A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease and Immune-mediated Inflammatory Diseases

A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in... Abstract Background Biologic therapies have revolutionised the treatment of immune-mediated diseases including inflammatory bowel disease [IBD] and rheumatological disorders. However, biologic treatments are associated with an increased risk of reactivation of latent tuberculosis. Data from regular monitoring for latent tuberculosis infection [LTBI] during biologic treatment are lacking. Methods Consecutive patients eligible for biologic therapies were screened for LTBI and prospectively followed up for 3 years. Incidence and risk factors of latent tuberculosis tests conversion (interferon gamma release assays [IGRA], tuberculin skin tests [TST], and chest radiography [CXR]) with clinical outcomes were studied. Results A total of 108 patients [83 IBD; 25 rheumatological disorders] were included. At baseline, 18/108 [16.7%] patients [five IBD; 13 rheumatological disorders] were tested positive for LTBI. Of these, 14/18 [77.8%] patients received isoniazid monotherapy for 9 months. Of the remainder, 17/90 [18.9%] patients had LTBI test conversion while on biologic therapies and of these 14/17 [82.4%] received isoniazid monotherapy for 9 months. Age, sex, smoking status, alcohol use, travel history, disease type, and immunosuppressive therapy were not associated with LTBI test conversion. In subjects with IGRA conversion, serial IGRA levels normalised after completion of isoniazid except in one patient whose IGRA remained persistently elevated despite isoniazid and who subsequently developed active TB. Conclusions Conversion of LTBI is common and occurred early during biologic therapy in an area with intermediate TB burden. Subjects with latent TB tests conversion and persistently high IGRA levels may have an increased risk of TB reactivation or development of active TB, and they require close observation or intensive workup for active TB. Biologic therapy, tuberculosis, inflammatory bowel disease 1. Introduction Biologic agents, including tumour necrosis factor [TNF] antagonist, are effective and are increasingly being used for the treatment of immune-mediated inflammatory diseases [IMIDs], including rheumatoid arthritis [RA], inflammatory bowel disease [IBD], ankylosing spondylitis, and psoriasis.1–3 Exposure to Mycobacterium tuberculosis [Mtb] often results in the development of latent tuberculosis infection [LTBI] with a 5–10% lifetime risk of progressing to active tuberculosis [TB] in immunocompetent hosts.4 However, reactivation of latent TB is more common in the setting of biologic therapies.5–8 The use of anti-TNF treatment in patients with Crohn’s disease and rheumatoid disorders has been associated with an approximately 14-fold increase risk of TB reactivation compared with healthy controls.9 The risk is further increased to over 40-fold if a combination of anti-TNF agent and immunomodulator is used.8 More than 50% of cases were extra-pulmonary disease and most cases occurred in endemic regions.4 Hong Kong is a region of intermediate TB burden, and the reactivation of latent TB in patients treated with biologics is a major public health concern. Current guidelines recommending TB screening10,11 and LTBI treatment before using biologics have had a substantial impact on reducing the incidence of TB.12,13 Preventive therapy with daily isoniazid offers 60% to 90% protection and combination therapies [daily isoniazid-rifampicin or weekly isoniazid-rifapentine] are effective alternatives.14 Tuberculin skin testing [TST] and interferon gamma release assay [IGRA] are currently two accepted methods for screening Mtb-exposed individuals for LTBI. False-positive results can occur as a result of boosting from repeated TST, previous bacillus Calmette-Gu′erin [BCG] vaccination, or infection with non-tuberculous mycobacteria.15 Since BCG vaccination was introduced in Hong Kong in 1952, more than 99% of newborn infants have received BCG vaccination at birth.16 TST may also be falsely negative in immunocompromised patients, due to either the underlying diseases or the immunosuppressive therapy.17–19 A false-negative TST may also occur during active IBD without immunosuppression.20 Recently interferon gamma release assays [IGRAs] have been introduced to compensate for the drawbacks of TST in detecting LTBI. Studies have shown that IGRAs are superior to TSTs in identifying LTBI in immunosuppressed and BCG-vaccinated populations.21,22 However, work from our group23 and a meta-analysis24 have shown that immunosuppressive therapy may also negatively affect the results of IGRA. Although studies have shown that both IGRA conversion and reversion may occur during the course of immunosuppressive therapy,25,26 prospective studies assessing the value of monitoring IGRAs in patients with IMID on biologic therapy in countries with intermediate to high TB incidence are lacking. This is particularly important, as these countries are also experiencing a rising incidence of IBD accompanied by increased use of biologics in the past decade.27 This study aimed to assess the frequency of LTBI test conversion and the subsequent risk of TB during long-term biological therapy in patients with IMIDs. Such data will inform us whether regular TB monitoring is required during biologic therapy in TB-endemic areas. This study can potentially have an impact on the current guidelines regarding monitoring of TB during biologic therapy. 