the mean interval between malignancy and anti-TNF commencement was long at 11.5 years [143]. Fifty-three new malignancies were identified in this cohort, with no significant difference in the rate of new malignancies between groups. This is in keeping with previous data from the ARTIS [144] and RABBIT [120] registries. Furthermore, a 2016 systematic review observed similar rates of cancer recurrence in anti-TNF-treated individuals (which consisted of patients with RA, psoriasis and IBD) compared with the control csDMARD population (28.8 vs 35.1 events/1000 person-years) [145]. Additionally, these rates were also not significantly different from those observed in patients receiving no immunosuppressive therapy. Two recent studies have looked specifically at the risk of recurrence of NMSC in patients receiving anti-TNF; results from these studies have been conflicting. BSRBR-RA found no increased risk of NMSC recurrence among 177 RA patients with a past history of NMSC receiving anti-TNF treatment compared with DMARD-treated patients, over a median follow-up of 4 years [139]. In contrast, a larger observational study of 6841 RA patients found that anti-TNF use increased the risk of a subsequent NMSC by 49% above that seen in RA patients treated with MTX alone [140]. There is a lack of data regarding the risk of malignancy recurrence in patients with PsA or AS treated with anti-TNF therapy. Non-anti-TNF biologics A small study from the BSRBR-RA followed up 23 patients with a prior malignancy who had received RTX as a first biologic for RA. Over a total follow-up time of 81 person-years, no increased rate of further malignancy was observed compared with csDMARD controls (unadjusted HR = 0.45, 95% CI: 0.11, 1.87). Similarly, RTX and ABA were not associated with an increased risk of a second NMSC in a Medicare cohort of 6841 patients with a history of NMSC receiving biologics for RA [140]. Data on the use of TCZ or UST in patients with a history of malignancy are lacking. Due to the theoretical risks, the advice substantiated by evidence for anti-TNF therapies should be applied to patients receiving these therapies. (vi) The effect of biologics on pre-malignant conditions remains unclear. Caution should be exercised in the use of biologics in such patients. RTX may be considered as a first-line biologic option is these patients (grade 2C, SOA 97%). Anti-TNF biologics There is little information concerning the risk of using anti-TNF therapy in patients with pre-malignant conditions. Two studies to date have examined the risk of malignancy in female patients with a past history of cervical dysplasia or carcinoma in situ (CIS) of the cervix, treated with anti-TNF. The BSRBR-RA compared 190 RA patients with a past history of CIS of the cervix who were receiving anti-TNF therapy (73% of whom started anti-TNF therapy within 10 years of CIS) against csDMARD controls [146]. Over 893 person-years of follow-up, two new genital cancers were observed in the csDMARD group vs no new genital cancers in the anti-TNF group. Due to the low number of new malignant events in the trial, this study was underpowered to draw firm conclusions. Similarly, the DANBIO registry found no new genital malignancies among 208 patients with RA, AS or PsA and a past history of cervical dysplasia or CIS, who had been treated with anti-TNF therapy [147]. Limitations of this study included its relatively short follow-up period of mean 3.5 years for the anti-TNF patients, and the fact that the mean interval between CIS or cervical dysplasia diagnosis and commencement of anti-TNF therapy was 17.7 years. To date, no studies have examined the risk in other pre-malignant conditions such as Barrett’s oesophagus or colonic polyps. Non-anti-TNF biologics To date, there are no data concerning the use of RTX, ABA, TCZ or UST in pre-malignant conditions. Overall, given the implications of malignancy and the relative lack of safety data in patients with an established or potential malignancy, biologics cannot be recommended at present. Cardiac problems (i) Although recent data are reassuring, biologics should be used with caution in patients with class III or IV cardiac failure, working closely with a cardiologist (grade 2C, SOA 96%). Anti-TNF biologics TNF-α levels are increased in the general population with heart failure [148] and experimental models have suggested that anti-TNF therapy may improve ventricular dysfunction [149]. However, early clinical trials of ETN and IFX used as a treatment of heart failure reported an increased risk of worsening chronic heart failure [150–152]. As a result the presence of a class III or IV heart failure was a contraindication to the use of anti-TNF therapy in RA (Table 6) [1]. Recently, an observational study compared 8656 patients starting treatment with traditional DMARDs with 11 587 starting an anti-TNF therapy and reported that anti-TNF therapy was not associated with an increased risk of hospital admissions due to cardiac failure compared with traditional csDMARDs [153]. Furthermore, in a recent systematic review and meta-analysis, no significant effect of treatment with TNF inhibitors on CF was observed in RA patients [154]. Interpretation of the results from these studies is hampered by issues relating to potential confounding by indication or contraindication and by lack of control for confounding conditions or severity of RA. Table 6 New York Heart Association classification of heart failure Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Table 6 New York Heart Association classification of heart failure Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Class Patient symptoms I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath) II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation or dyspnoea IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases Non-anti-TNF biologics At present, there are no safety signals to suggest that RTX is associated with deterioration of cardiac function. A pooled case analysis of 1246 patients receiving RTX for >5 years found no difference in cardiac events compared with the general RA population [13]. Studies have shown that IL-6 is associated with exacerbation of ischaemic heart disease and cardiomyopathy [155]. Suzuki et al. [156] used i.v. TCZ in a patient with severe RA, with triple vessel coronary artery disease and severely impaired left ventricular function, with no worsening of cardiac function but good results for RA control. There is currently no evidence to suggest that TCZ increases the risk of cardiac failure. However, as with all other biologic clinical trials, patients with moderate to severe heart failure were excluded from the studies and so the risk of biologic therapy in such patients has to be weighed against the potential risk of alternative therapies (such as steroids). There are no data to suggest that ABA or UST is associated with exacerbation of cardiac failure. (ii) Biological therapy may be used in patients with previous myocardial infarction or cardiovascular (CV) events (grade 2B, SOA 99%). Data thus far appear to be reassuring with a potential beneficial effect of anti-TNF therapy on the risk of MI. Recently, a cohort study linking the Swedish National Patient Register and the Swedish Biologics Register [157] compared 7704 RA patients receiving anti-TNF therapy to matched biologic-naïve RA patients at a 3:1 ratio (n = 23 112). There was a significantly lower risk for acute coronary syndrome among RA patients, who were exposed to anti-TNF therapy compared with the biologic naïve patients (HR = 0.82, 95% CI: 0.70, 0.95). This is consistent with the results of a systematic review and meta-analysis that found that anti-TNF therapy in patients with RA was significantly associated with a reduction in the risk of MI [154]. Data from the BSRBR-RA showed no significant difference in the incidence of first MI between RA patients taking TNF inhibitors and csDMARD-treated RA controls [158]. However, the subgroup of anti-TNF-treated patients with a good or moderate EULAR response at 6 months had a lower incidence of MI (3.5/1000 events in responders compared with 9.4/1000 events in non-responders). Similarly, there appears to be a potential beneficial effect of anti-TNF therapy on CV events but further data are required before firm conclusions can be drawn. Potential confounding by indication or contraindication and by lack of control for confounding conditions or severity of RA should be taken into account, but this would be compatible with the hypothesis that inflammation contributes to development of CV events. In a recent systematic review and meta-analysis, in RA TNF inhibitors were significantly associated with a reduction in the risk of all CV events (risk ratio (RR) = 0.70, 95% CI: 0.54, 0.90), as well as in myocardial infarctions (RR = 0.59, 95% CI: 0.36, 0.97), strokes (RR = 0.57, 95% CI: 0.35, 0.92) and major adverse cardiac events (RR = 0.3, 95% CI: 0.15, 0.57) [154]. There is a lack of data regarding the use of anti-TNF therapy in patients with PsA or AS in patients with previous myocardial infarction or CV events. Non-anti-TNF biologics No data exist to suggest that any of the non-anti-TNF biologics increase the risk of myocardial infarction or CV events. In view of the evidence from anti-TNF therapies and a lack of a mechanistic reason, we suggest that the recommendation be applied across biologic therapies. Respiratory disease Pre-existing ILD is not a specific contraindication to biologic therapy; however, caution is advised in patients with poor respiratory reserve (in whom a significant drop in lung function would be potentially life threatening); in this situation it is advised to work closely with a respiratory physician with a specialist interest in ILD (grade 2C, SOA 99%). RTX or ABA may be considered a first-line biologic in patients with ILD (grade 2C, SOA 84%). ILD is a common manifestation in patients with RA (prevalence 10–30%) and is generally associated with more severe disease [159, 160]. Uncertainty remains surrounding the natural history of RA-ILD and the effects of biologics (and csDMARDs) on this disease. Predominantly studies are centred on RA-ILD although there are pulmonary manifestations associated with other forms of IA, such as a prevalence of 0–30% for lung involvement in AS patients, most commonly upper lobe fibrosis. Anti-TNF biologics Since the 2010 guideline there have been several observational retrospective cohort studies assessing the relationship