2. Materials and Methods 2.1. Data source and study design Patients with a confirmed diagnosis of inflammatory bowel disease [IBD] (including Crohn’s disease [CD] and ulcerative colitis [UC]), rheumatoid arthritis [RA], ankylosing spondylitis [AS], psoriasis, psoriatic arthritis [PA], or other rheumatic diseases who are considered for biologic therapy at the Prince of Wales Hospital, Hong Kong, were prospectively recruited from January 2012 and followed up till September 2017. Clinical data of disease characteristics and concomitant medications were collected at baseline and at each follow-up. At baseline, history of BCG vaccination, previous personal, family, and occupational tuberculosis exposure, travel and immigration history, and smoking status were recorded. Travel history to a high-risk area during the study period was defined as any visit to high TB-burden countries according to the World Health Organization Global Tuberculosis Report 2016. A history of comorbidities including diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease [COPD], nad chronic kidney disease [CKD], were recorded from the clinical consultation notes. Bfore commencement of biologic therapy, the TST and IGRA tests and a chest X-ray [CXR] were performed in all patients. Patients with a positive TST, IGRA or CXR indicative of latent tuberculosis were given prophylactic TB treatment based on the clinician’s assessment and discretion before commencement of biologic therapy. We followed local guidelines by using isoniazid monotherapy for 9 months,28 and the biologics were not started until completing 1 month of isoniazid prophylaxis. Subjects were followed up every 4 months. At each visit, a detailed interview including history of fever, weight loss, chills, cough, and exposure to TB were obtained. All subjects had a CXR every 6–8 months, repeat IGRA every 4months, and a TST every 12 months during biolog therapy for up to 3 years. Any individual with a positive TST, IGRA, or CXR indicative of latent tuberculosis were screened for active TB, and referred to an infectious disease physician for management as necessary. This study was approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. Informed consent was signed by all participants before participation in this study. 2.2. Definitions 2.2.1. TB screening test IGRA was performed using the QFT-G assay [Cellestis, Melbourne, Australia] by a trained technician blinded to the results of the diagnosis and blood tests, in accordance with the manufacturer’s instructions. In brief, 1 mL aliquot of heparinised blood from each subject was incubated within 12 h of blood collection with stimulation antigens [ESAT-6, CFP-10, TB-7.7, and mitogen] and nil control for 16 to 24 h at 37°C. Plasma was then harvested for interferon gamma measurement using enzyme-linked immunoassay. The result was calculated using the QFT-G analysis software. The result was considered positive if ESAT/CFP-10 minus nil control were ≥0.35 IU/mL and ≥25% of nil, or negative if mitogen minus nil was ≥0.5 IU/mL, or indeterminate if mitogen minus nil was <0.5 IU/mL. TST was performed by injecting 0.1 mL [2 units] of tuberculin purified protein derivative RT23 [Statens Serum Institut, Copenhagen, Denmark] intradermally over the forearm. The induration was evaluated 48 to 72 h after the injection, by a trained physician. TST was considered positive if the diameter of induration was ≥5 mm in size. Postero-anterior CXRs were interpreted by an experienced radiologist [EH]. Findings were divided into three categories: normal, positive with suspicion of latent TB, or positive with suspicion of consolidation, malignancy, or other findings. Findings on CXR indicative of latent TB included apical or basal pleural thickening, fibrous scarring, calcified granuloma, or lymph nodes. 2.3. Latent TB infection and active TB LTBI was defined as having at least one screening test [TST, IGRA, or CXR] positive, whereas active TB was defined as having active symptoms consistent with TB with positive microbiological evidence of TB (positive acid-fast bacillus smear, TB culture, or polymerase chain reaction [PCR]). IGRA conversion was defined by a reproducibly positive result under biological therapy after a negative baseline test. TST conversion was defined by the negative baseline TST becoming positive [≥5 mm of induration] under biological therapy.29 CXR conversion was defined by new X-ray features indicating active TB after a normal CXR at baseline. Reversion was defined as a negative test result after a positive result in previous tests. 2.4. Biologic and immunosuppressive therapies The dosage, frequency, and route of administration of biologic therapies were given according to the standard prescription information of the respective drugs, and adjustments were made accordingly based on patients’ clinical conditions and clinicians’ discretion. Immunosuppressive medication was defined as ≥15 mg/day of prednisone or equivalent for 1 month or longer,29,30 or any dose of azathioprine, 6-mercaptopurine, or methotrexate and leflunomide. Biological therapies included infliximab, adalimumab, certolizumab, golimumab, etanercept, ustekinumab and tocilizumab. 2.5. Statistical analysis Data were presented as frequencies and percentages as mean and standard deviation or median values with range, respectively. Group data were compared using Student’s t test for quantitative variables and the chi-square [x2] test or Fisher’s exact test for categorical variables. Logistic regression analysis was performed to study the factors associated with conversion of LTBI tests. Statistical analysis was conducted using SPSS Statistics V.17.0 [SPSS, Chicago, IL, USA] and STATAV.11.1 [StataCorp, College Station, TX, USA]. Statistical significance was set at p <0.05. 3. Results 3.1. Patient characteristics A total of 108 patients on biologics were recruited (70 Crohn’s disease [CD], 12 ulcerative colitis [UC], one IBD unclassified [IBDU], eigh rheumatoid arthritis [RA], two ankylosing spondylitis [AS], one psoriasis, and 14 psoriatic arthritis [PA]) [Table 1]. All subjects were of Chinese ethnicity apart from four subjects [three Caucasians; one Indo-Chinese]. Table 1. Patient characteristics. Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] aConverters are defined as patients with conversion of at least one screening assay. bNot mutually exclusive, four patients on two biologics. LTBI, latent tuberculosis infection; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. View Large Table 1. Patient characteristics. Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] aConverters are defined as patients with conversion of at least one screening assay. bNot mutually exclusive, four patients on two biologics. LTBI, latent tuberculosis infection; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. View Large Patients were treated with infliximab [n = 63], adalimumab [n = 28], certolizumab [n = 5], golimumab [n = 9], etanercept [n = 2], ustekinumab [n = 5], or tocilizumab [n = 2]. Among these patients, four were initially on infliximab and subsequently switched to adalimumab due to a loss of response, and two switched from etanercept to golimumab. At baseline, 18 patients [16.7%] tested positive for LTBI [three IGRA-positive, nine TST-positive, one CXR-positive, and five both IGRA- and TST-positive]. These patients positive for LTBI at baseline comprised one UC and two PA patients with IGRA positivity alone; three CD, three RA, one AS, and two PA patients with TST positivity alone; one CD patient with CXR positivity alone; and one RA, one psoriasis and three PA patients with both IGRA and TST positivity [Table 2]. Table 2. Positive latent tuberculosis infection screening tests at baseline. N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray. View Large Table 2. Positive latent tuberculosis infection screening tests at baseline. N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray. View Large A total of 14 out of 18 patients positive for latent TB infection were given isoniazid monotherapy before commencing biologic therapy. Three of the psoriasis patients [two IGRA-positive and one both IGRA- and TST-positive] were diagnosed with latent TB previously [between 2008 and 2010 and completed isoniazid prophylaxis] and one CD [with CXR suggestive of LTBI which showed right upper and middle zone fibrosis] had a history of mycobacterium avian complex disease in 2006 and had completed a full course of anti-mycobacterial treatment. All these four patients were not given any more isoniazid prophylaxis before initiation of biologic therapy. 3.2. Conversion of LTBI tests Patients were followed up for a median of 16 months (interquartile range [IQR]: 6–24). Among patients with a negative baseline test for LTBI [n = 90; 18 patients with IBD, 12 with rheumatic diseases patients with rheumatic diseases], 17 [18.9%] had a conversion with one or more of the TB tests from negative to positive [Table 3]. Fourteen of these patients with conversion of LTBI tests received isoniazid prophylaxis during their course of biologic treatment which was not interrupted. One patient with CD had conversion of TST and IGRA, and later developed active TB despite completion of isoniazid treatment. One CD patient had only IGRA conversion 5 months after stopping the biologic treatment [biologic treatment was stopped earlier, as patient achieved mucosal healing and was in deep remission]. Another two CD patients with TST conversion were not given isoniazid, based on the discretion of the treating doctors. Table 3. Characteristics of patients who converted at least one screening test during biological therapy. Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab M, male; F, female; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray; CD, Crohn’s disease; PsA, psoriatic arthritis aPreviously on infliximab. View Large Table 3. Characteristics of patients who converted at least one screening test during biological therapy. Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab M, male; F, female; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray; CD, Crohn’s disease; PsA, psoriatic arthritis aPreviously on infliximab. View Large 3.3. Factors associated with TB test conversion Univariate analysis was performed to examine factors associated with LTBI conversion. None of the factors, including age, sex, smoking status, alcohol, travel history to high TB-burden countries, type of disease, type of biologic treatments [anti-TNF or non anti-TNF], or changes of immunosuppressive therapies after initiation of biologic treatment, was significantly associated with LTBI conversion in univariate analysis [Table 4]. There were nor significant association factors in terms of IGRA conversion [Table 5]. Table 4. Univariate analysis of factors associated with conversion of at least one screening assay during anti-TNF therapy. OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference cAddition of immunosuppressnats or increase in dose View Large Table 4. Univariate analysis of factors associated with conversion of at least one screening assay during anti-TNF therapy. OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference cAddition of immunosuppressnats or increase in dose View Large Table 5. Univariate analysis of factors associated with IGRA conversion during anti-TNF therapy. OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference. cAddition of immunosuppressant or increase in dose. View Large Table 5. Univariate analysis of factors associated with IGRA conversion during anti-TNF therapy. OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference. cAddition of immunosuppressant or increase in dose. View Large 3.4. Patient developing active tuberculosis Out of 108 patients, one CD patient [male, aged 27] developed active TB at 20 months after commencement of infliximab. Initial screening for TB was negative. This patient had IGRA seroconversion 4 months after initiation of infliximab. He received isoniazid prophylaxis for 9 months. Seven months after completion of LTBI treatment, he presented with fever and cough with whitish sputum. His chest radiography showed right upper zone consolidation. Bronchoscopy was performed, and bronchoalveolar lavage was positive for acid-fast bacillus [AFB] smear and culture yielded Myobacterium tuberculosis. He was started on isoniazid [H], rifampicin [R], ethambutol [M], and pyrazinamide [Z]. Infliximab was stopped after the diagnosis of active TB. His IGRA level became negative at the end of TB treatment and remained negative on subsequent tests. His CD was under control with weekly methotrexate. 3.5. Pattern of changes of IGRA levels for baseline LTBI-positive patients and those with LTBI tests conversion Eight subjects [one UC; seven rheumatic diseases] had a positive IGRA at baseline [three with IGRA alone and five with both IGRA and TST] at baseline. All patients with rheumatic diseases were on methotrexate. Three of the patients with rheumatic diseases did not receive isoniazid prophylaxis. They all showed fluctuating levels of IGRA, and one patient had persistent low positive IGRA levels <4 [0.47–0.65] with spontaneous reversion in between. The other two had intermittent levels of >4 [Figure 1]. None of these patients developed active TB during the study period. Figure 1. View largeDownload slide Pattern of changes of IGRA levels for baseline IGRA-positive patients. Figure 1. View largeDownload slide Pattern of changes of IGRA levels for baseline IGRA-positive patients. For those with IGRA conversion [n = 6; three with IGRA alone, three with both IGRA and TST], their IGRA at conversion was in the range of 0.57–20.57. Most of them [4/6, 66.7%] had conversion during the first 6 months of initiation of biologic treatment. Among those who were treated with isoniazid [four CD and one psoriasis; one CD was not treated, as mentioned earlier], the IGRA was negative at the end of isoniazid treatment [Figure 2] except one [IGRA of 20.57 during conversion, remaining elevated at 7.58 after 3 months’ completion of isoniazid prophylaxis] who subsequently developed active TB. Figure 2. View largeDownload slide Pattern of changes of IGRA levels for IGRA-conversion patients. Figure 2. View largeDownload slide Pattern of changes of IGRA levels for IGRA-conversion patients. 