between ILD and anti-TNF therapy. The BSRBR-RA found no significant increase in mortality in 356 patients with RA-ILD treated with ETN, ADA or IFX, compared with those receiving csDMARD alone [161]. Selection bias could be an explanation for these results as this could have led to increased mortality in the traditional DMARD group and a favourable reduction in the mortality rate ratio for biologics use. The conclusion was that UK physicians were appropriately selecting patients suitable for anti-TNF therapy when underlying ILD was present. Where there is no pre-existing ILD, a US study found that anti-TNF therapy was not associated with a diagnosis of ILD among patients with RA over a mean follow-up of 3 years [162]; comparisons across anti-TNF agents found no differences in risk. The number of cases was limited in this study, with only 38 new ILD cases (23 on anti-TNF) among the 8417 persons included (0.4%). In terms of selection of patients, univariate analysis in a small Korean study suggested age at initiation of anti-TNF therapy was a risk factor for death when looking at a population of 24 RA-ILD patients on anti-TNF (76 vs 64 years old, P = 0.043) [163]. A Japanese study [164] found that over 1 year of follow-up of 58 RA patients with pre-existing ILD, 14 had ILD events and that the proportion was greater than the comparator arm without pre-existing ILD (24 vs 3%, P < 0.001). Pre-existing lung disease should not be considered an absolute contraindication to an anti-TNF. However, in patients with poor respiratory reserve (in whom a significant drop in lung function would be potentially life threatening), caution should be exercised when choosing an anti-TNF. Decisions should be made on an individualized basis in conjunction with a respiratory physician, and with full appreciation of the limited evidence base. Non-anti-TNF biologics There is little evidence on the impact of RTX, ABA, TCZ and UST on the occurrence or exacerbation of ILD, and this is often limited to case reports. A 2014 systematic review of case reports and series (from 1975 to 2013) of biologics causing ILD or worsening pre-existing ILD in RA patients found eight case reports for TCZ, three for RTX and one for ABA [165]. A US database study of 11 219 RA patients [166] found the lowest IR of ILD occurrence was with ABA (IR = 4.0/1000 person-years, 95% CI: 1.6, 8.2/1000 person-years); the highest being with INF (IR = 12.2/1000 person-years, 95% CI: 5.6, 23.2/1000 person-years); however, no significant differences in the incidence of ILD was found between the different biologic classes. No studies to date have examined the relationship between UST and ILD in PsA. Until further data are available concerning any causal relationship between non-anti-TNF biologics and ILD, we suggest that recommendations given for anti-TNF therapies should be followed. There is a weak evidence base to suggest that ABA and RTX might have less effect on ILD than other biologics [165–167]. Uveitis (i) ADA and INF can be considered for the treatment of uveitis, in preference to ETN, which appears to be associated with lower rates of treatment success and has been associated with the development of uveitis. The relative risks of these agents should be taken into account when selecting which treatment to use (grade 1 C, SOA 96%). Anti-TNF biologics A systematic review by Levy [168, 169] concluded that ADA and INF can be considered as second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy and scleritis in patients requiring immunomodulation who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. INF and ADA can be considered in these patients in preference to ETN, which appears to be associated with lower rates of treatment success. At present, ADA is the only anti-TNF agent licensed by the European Medicines Agency for the treatment of uveitis. While ADA and INF [168, 169] have successfully treated uveitis, there are several case reports of uveitis developing in patients treated with ETN [170, 171]. A registry-based study by Lim et al. [172] reported 43 cases of uveitis in patients who were receiving anti-TNF treatment over a period of 8 years. The number of patients taking ETN, INF or ADA in this group was 20, four and two, respectively; ETN therapy was associated with a significantly greater number of reported uveitis cases in comparison with INF (P < 0.001). This study was, however, limited by the information on the clinical diagnoses available to the authors. More data are required on uveitis associated with each of the anti-TNF agents before further conclusions can be drawn on the risks associated with these agents. Non-anti-TNF biologics There is a paucity of data concerning the safety of non-anti-TNF biologics in patients with a history of uveitis. There is one case report of a patient with RA treated with TCZ who developed acute anterior uveitis 5 weeks after stopping the therapy; however, causality is difficult to establish in this scenario [173]. Aside from that, there have not been any safety signals to suggest that there is concern about using these drugs in this patient cohort. There is some, mostly observational, data to suggest that non-anti-TNF biologics can successfully treat patients with refractory uveitis. A systematic review by Simonini et al. identified nine articles reporting data on the use of non-anti-TNF biologics to treat refractory uveitis (six retrospective chart reviews, two case series and one single-blind RCT of 16 patients) [174]. ABA, TOC and RTX all demonstrated efficacy in selected categories of chronic uveitis, refractory to previous DMARDs and anti-TNF agents; further randomized clinical trials in this area are needed. Demyelinating disease (i) Anti-TNF therapy should not be given when there is a personal history of multiple sclerosis or other demyelinating diseases. Consider using a non-anti-TNF biologic in this situation (grade 2B, SOA 97%). Anti-TNF biologics Studies have suggested an aetiological role for anti-TNF therapies in the development of neurological disorders; the disease is temporally associated with initiation of therapy, the symptomatology is suggestive of an antigen-mediated hypersensitivity process, and the disease improves or resolves after discontinuation of therapy and a positive rechallenge phenomenon is observed [175, 176]. Multiple sclerosis TNF blockade was shown to cause worsening of demyelinating disease in early studies of an anti-TNF therapy, in which patients with active multiple sclerosis (MS) documented an increase in MS flares on this therapy [177]. The prevalence of demyelinating disease induced by biologic therapies, reported in RCTs and post-marketing studies, has been estimated to range from 0.02 to 0.2% [178]. In a Canadian database of 105 000 RA patients there was a trend towards around a 30% increase in demyelinating events after exposure to anti-TNF agents, but this was not statistically significant [179]. A Danish registry study of almost 28 000 patients with IA found a significantly increased standardized incidence ratio of MS in men with RA or AS treated with anti-TNF therapy (SIR = 3.48, 95% CI: 1.45, 8.37), but not in women [180]. Optic neuritis Case reports of patients developing optic neuritis during anti-TNF treatment exist. A pooled case report study detailed 15 patients who developed optic neuritis while on anti-TNF therapy; eight of these patients had received IFX, five ETN and two ADA [181]. On stopping anti-TNF treatment, seven patients experienced either partial or complete resolution of their symptoms while four patients continued to have symptoms. Recently there has been a USA-based study of 61 000 individuals with inflammatory disease and new anti-TNF or non-biologic DMARD use. Among this cohort, three optic neuritis cases (two with IFX and one with ETN) were detected among anti-TNF new users, providing a crude IR of 10.4 (95% CI: 3.3, 32.2) cases per 100 000 person-years. No cases occurred in the csDMARD comparison group. However, in a secondary analysis of current and past users of csDMARDs and anti-TNF, optic neuritis rates were similar in the anti-TNF and comparison groups, respectively, leading the authors to conclude that anti-TNF therapy does not appear to promote the development of optic neuritis in patients who lacked a prior documented history of optic neuritis [182]. Demyelinating peripheral nervous system disease The association between anti-TNF treatment and various disorders of peripheral nerves such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and mononeuropathy multiplex has been highlighted in various case series and case reports [183]. Cases were reported for all three first generation anti-TNF agents with symptoms developing over a wide range of time intervals from starting anti-TNF treatment (8 h to 2 years) and lasting for varying time periods from 3 weeks to 35 months. Withdrawal of anti-TNF resulted in slow resolution of symptoms in many cases; however, additional treatment was required for others. A small minority of patients, however, never achieved symptom resolution. Prognosis following demyelinating disease or peripheral neuropathy In the BIOGEAS registry, 30% of patients with demyelinating disease (n = 44) had no resolution of symptoms. Eleven per cent of peripheral neuropathies had no resolution of symptoms on stopping therapy [175, 178]. Similarly, in a French registry, 22% of patients developing CNS demyelination on biologics went on to develop MS despite cessation of biologic therapy [184]. In light of these findings, individuals with a personal history of multiple sclerosis or other demyelinating diseases should not start anti-TNF therapy. Non-anti-TNF biologics There is no evidence to suggest that RTX, ABA or UST increases the risk of demyelinating diseases. Likewise, there is no consistent evidence to argue against the use of TCZ in demyelinating diseases; indeed there is ongoing interest in its use for the treatment of certain autoimmune neurological disorders such as neuromyelitis optica spectrum disorder [185]. Sato et al. [186] used TCZ in treating RA in a patient with multiple sclerosis for 5 years with no progression of her MS. In view of the above evidence, we suggest that a non-anti-TNF biologic is used in preference to anti-TNF therapy in patients with a personal history of demyelinating disorder. Diverticular disease (i) Exercise caution with TCZ in patients with diverticular disease, particularly when using concurrent NSAIDs and/or steroids (grade 2C, SOA 