3.6. Pattern of changes of tuberculin tests for baseline LTBI=positive patients and those with LTBI tests conversion There were 14 patients with baseline positive tuberculin tests. Twelve of these received isoniazid and the other two had completed isoniazid prophylaxis before recruitment into the study. After completion of isoniazid, seven had persistently positive tuberculin tests at 1 year as per protocol. Three other patients had subsequent negative tuberculin tests. For those not treated with isoniazid, one had persistently positive tests and one had negative tuberculin tests upon repeated testing. Overall, the reversion rate of those with baseline positive tuberculin tests after completion of isoniazid was 30% [3/10 excluding two subjects who had not yet repeated their tuberculin tests]. On the other hand, nine patients had conversion of their tuberculin tests, all of whom received isoniazid prophylaxis. For those with conversion of tuberculin tests upon completion of LTBI treatment, three had reversion, two remained positive, and another four had yet to repeat their tuberculin tests. 4. Discussion In this prospective study comprising mainly IBD patients followed up for a median of 2 years, we found that latent TB tests conversion is common in a region of intermediate to high TB incidence. During the follow-up, none of the subjects who had positive LTBI tests at baseline developed active TB during or after treatment with isoniazid prophylaxis. Furthermore, in those who had LTBI test conversion after initiation of biologic therapy, one patient with IBD developed active TB despite isoniazid prophylaxis. Overall, 16.7% patients had baseline positive latent TB before biologic treatment [most of whom received isoniazid] and 18.9% of the remaining patients had conversion of any one of the latent TB tests during biologic therapy. Isoniazid monotherapy showed effective protection in 96% [27/28] of subjects against the development of active TB in our IMID cohort with LTBI. Our findings were slightly higher compared with an earlier study reporting an incidence of active TB of 1.65% despite LTBI screening and treatment, and the majority of cases appeared within the first 4 months after starting therapy.31 All six patients who had IGRA conversion were on other immunosuppressive medications, which may explain the possibility of false-negative results at baseline. We repeated TST on an annual basis rather than at shorter intervals, in order to reduce the ‘boosting phenomenon’ due to repeated TST. Boosting is maximal if the interval between the first and second test is between 1 and 5 weeks32,33 and is much less frequent if the interval is only 48 h34 or more than 60 days.32 Hence in this group of patients, even though the IGRAs were negative, we believe the TST conversion was genuinely representative of latent TB due to likely re-exposure in this country after initiation of biologic therapy. The lower prevalence of LTBI among IBD patients could be due to false-negative results secondary to steroid use which is common in IBD patients before escalation to immunomodulators or biologics. In contrast, steroids are less commonly used in the rheumatological cohorts comprising mostly patients with psoriasis. The exact cause for the higher conversion on biologics in CD [most of whom were on infliximab] compared with UC or rheumatology patients is unclear, but may relate to disease and patient factors whereby CD patients require more frequent visits or hospitalisation and are more likely to be exposed. The value of monitoring IGRA during treatment of both active and latent TB has been controversial. However, we believe that IGRA in addition to CXR has an important role in detection of TB, since more than 50% of reactivation occurred at extrapulmonary sites. A recent meta-analysis showed that IGRA quantitatively dropped with treatment but with substantial variation among studies, and hence it may not be useful in clinical practice.35 Our cohort showed that IGRA levels dropped in those who had conversion but not in those with baseline IGRA positivity after treatment with isoniazid. Besides, all three psoriasis patients with baseline IGRA positivity, yet not treated with isoniazid [background history of past latent TB and completed treatment many years ago], demonstrated great variation in changes of IGRA level during biologic treatment. One recent study had shown that conversion at interferon gamma values higher than 4.00 IU/mL was linked to a more than 40 times higher risk of developing tuberculous disease in the following 6 to 24 months (incidence rate ratio [IRR] 42.2, 95% confidence onterval [CI] 17.2–99.7, p <0.001]. In contrast, conversion values in the range of 0.35–4.00 IU/mL had low predictive value for tuberculous disease [IRR of 3.7; 2.5 per 100 person-years as compared with 0.7 person-year in IGRA-negative subjects] and were associated with high rates [77%] of reversion.36 Our data were consistent with this observation, even though the number of IGRA conversions was small. Five out of the six IGRA converters had levels below 4 IU/ml, and none of them developed active TB after isoniazid prophylaxis. Papay et al. showed that in patients with negative LTBI at baseline, IGRA conversion during biologic therapy occurred but was usually transient and results generally turned negative upon repeated testing. Although no was isoniazid given, none of the