98%). Gastrointestinal perforation has been reported in patients treated with TCZ for RA. An occurrence of 2.8/1000 person-years was reported by Schiff et al. [187] in a pooled meta-analysis of five RCTs and two long-term extension studies, compared with 2.0/1000 person-years reported in the control group. Diverticulitis was present in 16 of the 18 patients who had a gastrointestinal (GI) perforation while receiving TCZ; most patients had also been treated with NSAIDs and/or steroids. A systematic review by Gout et al. [188] found that the risk of GI perforation with TCZ was lower than the risk with steroid and NSAID use, but higher than with anti-TNF therapy. A large study by Curtis et al. [189] looking at administrative data from a large US health plan showed that there was no increased risk of GI perforation with the use of non-TCZ biologics or MTX, but there was an increased risk with concomitant use of steroids and NSAIDs. The factor leading to the highest increase in risk was previous diverticulitis. Vaccinations (Also refer to vaccination recommendations while on biologic therapy). (i) HBV immunization should be considered for at risk patients (grade 2C, SOA 94%). Individuals with ongoing risk factors for hepatitis B infection [as outlined in recommendation (i) for active TB] should undergo immunization prior to starting anti-TNF treatment. Hepatitis B vaccines are inactivated vaccines and therefore do not contain live organisms and cannot cause hepatitis B in an immunosuppressed individual. There are limited data with regard to response to hepatitis B immunization in patients with rheumatic disease receiving biologic therapy. There is circumstantial evidence indicating that TNF blockade may directly modulate humoral responses [190], with one study suggesting that TNF blockade with ETN decreases responses to the hepatitis B vaccine; patients with RA who were treated with MTX had very good response rates, whereas those treated with an MTX–ETN combination or ETN alone had poor response rates [191]. Therefore, though it is safe to give hepatitis B vaccine to a patient on anti-TNF treatment, if possible, the first hepatitis B vaccine should be given prior to commencing anti-TNF therapy. Due to the risk of poor response, it is important that immunization against hepatitis B does not encourage relaxation of other measures to prevent exposure to the virus, such as condom use and needle exchange [192]. (ii) Patients >50 years should undergo vaccination against herpes zoster (HZ) assuming there are no contraindications (e.g. treatment within the past 3 months with >40 mg prednisolone per day for >1 week, >20 mg prednisolone per day for >14 days, MTX >25 mg/week, AZA >3.0 mg/kg/day). This should be administered preferably >14 days before starting biologic therapy (grade 2C, SOA 97%). The risk and severity of shingles (HZ infection) is considerably higher among immunosuppressed individuals, with evidence suggesting that people with rheumatic diseases have around double the incidence of shingles of the general population [193, 194]. A 2014 meta-analysis including ACR, EULAR and BSR registry data found that the pooled risk ratio for HZ in patients with IA on anti-TNF agents was 1.61 (95% CI: 1.16, 2.23). The proportions of severe HZ ranged from 2.0 to 5.5% with csDMARDS, compared with 4.9–20.9% with TNF-blockers [195]. According to Public Health England recommendations, eligible individuals anticipating immunosuppressive therapy should ideally be assessed for vaccine eligibility before starting treatment that may contra-indicate future vaccination [196]. Eligible individuals who have not received Zostavax should receive a single dose of vaccine at the earliest opportunity and at least 14 days before starting immunosuppressive therapy. HZ vaccine is now recommended in the UK for all individuals aged 70–79 and a national vaccination programme is underway. Zostavax reduces the risk of shingles by ∼50% in immunocompetent adults aged ⩾60 years [197]. Efficacy of the vaccine appears to wane within the years after vaccination, with studies suggesting efficacy of 39.6% for prevention of HZ and 60.1% for prevention of postherpetic neuralgia 4–7 years post-vaccination [198]. It is licensed for the use in individuals aged ⩾50 years, and therefore could not be recommended for patients younger than this [199]. Vaccination has been shown to be associated with reduced incidence of HZ in a study of over 460 000 patients aged ⩾60 years with autoimmune diseases [200]. As HZ vaccine is a live attenuated vaccine, it carries a small risk of infection, particularly in immunosuppressed individuals. However, in this study, among 633 patients with recent or current exposure to biologics at the time of vaccination, no case of HZ or varicella occurred. These data were, however, extracted from administrative claims from hospitals and cases of HZ and varicella were not confirmed with medical records review. Encouragingly, in two further studies, no increased incidence of HZ or varicella zoster was shown following vaccination in individuals with autoimmune disease receiving a variety of biologic therapies [201]. Nonetheless, Public Health England currently recommends that HZ vaccine should not be given to individuals already on biologic therapy or who, in the past three months have received >40 mg prednisolone per day for >1 week, >20 mg prednisolone per day for >14 days, non-biological oral immune modulating drugs (e.g. MTX >25 mg/week, AZA >3.0 mg/kg/day) [196, 202]. (iii) Patients who do not have a positive history of varicella zoster (chickenpox) infection should have a varicella zoster virus antibody test. If this is negative, and there are no contraindications (as listed in (ii)) varicella zoster vaccination should be offered prior to biologic commencement (grade 2C, SOA 98%). Varicella zoster virus, which causes chickenpox, is more common and serious in immunosuppressed individuals, as they are at risk of severe and potentially fatal disseminated varicella infections [203, 204]. It is the most frequent viral opportunistic infection (OI) seen in patients on MTX or anti-TNF agents [23]. The varicella vaccine is a live attenuated vaccine, and the two-dose vaccination schedule provides around 75% protection in adolescents and adults—mild breakthrough infections can occur in around 10% of adults [205]. For this reason it is not recommended for those already on immunosuppressive medication, such as AZA (>3.0 mg/kg/day), ciclosporin, MTX (>25 mg/week), CYC, LEF or equivalent 40 mg prednisolone/day); this group will cover a significant proportion of patients due to start anti-TNF therapy. In individuals due to start biologic therapy who are not in the above category, varicella zoster vaccination is recommended, in addition to vaccination of healthy susceptible close household contacts of immunocompromised patients (e.g. children of a patient due to start biologic therapy who have not had varicella zoster). Patients without a definite history of varicella zoster virus infection should undergo a varicella virus antibody test. If negative, and there is no contraindication, they should be offered vaccination on the two-dose schedule. Personal recall of varicella infection has been shown to be a good predictor of serological immunity [206, 207]. For patients receiving biologic therapy Monitoring on treatment (i) All patients should be reviewed for drug safety in a specialist department at least every 6 months. High risk patients (e.g. those at high risk of TB) should be reviewed every 3 months (grade 2C, SOA 94%). There is no evidence on the optimal monitoring requirements for patients receiving biologics. However, in view of the aforementioned potential risks associated with these treatments, and the NICE requirements to ensure a satisfactory clinical response to treatment, we suggest that patients are reviewed at least every 6 months by a rheumatology specialist. Higher risk patients may require more frequent review, as supported by NICE guidance. The 2011 NICE guideline cg117 [76] and the 2005 BTS guideline [208] recommend that high-risk TB patients should be monitored every 3 months (with a CXR and sputum cultures, if respiratory symptoms develop). (ii) Patients prescribed a biologic (other than TCZ) without concomitant csDMARD (or with csDMARDs that do not require blood test monitoring), should have monitoring blood tests (FBC, creatinine/calculated GFR, ALT and/or AST and albumin every 3–6 months (grade 2C, SOA 97%). Anti-TNF biologics Haematological abnormalities have been reported in patients treated with anti-TNF agents but in many cases there have been other co-prescribed medications that may have been responsible for these changes. One case series reported neutropaenia (<2.0 × 109/l) in 14.3% of 133 RA patients on anti-TNF therapy [209]. A history of previous neutropaenia on csDMARD therapy and a low baseline neutrophil count were shown to be predictors of neutropaenia. Two other studies have reported rates of anti-TNF-induced neutropaenia of 8 and 14% [210, 211]. The majority of reported cases of anti-TNF-induced neutropaenia were mild, did not result in any significant clinical complications and did not require modification in anti-TNF therapy. Reports of anti-TNF-associated pancytopenia and aplastic anaemia are rare but in some cases have been fatal [212]. More recently, a US cohort of 1322 patients receiving anti-TNF therapy had no increase in prevalence of anaemia, leucopenia or thrombocytopenia [213]. Other studies have shown resolution of anaemia of inflammation following treatment with anti-TNF agents. Niccoli et al. [214] monitored the FBC of 106 patients with AS over a 6-month period and found Hb, MCV, iron, ferritin, CRP and ESR improved, reaching statistical significance. However, this study is confounded by the simultaneous stopping of NSAIDs on commencement of anti-TNF, perhaps leading to a reduction in insidious GI bleeding. Liver function test derangement has also, albeit rarely, been associated with anti-TNF therapy. In an observational study of 6861 RA patients, over 6.5 years of follow-up, elevations in AST and ALT were found in 6.67% of patients [215]; however, only 0.77% had levels more than twice the upper limit of normal. IFX (as opposed to ADA or ETN) was associated with the highest frequency of elevations. Anti-TNF therapy is not known to affect renal function [216]; however, IA is associated with chronic kidney disease [217]. Hence in individuals already undergoing blood monitoring, an assessment of renal function may be useful to detect any deterioration in renal function and enable early investigation and treatment that may prevent further decline. Thus, in light of reports of pancytopenia and liver function test elevation with anti-TNF therapy, it is recommended that patients undergo blood monitoring on a regular basis (every 3–6 months). Non-anti-TNF biologics Late-onset neutropaenia is a recognized side effect of RTX therapy and, although it usually follows a benign course and is infrequent, can present with infection [214, 215]. A UK study of 108 patients receiving RTX for RA between October 2007 and July 2011 identified five patients (4.6%) who developed late-onset neutropaenia (LON; neutrophil count ⩽1.5 × 109 after a median of 151 days [70–181, 215]; two patients developed pneumonia. A similar rate of 6% (eight patients) was observed in a Norwegian single-centre case review analysis of 133 RA patients, and was more common in those with low IgM and IgG levels [12]. Fifty per cent of patients with LON had infection at the onset of neutropaenia; six patients were rechallenged with RTX without recurrence of LON. In this study it took a median of 6.5 days for recovery of LON. (iii) Patients receiving csDMARD may require more regular laboratory monitoring (as per BSR/BHPR non-biologic DMARD guidelines, 2017) (grade 2B, SOA 96%). Patients receiving biologic therapy alongside a csDMARD may require blood test monitoring more frequently than every 3 months, depending on which csDMARD they are receiving. Minimal monitoring requirements for the different csDMARDs and the blood results that require action are given in the 2017 BSR/BHBR non-biologics DMARD guidelines [5]. The blood results that require action are the same as those defined in the BSR 2017 csDMARD guideline [5]. (iv) Patients receiving RTX should have serum immunoglobulins (especially IgG and IgM) checked prior to each cycle of RTX. Clinicians and patients should be aware that the risk of infection increases as serum IgG levels fall below normal. Lower dose RTX may be considered in this situation (grade 2A, SOA 99%). Lower levels of IgG have been associated with an increased risk of infection in individuals receiving RTX [13]. Van Vollenhoven et al. [13] monitored Ig levels every 8–16 weeks in patients with RA receiving RTX and found that following RTX therapy ⩽3.9% had low IgA or total Ig levels at any time, while 14.8 and 37.9% had below normal IgG and IgM levels, respectively, any time. Over the first 5 years of treatment the proportion of patients with IgM but not IgG or IgA below the lower limit of normal continued to increase. Serious infection rates in those patients who developed low IgG levels were higher than the serious infection rates in patients who never developed low IgG; however, this study was limited by low numbers in the low IgG subgroup (143 patients). Although there is no evidence to suggest an absolute total Ig, IgM or IgG threshold where RTX should not be given, clinicians and patients should be aware that the risk of serious infection increases as serum IgG level falls. Lower dose RTX (such as 2 × 500 mg infusions) may be considered in this situation [13, 218]. (v) Patients receiving i.v. or s.c. TCZ, with or without MTX, should have laboratory monitoring every 4 weeks for neutrophils and ALT/AST (grade 2B). Blood tests should ideally be in the week before i.v. TCZ, and in the 3 days before every fourth s.c. injection. Any decision to halt treatment should be made in accordance with the guidance in the TCZ SPC (grade 2C, SOA 96%). TCZ has been found to cause a reduction in absolute neutrophil count (ANC) in a number of studies [219–221]. This is thought to be due to peripheral margination of neutrophils, but is not associated with an increased frequency of infection. Nishimoto et al. [220] found that 6% of patients on TCZ experienced neutropaenia grade 3 or 4, with a further 15% having grade 1 or 2. Interestingly, these events were not associated with infection. Nakamura et al. [219] found ANC to drop in the first 24 h after i.v. TCZ administration, but the ANC recovered by the next infusion 4 weeks later. Maini et al. [221] found ANC to reach a nadir at 2 weeks post-infusion, with recovery occurring within the following 2 weeks. More recently, a double blind, double dummy RCT [222] compared patients receiving TCZ vs MTX vs TCZ + MTX. No significant difference was seen between the groups in terms of infection or drop in ANC. A 97-week open label extension of a 24-week double blind study comparing i.v. and s.c. formulations of TCZ has shown that even at 97 weeks, a small number of patients still develop new grade 3 or 4 neutropaenia, with numbers similar in both i.v. and s.c. groups (0.81 and 0.76%, respectively) [223]. Rises in transaminases (ALT and AST) have been found with TCZ in a number of studies. Various studies have noted raised transaminases that spontaneously resolved without the need for TCZ dose change [224–228]. Dougados et al. [229], and others, found that 41–51% of patients on TCZ in combination with a conventional DMARD will have spontaneously resolving episodes of raised ALT up to three times the upper limit of normal [224, 225, 228, 229]. In a retrospective cohort study looking back over 45 months, Machado-Alba et al. [230] found 5/51 (9.8%) patients on TCZ developed a rise in ALT up to three times the upper limit of normal. The TCZ SPC has detailed guidance concerning when to stop or change therapy in the context of blood test abnormalities and should be referred to (http://www.medicines.org.uk/emc/medicine/22311/-SPC/RoActemra). (vi) Patients receiving TCZ should have their serum lipids checked at 3 months, and treated appropriately if abnormal; they may be checked again thereafter at physician’s discretion (grade 2A, SOA 99%). TCZ has been noted to cause an initial rise in serum lipids [187, 221, 231], but long-term extension studies have shown them to broadly stabilize within 3 months [232]. A post hoc analysis by Gabay et al. [233] of 324 patients in the ADACTA trial up to 24 weeks showed that compared with ADA, TCZ was associated with a slightly raised LDL cholesterol level, but the overall lipid profiles were similar. An increase in cardiac events has not been found, perhaps with the deleterious effect of higher lipids being offset by better control of inflammatory disease. Further work is required in this area. Co-morbidity management on treatment (i) Patients with significant co-morbidities who are also receiving biologic therapies, should have close involvement with specialists in that field (grade 1C, SOA 99%). Infection In general: (i) All biologics should be discontinued in the presence of serious infection, but can be recommenced once the infection has resolved (grade 1A, SOA 99%). Anti-TNF biologics No studies to date have assessed outcomes in patients with IA receiving anti-TNF therapy who did not stop treatment in the presence of severe infection; however, there are data, primarily from case reports, suggesting that infections may become more severe if patients continue with anti-TNF therapy [234]. Patients should be made aware of the increased risk of infection, and should be advised to stop therapy until the infection has resolved. Non-anti-TNF biologics As no studies have investigated the outcome in patients continuing with these drugs in the presence of active infection, caution is advised and it is suggested that non-anti-TNF biologics should also be stopped until infection has cleared. Further data in this area are required. Mycobacterium tuberculosis (i) Patients commenced on biologics should be closely monitored for TB while on treatment and for at least 6 months after stopping treatment (grade 2C, SOA 98%). This recommendation is largely based on expert opinion from NICE [76] and the BTS guidelines [208]. Any patient who develops symptoms consistent with TB, even if their pre-biologic TB screening was negative, should be investigated for active TB, initially with a chest X-ray and sputum examination. Up to a 19% risk of TB reactivation has been reported; however, this varies according to the local rates of a positive TST/IGRA and the local incidence of TB. Most cases of reactivation have occurred during the first year of anti-TNF treatment after completion of chemoprophylaxis [235]. (ii) Patients on biologics who develop symptoms suggestive of TB should receive full anti-TB treatment but may continue with their biologic if clinically indicated after risk/benefit analysis (grade 2C, SOA 96%). Patients who develop active TB while on biologic treatment should receive full anti-TB chemotherapy [236]. In these circumstances, treatment can be continued if clinically indicated because the patient would otherwise be prevented from receiving the continued clinical benefit to their underlying disease and may have a flare up or major clinical deterioration. While there is limited evidence in this area, it is reported that HIV positive individuals with reduced CD4 counts and clinical TB, who are even more immunosuppressed than those on anti-TNF treatment, respond equally well to TB treatment as those who are HIV negative [237]. Opportunistic infection (i) Health-care professionals should have a high index of suspicion for atypical/OIs, especially if current or recent steroid use. Biologic therapy should be promptly stopped in suspected cases. Patients should have rapid access to specialist health care for consideration of early treatment (grade 1B, SOA 99%). Anti-TNF biologics There have been a few observational cohort studies investigating the association between OIs and anti-TNF use. The largest of these studies, the US Safety Assessment of Biologic Therapy project, found a higher incidence of non-viral OIs compared with patients initiating non-biologic DMARDS [238]. Within the cohort of 33 324 new anti-TNF users over a 9 year period, 80 non-viral OIs were identified with pneumocystosis being the most common, accounting for 20% of OI cases (n = 16); histoplasmosis (n = 9) and cryptococcus (n = 3) were the next most frequently observed fungal OI. Nocardiosis (n = 12) had the highest incidence for opportunistic bacterial infection (n = 12), followed by salmonellosis [8] and listeriosis (n = 4). The overall crude rate of non-viral OI in the TNF group was 2.7 vs 1.7 per 1000 person-years in those receiving only csDMARD (adjusted HR = 1.6, 95% CI: 1, 2.6). Data collected from the US CORONNA