subjects developed active TB after a median of 39 months’ follow-up.26 However, in our cohort, the decision to initiate isoniazid prophylaxis was based on a single IGRA conversion result rather than repeated samples. In contrast, the one patient who had IGRA levels persistently higher than 4 IU/ml developed active TB despite completion of isoniazid prophylaxis. The most reassuring observation from this study is that none of the patients with negative IGRA tests during biologic treatment developed TB during follow-up. These data suggest that false-negative results during therapy are less likely. In addition, our study showed that serial IGRAs have a meaningful role in monitoring subjects who had LTBI test conversion during biologic therapy. Subjects with persistently high IGRAs of more than 4 IU/ml upon completion of isoniazid prophylaxis may be at an increased risk of development of active TB, and require closer observation or intensive workup for active TB. In contrast, in subjects with a positive baseline latent TB tests, the role of serial IGRA monitoring during biologic treatment remains to be defined by longer and larger prospective studies. The main limitation of our study is a modest sample size and a relatively short period of follow-up for patients with baseline IGRA positive results, who may develop active TB later. It is also likely that monitoring with yearly CXR and IGRA will be sufficient for latent TB monitoring. In clinical practice, we often face the conundrum of indeterminate IGRA results, especially in patients on immunosuppressive treatments. Studies have shown that indeterminate results are associated with steroid and immunosuppressants use.37,38 Hence we recommend latent TB testing before initiation of immunosuppressants in patients at high risk in anticipation of escalation of treatment.23 In conclusion, latent TB tests conversion is common and occurs early during biologic treatment. Isoniazid monotherapy prophylaxis is effective in prevention of active TB. Serial IGRAs may have a role in monitoring those with latent TB tests conversion. Funding We would like to acknowledge the funding from the Food and Health Bureau [CU-15-A6]. Conflict of Interest None declared. Author Contributions CKL, SHW, GL, WT, LST, MI, EH, MC, JCW: study design, patient identification, data collection, and manuscript revision. SCN: study design, supervision of the study,. SCN had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. References 1. Hanauer SB , Feagan BG , Lichtenstein GR , et al. ; ACCENT I Study Group . Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial . Lancet 2002 ; 359 : 1541 – 9 . Google Scholar CrossRef Search ADS PubMed 2. Braun J , Brandt J , Listing J , et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial . Lancet 2002 ; 359 : 1187 – 93 . Google Scholar CrossRef Search ADS PubMed 3. Saag KG , Teng GG , Patkar NM , et al. ; American College of Rheumatology . 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Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease and Immune-mediated Inflammatory Diseases

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Elsevier Science
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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
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10.1093/ecco-jcc/jjy057
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Abstract

Abstract Background Biologic therapies have revolutionised the treatment of immune-mediated diseases including inflammatory bowel disease [IBD] and rheumatological disorders. However, biologic treatments are associated with an increased risk of reactivation of latent tuberculosis. Data from regular monitoring for latent tuberculosis infection [LTBI] during biologic treatment are lacking. Methods Consecutive patients eligible for biologic therapies were screened for LTBI and prospectively followed up for 3 years. Incidence and risk factors of latent tuberculosis tests conversion (interferon gamma release assays [IGRA], tuberculin skin tests [TST], and chest radiography [CXR]) with clinical outcomes were studied. Results A total of 108 patients [83 IBD; 25 rheumatological disorders] were included. At baseline, 18/108 [16.7%] patients [five IBD; 13 rheumatological disorders] were tested positive for LTBI. Of these, 14/18 [77.8%] patients received isoniazid monotherapy for 9 months. Of the remainder, 17/90 [18.9%] patients had LTBI test conversion while on biologic therapies and of these 14/17 [82.4%] received isoniazid monotherapy for 9 months. Age, sex, smoking status, alcohol use, travel history, disease type, and immunosuppressive therapy were not associated with LTBI test conversion. In subjects with IGRA conversion, serial IGRA levels normalised after completion of isoniazid except in one patient whose IGRA remained persistently elevated despite isoniazid and who subsequently developed active TB. Conclusions Conversion of LTBI is common and occurred early during biologic therapy in an area with intermediate TB burden. Subjects with