registry found that anti-TNF drugs were an independent predictor of OI (bacterial and viral) [23]. One hundred and sixty-four OIs were observed in the TNF-treated group, with an IRR of 1.18 (95% CI: 1.08, 1.32) compared with MTX alone. The combination of MTX and anti-TNF did not appear to further increase the risk of OI above that of anti-TNF alone. In both studies, baseline steroid use was an independent risk factor for OI; however, to date there is insufficient evidence to support the use of primary prophylaxis in this group. Non-anti-TNF biologics The risk of non-TB atypical OIs does not seem to be increased with RTX, TCZ, ABA or TCZ compared with other biologics, but long-term data are lacking [59]. Vallabhaneni et al. [239] looked at 4000 patients who had received TCZ, and 11 of these (0.28%) developed invasive fungal infections, which is non-inferior to other biologics. There are no observational data regarding the long-term risk of UST and atypical OI. (ii) In patients exposed to primary varicella through a close household contact [and without a positive history of varicella zoster (chickenpox) infection or vaccination], post-exposure prophylaxis with varicella zoster immune globulin should be considered if the risks from infection are perceived to be significant. Shingles should be treated conventionally (grade 2C, SOA 94%). Anti-TNF biologics Several studies have found a significant association between anti-TNF therapy and risk of HZ. The most recent data comes from the Australian ARAD database of 2157 RA patients [42]. RA patients receiving IFX, ETN or ADA had a 37% higher risk of shingles (adjusted hazard ratio (aHR) 1.37, 95% CI: 1, 2.92) compared with csDMARD users. Data from BSRBR-RA showed that patients receiving first generation anti-TNF were found to have an up to 80% higher risk of shingles (aHR = 1.8, 95% CI: 1.2, 2.8; crude incidence of 1.6/100 person-years) [240]. This study, along with data from the RABBIT, BIOBADASER and CORRONA registries, was included in a 2014 meta-analysis, which found a pooled risk ratio for HZ with TNF inhibitors of 1.61 (95% CI: 1.16, 2.23) [195]. Relatively fewer studies have focused on varicella zoster (chickenpox) risk and anti-TNF therapy. Higher rates of hospitalized chickenpox and shingles compared with the general population have been observed in a study combining the BIOBADASER registry with the Spanish national hospital discharge database [241]. The IR for hospitalized shingles and chickenpox in patients receiving anti-TNF therapy was 44 and 26 per 100 000 person-years, compared with an expected IR of 3.4 and 1.9 per 100 000 person-years, respectively, in the general population. There remains little evidence on the effectiveness of varicella zoster immune globulin (VZIG) in preventing infection in immunosuppressed patients. A study of 81 immunosuppressed children who received VZIG following household exposure to varicella, found a moderate response to VZIG, although 49 children still developed varicella infection, including some who had serological evidence of past exposure [242]. Until more data are available, we feel that it is appropriate to recommend that VZIG is considered as a post-exposure prophylaxis for patients receiving biologic therapies who are exposed to varicella infection in whom the risks of infection are perceived to be high. VZIG is an intramuscular injection, and should be given as soon as possible—not later than 10 days after exposure; a second dose should be given if further exposure occurs >3 weeks after the first dose. Non-anti-TNF biologics There have been reports of higher than expected episodes of HZ in patients receiving RTX and ABA from cohort studies [35, 243]. Data are lacking on the risk of TCZ and UST and HZ. Until more data are available, we suggest that the recommendations for anti-TNF therapies be applied to all biologics. (iii) Clinicians should be vigilant for progressive multifocal leukoencephalopathy (PML), which has been primarily associated with RTX but has also been reported with anti-TNF therapy. Treatment should be stopped if PML develops. Rechallenge is not recommended (grade 1C, SOA 99%). PML has been reported in a few more patients than was reported on the previous guideline and to date there have been 11 cases in patients with RA [244]. The majority of case have been in association with RTX use, but rarely cases have been reported with other agents [245]. Considering how many more patients have been treated with RTX since the last guideline, this should be reassuring of the lack a major signal, but vigilance should still be maintained. The prognosis for PML is poor, with a high level of mortality at 1 year. Although there is no treatment for PML, stopping biologic therapy may slow progression. There are no data regarding PML receiving biologic therapies for non-RA IA. No cases of PML have been reported with TCZ, ABA or UST. Hepatitis B and C infection (i) Close monitoring of serum amino-transaminases and HBV DNA load is recommended in patients with occult or overt HBV infection treated with biologic therapy (grade 1C SOA 99%). Patients should be followed carefully by means of ALT and HBV DNA testing and treated with anti-viral therapy upon confirmation of HBV reactivation before ALT elevation. The frequency of monitoring can range from 1 to 3 months depending on the type of immunosuppressive therapy and comorbidities [93]. (ii) Close monitoring of serum amino-transaminases and HCV RNA during therapy should be considered in patients with HCV treated with a biologic (grade 1C, SOA 99%). Studies to date continue to show that biologic (especially anti-TNF) therapies do not have a detrimental effect on HCV infection [99, 101], but it would be prudent to work closely with a hepatologist and arrange monitoring. (iii) Patients with serological evidence of occult HBV infection may require concomitant anti-viral treatment if detrimental changes in monitoring tests develop (grade 1B, SOA 99%). Patients with previous occult HBV infection treated with biologic therapy who reactivate their HBV have generally good outcomes even if anti-viral treatment was required [90, 92, 246]. In these studies anti-viral treatment was generally given if HBV DNA level was >105 IU/ml, although we recommend that thresholds of treatment should be decided working with a hepatologist given that European Association for the Study of the Liver guidelines recommend treatment based on a combination of raised ALT, HBV DNA level >2000 IU/ml and severity of liver disease [93]. HIV (i) Patients with HIV receiving anti-TNF therapy require close monitoring of viral load and CD4 count. Treatment changes should be made in light of results, with guidance from an HIV specialist (grade 2C, SOA 99%). Refer to the earlier section on HIV. Malignancy Patients should be encouraged to comply with national cancer screening programmes (grade 1C, SOA 99%). Patients should be investigated for potential malignancy if clinically suspected and biologics should be stopped if non-BCC malignancy is confirmed (grade 1C, SOA 97%). There is an absence of evidence regarding the cessation of biologic therapy in the presence of proven malignancy; certainly no studies to date have investigated whether continuing or stopping biologic therapy in this situation has any effect on prognosis. Until any further evidence is available, it is suggested that all biologic therapies should be stopped if malignancy (excluding skin BCC) is confirmed, and any ongoing future treatment discussed with oncology specialists on a case by case basis. (iii) Biologic therapies may be continued in patients who develop a BCC that is fully excised, after careful discussion with the patient and a risk–benefit analysis (grade 2C, SOA 97%). There have been no studies to date assessing the outcome of biologic-treated patients who undergo complete excision of a NMSC and continue with biologic therapy. As described earlier, there is evidence to suggest that anti-TNF agents increase the risk of a future NMSC in individuals who have a past history of them [140], but conflicting results have also been reported in other studies [140]. Due to the low inherent risk of metastasis following the complete excision of a BCC, we suggest that in this situation biologic therapies may be continued after careful discussion with the patient and possible input from a dermatology specialist. Cardiac problems (i) If patients develop worsening cardiac failure while on anti-TNF, consideration should be given to stopping therapy if no other explanation for worsening cardiac failure is found following input from a cardiologist (grade 2C, SOA 99%). Although recent studies have reassuringly not found a significant effect of TNF inhibitors on cardiac failure [153, 154], early clinical trials did report a detrimental association [150–152]. There are numerous causes of cardiac failure including ischaemic heart disease, hypertension and valvular heart disease, all of which are more common than drug-induced causes. With this in mind, we suggest that consideration is given to stopping anti-TNF agents in individuals with worsening cardiac failure if this cannot be attributed to other pathologies after specialist input from a cardiologist. Respiratory disease (i) Patients with ILD receiving biologics should be regularly reviewed by a respiratory physician with a specialist interest in ILD, and ideally in a combined rheumatology/respiratory clinic. Pulmonary function tests (PFTs) should be performed as clinically indicated, usually every 4–6 months (grade 2C, SOA 99%). Most ILDs share a restrictive pattern, with reductions in lung volumes and a reduced diffusing capacity for carbon monoxide (DLCO). Low baseline forced vital capacity (FVC) and DLCO (e.g. FVC <60% and DLCO <40% of predicted values) are independent predictors of early death in patients with IPF. Serial PFTs add information on disease trajectory. Importantly, a short-term (6–12 month) decline in FVC of ⩾10%, or a decline in DLCO of ⩾15%, is associated with increased mortality in IPF [247]. In one systematic review, where ILD occurs subsequent to introduction of anti-TNF, ∼80% of cases were found in the first 20 weeks with a mean of 26 weeks [167]. Although there are no data to suggest the optimal frequency of pulmonary monitoring, we suggest that routine PFT monitoring should be performed as clinically indicated, usually every 4–6 months. (i) Consideration, in consultation with a respiratory physician with a specialist interest in ILD, should be given to stopping biologic therapy in patients with worsening or new features of ILD. RTX or ABA may be considered in patients with worsening or new ILD (grade 2C, SOA 90%). Anti-TNF biologics Patients demonstrating worsening respiratory symptoms or lung function should have the input of a respiratory physician with a specialist interest in ILD to consider the possible causes of the decline as the differential includes causes potentially related to biologic therapy such as infection, congestive heart failure, progression of RA-ILD, drug-induced pneumonitis or other causes not related to biologic therapy such as COPD or pulmonary emboli. Although it is difficult to establish causation of worsening or new features of ILD to anti-TNF, and in fact an observational study by Herrinton et al. [162] found that anti-TNF therapy was not associated with a diagnosis of ILD in RA patients over a mean follow-up of 3 years, we would still recommend consideration of discontinuation of anti-TNF in these circumstances until data from further, larger studies is available. Non-anti-TNF biologics Although it is difficult to establish causation of worsening or new features of ILD to any of the non-anti-TNF biologics, a decision to discontinue therapy should be taken in conjunction with respiratory specialist colleagues with the understanding that based on current levels of evidence, ILD is unlikely to be caused or exacerbated by RTX, ABA or TCZ. There are no data available regarding UST in this context. Uveitis If patients develop uveitis while on a biologic a trial of an alternative biologic could be considered, bearing in mind the latest reported relative risks (grade 1C, SOA 99%). Consider switching patients with uveitis currently taking ETN to INF or ADA (grade 2C, SOA 98%). Anti-TNF biologics Refer to the earlier section on uveitis. Non-anti-TNF biologics There has been one case report of a patient with RA treated with TCZ who developed acute anterior uveitis 5 weeks after stopping TCZ [248]. Causality is difficult to establish here and indeed TCZ has been used with moderate success in patients with uveitis [173]. There are no data concerning RTX, ABA or UST and the development of uveitis. Demyelinating disease (i) Anti-TNF should be withdrawn if demyelination occurs. Rechallenge with anti-TNF therapy is not recommended (grade 2B, SOA 99%). Any suspected cases of demyelination should be investigated and reported appropriately and referred urgently to a neurologist. The rationale behind this statement is covered in the earlier section on demyelinating disease. Sixteen cases of Guillain–Barré syndrome were identified from the FDA database following anti-TNF therapy [249]. Among the 13 patients for whom follow-up data were available, one patient experienced no resolution, nine patients had partial resolution and three patients had complete resolution of Guillain–Barré syndrome following therapy. There are some reports of successful rechallenge with anti-TNF without recurrence of neurological symptoms, but there are also reports of worsening symptoms or recurrence on rechallenge. Diverticular disease (i) TCZ should be withdrawn if bowel perforation occurs; reintroduction of TCZ in such patients is not recommended (grade 2C, SOA 99%). Refer to the earlier section on diverticular disease. CTD (i) If a lupus-like syndrome or other significant autoimmune disease develops while on anti-TNF therapy, treatment should be discontinued and appropriate interventions should be initiated. In such instances, a non-anti-TNF biologic should be considered. Rechallenging with an alternative anti-TNF agent should only be undertaken with caution (grade 1C, SOA 99%). Anti-TNF biologics There continue to be further case reports of lupus-like syndromes, vasculitis and other autoimmune conditions developing after the commencement of anti-TNF therapy that improve on cessation of the anti-TNF, but often requiring alternative immunosuppression in more severe cases. Full-blown anti-TNF induced lupus or vasculitis remains rare. In a study by Takase et al. [250], 18% of patients had ANA seroconversion (83 of 454) when monitoring ANA results while on an anti-TNF, with seroconversion after a median period of 11 months. Only three of these patients were classifiable as lupus, however. BSRBR-RA reported on 11 394 anti-TNF patients followed for a total of 26 927 person-years [251]. Forty anti-TNF-treated patients developed a new lupus event, compared with only one of the DMARD-treated patients (adjusted IRR = 3.17, 95% CI: 0.38, 26.26). The most common lupus symptom was skin rash; LN or neuropsychiatric symptoms were not reported. Ramos-Casals et al. [252] identified 379 patients affected by an autoimmune condition induced by an anti-TNF through a Medline search up to May 2008. SLE/lupus-like disease was found in 105 patients. SLE criteria met were most commonly ANA positive, anti-dsDNA positive, malar rash then arthritis, with <10% having renal or CNS involvement. Treatment was anti-TNF withdrawal in 93% of cases. Thirty-six patients needed steroid or immunosuppression. Mean follow-up was 10 months, and all improved. A retrospective review of Mayo clinic records 1998–2011 [253] looked at the clinical features, histopathological features and outcomes where diagnosis of vasculitis induced by anti-TNF had been made. Cutaneous small vessel vasculitis was the most common but systemic involvement including peripheral nerve and renal vasculitis was frequently observed; mean duration of anti-TNF prior to development of vasculitis was 34.5 months (2–72 month range). Follow-up after vasculitis was a mean 27.1 months (1–108). No recurrence was seen in these patients on stopping anti-TNF and there was a mean time of 6.9 months to resolution of vasculitis after stopping anti-TNF with all receiving adjuvant treatment. No patients were rechallenged with an anti-TNF agent. In conclusion there are reports to suggest a small number of patients are at risk of developing a lupus or vasculitis problem when treated with anti-TNF but it is rare to have major organ involvement and symptoms usually resolve on stopping anti-TNF. Although only small numbers of patients have been rechallenged with anti-TNF, when undertaken this led to recurrence in up to 75%, hence the recommendation to use caution if considering rechallenge [252, 254, 255]. Non-anti-TNF biologics There are no data to suggest an association between any of the non-anti-TNF biologics and induction of autoimmune CTD or vasculitis. Haematological disorders (i) Biologic therapies may be continued in patients at increased risk of, or with, venous thromboembolism (VTE) (grade 2C, SOA 99%). Anti-TNF biologics Although some studies have reported a potential increased risk of VTE in anti-TNF users [256], a retrospective cohort study using BSRBR-RA data compared the rates of VTE in RA treated with anti-TNF (n = 11881) with those treated with csDMARD (n = 3673) and found no difference in the rates of VTE between anti-TNF and csDMARDs [257]; the risk was similar across all anti-TNF agents. The study was, however, not powered to detect differences of small magnitude. It should be noted that the observational nature of the BSRBR-RA predisposes to channelling bias (patients with more severe disease are more likely to be enrolled into the anti-TNF cohort). Therefore, continuation of biologic therapies in patients at increased risk can be recommended, as, in addition, higher disease activity may predispose to a prothrombotic state [258]. Risk would also be increased if active disease caused immobility. Non-anti-TNF biologics There are no data to suggest that any of the non-anti-TNF biologics increase the risk of VTE. Psoriasis (i) If psoriasis develops in patients treated with anti-TNF, conventional psoriasis treatment should be started and consideration should be given to stopping anti-TNF if the skin lesions persist despite specialist dermatology input or are severe (grade 2B, SOA 99%). Anti-TNF biologics Several studies have suggested that anti-TNF agents may paradoxically increase an individual’s risk of developing psoriasis, despite these agents being licensed and approved by NICE for the treatment of psoriasis. BSRBR-RA compared 9826 RA patients receiving anti-TNF agents (either IFX, ETN or ABA) against 2880 csDMARD patients [259]. Over 520 person-years of follow-up, 25 cases of new onset psoriasis were observed in those receiving anti-TNF, 52% of which occurred within the first 6 months of therapy, compared with 0 cases in the csDMARD group; this equated to a crude IR of 1.04 (95% CI: 0.67, 1.54) vs 0 (95% CI: 0.71) per 1000 person-years. In this cohort, the highest rates of psoriasis were found with ADA compared with ETN and INF. A higher incidence of psoriasis has also been found in the BIOBADASER cohort [260]. Out of 4437 patients receiving first-generation anti-TNF agents, 32 cases of psoriasis were observed, with an IR of 2.31 (95% CI: 1.69, 3.15). In this cohort, the highest event rate was noted for INF, and the lowest for ETN. The majority of patients who develop psoriasis while receiving anti-TNF agents do not stop therapy, and are able to manage the condition with add-on therapy [258, 260, 261]. In the BSRBR-RA cohort, only 4 of the 13 patients who developed psoriasis in the first 6 months of anti-TNF therapy stopped treatment due to psoriasis; all reported improvement in psoriasis after stopping therapy [258]. Similarly, a retrospective review of the Mayo clinic experience identified 56 RA patients who developed psoriasis while receiving anti-TNF treatment [260]. Of these, 62% continued with therapy and were treated successfully with add-on medication, although higher rates of complete skin remission were observed in those that stopped treatment. The most common forms of psoriasis that occurred in this cohort were plaque psoriasis and palmopustular psoriasis. A literature review by Collamer and Battafarano [262] found that around 50% of patients who switch to an alternative ant-TNF agent due to psoriasis will not experience a recurrence of their lesions. Non-anti-TNF biologics There is no convincing data to suggest an association between any of the non-anti-TNF biologics and the development of psoriasis. Vaccinations (i) The Public Health England recommendations on the use of immunizations in patients on immunosuppressive therapy should be adhered to in patients on biologics. Live attenuated vaccines, such as the HZ vaccine, oral polio or rabies vaccine, should be avoided (grade 2C, SOA 99%). Public Health England recommend that live attenuated vaccines should not be routinely given to individuals who are immunosuppressed (including those receiving biologic therapy). Live attenuated organisms can replicate in an immunosuppressed individual and cause an extensive, serious infection. If the use of live vaccines is necessary, at least 2 weeks, but preferably 4 weeks should be allowed before anti-TNF therapy is commenced. In terms of travel advice, yellow fever is a live vaccine and must not be given, and therefore patients should be advised not to travel to countries requiring this (e.g. mid-African nations). An exemption statement may be given if a patient has to travel but the patient will be at risk. Measles, mumps and rubella are live vaccines, so should not be given to a patient on anti-TNF but the vaccine is not contraindicated in household contacts. Exposure to measles should be treated with immunoglobulin regardless of prior immunization [263]. BCG vaccine for TB is contraindicated in patients on anti-TNF treatment as it is also a live vaccine [264]. Polio vaccine is an inactivated vaccine so may be given to immunosuppressed individuals (live polio vaccine was used up until 2004 in the UK) [265]. (ii) Although there may be an attenuated response (particularly if MTX is co-prescribed), patients on biologics should receive influenza and pneumococcal immunizations unless there are contraindications (grade 1C, SOA 99%). Patients receiving immunosuppressive therapy are advised to have both influenza and pneumococcal immunization. A limited number of studies are available investigating the response to vaccination in rheumatoid patients, with assessments made on RA patients treated with either MTX alone or in combination with anti-TNF. Influenza immunization Anti-TNF biologics There is some evidence that there are differences in response to immunization between each of the first-generation anti-TNF agents. While ADA has been shown not to reduce responsiveness to immunization [266], some studies have suggested that ETN and INF administration is associated with decreased response rates [267, 268]. A study by Elkayam et al. [269] showed an adequate response overall to influenza vaccine in patients with RA on INF, but a slightly attenuated response in the group that were vaccinated 3 weeks after receiving INF rather than on the same day. However, numbers were small (38 patients on INF, seven given vaccine 3 weeks after INF) [269]. A review [267] of influenza studies has indicated that this immunization is well tolerated; however, a subset of patients may remain unprotected. Some patients may be concerned that the influenza vaccine may provoke a flare of their RA. However, reassuringly, a recent study published by Milanetti et al. [270] noted no increase in flares of RA in patients receiving influenza immunizations, but a slight increase in minor systemic and local side effects such as fever, injection site swelling, headaches and myalgia. Non-anti-TNF biologics The efficacy of the influenza vaccine in patients treated with RTX has been examined in several cohort studies. A meta-analysis by Hua et al. [271] has shown that some response occurs, but it is attenuated if the patient is on the drug. Response rates may improve if vaccination is given further away from the last RTX infusion; Westra et al. [272] found that the IgG response to vaccination was restored in patients who had received RTX 6–10 months prior to vaccination. IgM response, however, did not change. There is a small amount of evidence regarding the other non-anti-TNF biologics and their effect on response to influenza vaccine. A small Brazilian study of 11 RA patients receiving ABA found a reduced immune response to the influenza vaccine [273]. There are no data concerning TCZ and UST and the influenza vaccination. Although there are limited data and the suggestion that response to vaccination may be attenuated, because non-anti-TNF biologics are immunosuppressive medications, it is recommended that all patients receiving biologic therapies continue to have a yearly influenza vaccination. Pneumococcal immunization Anti-TNF biologics While MTX is associated with lower response rates to pneumococcal vaccines in most studies [274–277], some studies have suggested that ETN or INF in combination with MTX are not associated with a poor response [266, 274–276]. The reasons for these differences are unclear, but the theory that certain anti-TNF agents can lead to enhanced immune responses was put forward from one study [274], where patients with MTX had lowered responsiveness, but this does not explain why those with the combination of INF or ETN with MTX had even better response rates than the healthy controls. In the case of ADA, ADA alone has not been shown to affect the antibody titre response to pneumococcal immunization, but the combination of MTX and ADA was shown to be associated with decreased response rates when compared with MTX alone [266]. More recent evidence from a Swedish case–control study [278] in a group of 505 patients with RA or SpA showed adequate response rates to pneumococcal vaccine. Better antibody response ratios were seen in patients on anti-TNF monotherapy, compared with those treated with MTX or MTX plus anti-TNF. Ongoing MTX was predictive of reduced response. Overall, pneumococcal vaccine is recommended in patients receiving anti-TNF therapy, but clinicians should be aware that the response to vaccination may be attenuated if anti-TNF and MTX are used in combination. Non-anti-TNF biologics A small study by Crnkic Kapetanovic et al. [279] found that among 88 patients with RA, the antibody response to the pneumococcal vaccine was reduced most notably for RTX, but also with ABA; TCZ, on the other hand, was associated with a sufficient antibody response. There are no data regarding treatment with UST and response to the pneumococcal vaccine. (iii) In patients who are currently receiving biologics, human papillomavirus vaccine for cervical cancer risk in young women is recommended if they have already received part of the vaccination schedule, as per national guidelines (grade 2C, SOA 99%). There is a national human papillomavirus (HPV) childhood vaccination programme in place in the UK, introduced in 2008 for secondary-school-age girls of 12–13 years, although girls may receive their HPV vaccination programme up to their 18th birthday. There are no data for the two-dose schedule for immunocompromised patients, and therefore the three-dose schedule should be given if a girl has already started or is due to start anti-TNF therapy. National advice states that re-immunization should be considered after treatment has finished or recovery occurred, and specialist advice may be required [280]. Kumar et al. [281] described reduced immunogenicity in organ transplant recipients. Although most at-risk individuals will have received papillomavirus vaccine in childhood, there may be scenarios where young adults receiving biologics over the age of 18 have not received vaccination. We suggest that in these circumstances, vaccination should be offered, even though the individual is outside of the national vaccination programme age window. Peri-operative care The potential benefit of preventing post-operative infections by stopping biologics (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a peri-operative flare in disease activity (grade 2B, SOA 97%). For most biologics (exceptions: RTX and TCZ), consideration should be given to planning surgery when at least one dosing interval has elapsed for that specific drug; for higher risk procedures consider stopping 3–5 half-lives (if this is longer than one dosing interval) before surgery (grade 2B, SOA 97%). Biologics may be recommenced after surgery when there is good wound healing (typically around 14 days), all sutures and staples are out, and there is no evidence of infection (grade 1B, SOA 99%). For patients receiving RTX, treatment should ideally be stopped 3–6 months prior to elective surgery (grade 2B, SOA 94%). For patients receiving TCZ, i.v. TCZ should be stopped at least 4 weeks before surgery; s.c. TCZ should be stopped at least 2 weeks before surgery (grade 1C, SOA 96%). Anti-TNF biologics Current literature provides conflicting data with regard to the risk of infection peri-operatively in association with anti-TNF therapy. A Dutch retrospective study [282] of 1219 surgical procedures in RA patients found that peri-operative continuation of anti-TNF therapy did not seem to be an important risk factor for surgical site infection. This is supported by evidence from several smaller studies [283, 284]. Larger studies from Canada [285], Japan [286] and Germany [287] showed no significant differences in surgical site infection rates in patients on anti-TNF therapy compared with csDMARDS; however, biologic therapy was withheld peri-operatively in >80% of cases. Another Japanese study of orthopaedic surgery found no statistically significant increase in the incidence of delayed wound healing or superficial infection with anti-TNF agents [288]. There was no correlation between peri-operative disease activity, dose of ETN (25 vs 50 mg) or preoperative waiting period off biologics (<14 or >14 days) and likelihood of adverse events. Conversely, other studies have reported an increased risk of peri-operative infection rates with continued use of anti-TNF agents [289]. One report showed that the continuation of anti-TNF therapy was associated with an increased risk of peri-operative infections (OR = 4.4, 95% CI: 1.10, 18.41) in a series of 91 RA patients undergoing orthopaedic procedures [290]. Data from the BSRBR-RA [291] showed that the risk of serious post-operative infection was nearly 2-fold higher in patients who received anti-TNF therapy in the 28 days prior to surgery than in those who were not exposed. Two further Japanese studies have supported these findings, with suggestion of even greater increased risk of peri-operative infection on anti-TNF. A retrospective cohort study of 420 women with RA, Momohara et al. [292] found that anti-TNF agents (INF, ETN, ADA) increased the risk of surgical site infection 9-fold. A higher risk still was identified in a smaller case–control study of 64 patients [293]; INF and ETN were associated with an OR of 21.8 for surgical site infection (95% CI: 1.231, 386.1; P = 0.036). ETN was withheld for 2–4 weeks prior to the operation and INF for 4 weeks prior to the surgery. Critics have suggested that the cases of infection were overstated, however, as infections were counted ‘when surgeons diagnosed or suspected a surgical infection, and antibiotics were given prophylactically’. Surgeons were not blind regarding which patients had been exposed to anti-TNF therapy, and so could have had a higher index of suspicion for infection in patients on anti-TNF and hence be more likely to prescribe antibiotics [294]. Blinded, prospective studies are therefore needed before firm conclusions can be drawn about the infection risk associated with anti-TNF agents. In 2008, Pappas and Giles [295] identified six major studies investigating the peri-operative infection risk of anti-TNF therapy associated specifically with orthopaedic surgery. All studies assessed involved retrospective outcome data and the source populations differed greatly between studies making direct comparison difficult. Of the six published major studies, only one study [290] identified an increased risk associated with peri-operative anti-TNF exposure, but the authors recommended that anti-TNF therapy should be stopped for a duration of three to five times their half-lives pre-operatively and restarted once the wound healing is deemed satisfactory (10–14 days). The half-lives of biologic therapies are shown in Table 7. This may be manageable for those biologic agents with reasonably short half-lives, but with agents such as ADA and ABA, where five times the half-life equates to >2 months, cessation for this prolonged period of time is likely to lead to potentially significant (and possibly irreversible) declines in the disease control and major flare, often requiring steroid therapy (and the associated risks, which may be higher than biologic therapy). Table 7 Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Table 7 Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Drug Dosing interval Period in which surgery should be scheduled (relative to last biologic dose administered) One half-life, days Five half-lives, days Adalimumab Every 2 weeks Week 3 14 70 Abatacept i.v./s.c. Monthly (i.v.) weekly (s.c.) Week 5 Week 2 14 70 Certolizumab Every 2 weeks Week 3 14 70 Every 4 weeks Week 5 Etanercept Weekly or twice weekly Week 2 3 15 Golimumab Every 4 weeks Week 5 14 70 Infliximab Every 4, 6 or 8 weeks Week 5, 7 or 9 9 45 Rituximab Two doses 2 weeks apart, no more frequent than every 6 months Months 4–7 18 90 Tocilizumab i.v. Every 4 weeks Week 5     4mg/kg 11 55     8mg/kg 13 65 Tocilizumab s.c. Every week Week 3 13 65 Ustekinumab Every 12 weeks Week 13 21 105 Pragmatically we suggest that surgery should be arranged for the week after the next scheduled dose of anti-TNF, and longer still (preferably five half-lives) if the surgery is deemed to be of especially high infection risk by the surgical team. With INF, five half-lives of the drug (45 days) may actually be shorter than the dosing interval, for example, patients receiving INF every 8 weeks. In this situation, ensuring that one dosing interval has elapsed before surgery should be sufficient even with procedures deemed to have a higher risk of infection. The idea behind this dosing principle is that the nadir of the drug’s effect would be at the end of its dosing interval. This is in line with advice from a recently published systematic review by the ACR and American Association of Hip and Knee Surgeons [296]. Non-anti-TNF biologics There is a paucity of data specific to non-anti-TNF biologics and peri-operative care. A retrospective study using the French AIR registry [297] identified 133 patients who had received RTX prior to a surgical procedure. Eight (6.7%) of the patients experienced a post-operative complication, including eight site infections and one deaths due to septic shock. Post-operative complications were higher in orthopaedic than abdominal surgery; however, only a significant association was seen with spinal surgery (P = 0.048). All patients had stopped RTX prior to surgery a mean of 6.4 months beforehand (interquartile range 4.3–8.7 months). There was no difference in event rates according to length of time off therapy prior to surgery. Unfortunately the study could not differentiate between acute and elective procedures, but 68% of procedures were orthopaedic. The number of complications was small and whether the time from infusion to complication of surgery is a major factor was difficult to interpret. TCZ is a very potent suppressor of acute phase response. A retrospective study looking at 161 patients on TCZ for RA undergoing orthopaedic surgery found 20 patients with wound healing delay, and three post-operative infections, two of which were superficial [292]. This study had no comparator, so conclusions are difficult to draw. Another study comparing patients undergoing surgery on TCZ and csDMARDS found those on TCZ did not mount as high a fever or as significant a rise in CRP as the csDMARD group. Following an infusion of i.v. TCZ, CRP and other markers of acute phase response reach a nadir between 1 and 3 weeks and then gradually return to normal. Although data are lacking, monitoring for post-operative infections in the first 4 weeks following a TCZ infusion is likely to be significantly hampered by a blunted acute phase response. Patients having i.v. or s.c. TCZ might need close monitoring in the post-operative period as the conventional indicators of sepsis (fever and acute phase response) might not be reliable. There are no data regarding ABA and UST in the peri-operative period. Until further evidence is available, and considering the balance between the potential risk of peri-operative complications vs the potential for disease flare if patients are without therapy for a prolonged period of time, we suggest that RTX is stopped at least 3–6 months prior to elective surgery; i.v. TCZ should be stopped at least 4 weeks prior to and s.c. TCZ at least 2 weeks prior to surgery. For all other non-anti-TNF biologics we suggest that surgery should be arranged for the week after the next scheduled dose of anti-TNF, and longer still (preferably five half-lives) if the surgery is deemed to be of especially high infection risk by the surgical team. Applicability and utility Clinician responsibility These guidelines represent a framework upon which clinical practice should be based. However, as with any guideline, individual patient circumstances can have important influences on clinical decision-making, and clinicians should continue to work alongside patients to make shared decisions about care. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. Potential organizational barriers to the guideline Biological therapy initiation should only take place under the supervision of an expert in the management of rheumatic disease (i.e. a consultant rheumatologist)—a recommendation supported across the NICE guidelines across the rheumatic disease areas. An important consideration regarding biologic therapy monitoring is the impact of frequent blood monitoring on health care services. Effective biologic therapy monitoring requires systems in place not only to ensure patients have regular blood tests, but also that the results of tests are reviewed and acted upon appropriately within a timely manner. The guideline makes three specific recommendations that will increase monitoring burden, as described below. All patients to be reviewed for drug safety in a specialist rheumatology department at least every 6 months. High risk patients (e.g. those at high risk of TB) should be reviewed every 3 months. Patients prescribed a biologic (other than TCZ) without concomitant csDMARD or with csDMARDs that do not require blood monitoring should have monitoring blood tests (FBC, renal and liver function) every 3–6 months. Patients prescribed i.v. or s.c. TCZ, with our without MTX, should have monitoring blood tests (FBC, liver function) every 4 weeks. Audit tool A model audit tool template is available for biologic therapy imitation and monitoring. The audit tool can be accessed via the BSR website. Overall summary and conclusions Biologic therapies represent a major advance in the treatment of IA, and appropriately their use continues to increase. Information on the longer term safety of these drugs continues to be collected both at a local level and through national registries across the world. Data remain scarce for the second-generation TNF inhibitors (CZB and GOL) and some of the newer non-anti-TNF biologic therapies (such as TCZ, ABA and UST). Similarly, there is a paucity of longer term observational safety data for any of the biosimilar therapies recently licensed and in increasing use worldwide. As questions in many commonly encountered clinical scenarios remain unanswered, it is essential that data on the safety of these products continue to be captured and reported, to inform further updates of this guideline. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: C.R.H. has been sponsored to attend meetings by AbbVie, Pfizer, Bristol-Myers Squibb and UCB and has received honoraria for speaking and attended advisory boards with AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Janssen and Novartis. R.S. has received sponsorship to attend the national BSR conference from Pfizer and has received honoraria to speak at regional educational meetings by AbbVie and Eli Lilly. M.B. has been sponsored to attend regional, national and international meetings by UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Janssen, Bristol-Myers Squibb, Novartis and Eli Lilly and received honoraria for speaking and attended advisory boards with Bristol-Myers Squibb, UCB Celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi aventis, Eli Lilly, Janssen and Novartis. A.M. has received honoraria for sponsored presentations from MSD, Bristol-Myers Squibb and Roche and received an honorarium from Pfizer for professional services. C.H. has received sponsorship to attend a national meeting by Pfizer. E.C. has received sponsorship to attend meetings by Pfizer and UCB and received honoraria for speaking for Eli Lilly. C.C. has received sponsorship to attend a national meeting by Pfizer. A.L. has received sponsorship to attend meetings and courses by AbbVie, Roche and UCB and has received honoraria for speaking by Roche/Chugai. 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Journal

Rheumatology – Oxford University Press

Published: Feb 1, 2019

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