latent TB tests conversion and persistently high IGRA levels may have an increased risk of TB reactivation or development of active TB, and they require close observation or intensive workup for active TB. Biologic therapy, tuberculosis, inflammatory bowel disease 1. Introduction Biologic agents, including tumour necrosis factor [TNF] antagonist, are effective and are increasingly being used for the treatment of immune-mediated inflammatory diseases [IMIDs], including rheumatoid arthritis [RA], inflammatory bowel disease [IBD], ankylosing spondylitis, and psoriasis.1–3 Exposure to Mycobacterium tuberculosis [Mtb] often results in the development of latent tuberculosis infection [LTBI] with a 5–10% lifetime risk of progressing to active tuberculosis [TB] in immunocompetent hosts.4 However, reactivation of latent TB is more common in the setting of biologic therapies.5–8 The use of anti-TNF treatment in patients with Crohn’s disease and rheumatoid disorders has been associated with an approximately 14-fold increase risk of TB reactivation compared with healthy controls.9 The risk is further increased to over 40-fold if a combination of anti-TNF agent and immunomodulator is used.8 More than 50% of cases were extra-pulmonary disease and most cases occurred in endemic regions.4 Hong Kong is a region of intermediate TB burden, and the reactivation of latent TB in patients treated with biologics is a major public health concern. Current guidelines recommending TB screening10,11 and LTBI treatment before using biologics have had a substantial impact on reducing the incidence of TB.12,13 Preventive therapy with daily isoniazid offers 60% to 90% protection and combination therapies [daily isoniazid-rifampicin or weekly isoniazid-rifapentine] are effective alternatives.14 Tuberculin skin testing [TST] and interferon gamma release assay [IGRA] are currently two accepted methods for screening Mtb-exposed individuals for LTBI. False-positive results can occur as a result of boosting from repeated TST, previous bacillus Calmette-Gu′erin [BCG] vaccination, or infection with non-tuberculous mycobacteria.15 Since BCG vaccination was introduced in Hong Kong in 1952, more than 99% of newborn infants have received BCG vaccination at birth.16 TST may also be falsely negative in immunocompromised patients, due to either the underlying diseases or the immunosuppressive therapy.17–19 A false-negative TST may also occur during active IBD without immunosuppression.20 Recently interferon gamma release assays [IGRAs] have been introduced to compensate for the drawbacks of TST in detecting LTBI. Studies have shown that IGRAs are superior to TSTs in identifying LTBI in immunosuppressed and BCG-vaccinated populations.21,22 However, work from our group23 and a meta-analysis24 have shown that immunosuppressive therapy may also negatively affect the results of IGRA. Although studies have shown that both IGRA conversion and reversion may occur during the course of immunosuppressive therapy,25,26 prospective studies assessing the value of monitoring IGRAs in patients with IMID on biologic therapy in countries with intermediate to high TB incidence are lacking. This is particularly important, as these countries are also experiencing a rising incidence of IBD accompanied by increased use of biologics in the past decade.27 This study aimed to assess the frequency of LTBI test conversion and the subsequent risk of TB during long-term biological therapy in patients with IMIDs. Such data will inform us whether regular TB monitoring is required during biologic therapy in TB-endemic areas. This study can potentially have an impact on the current guidelines regarding monitoring of TB during biologic therapy. 2. Materials and Methods 2.1. Data source and study design Patients with a confirmed diagnosis of inflammatory bowel disease [IBD] (including Crohn’s disease [CD] and ulcerative colitis [UC]), rheumatoid arthritis [RA], ankylosing spondylitis [AS], psoriasis, psoriatic arthritis [PA], or other rheumatic diseases who are considered for biologic therapy at the Prince of Wales Hospital, Hong Kong, were prospectively recruited from January 2012 and followed up till September 2017. Clinical data of disease characteristics and concomitant medications were collected at baseline and at each follow-up. At baseline, history of BCG vaccination, previous personal, family, and occupational tuberculosis exposure, travel and immigration history, and smoking status were recorded. Travel history to a high-risk area during the study period was defined as any visit to high TB-burden countries according to the World Health Organization Global Tuberculosis Report 2016. A history of comorbidities including diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease [COPD], nad chronic kidney disease [CKD], were recorded from the clinical consultation notes. Bfore commencement of biologic therapy, the TST and IGRA tests and a chest X-ray [CXR] were performed in all patients. Patients with a positive TST, IGRA or CXR indicative of latent tuberculosis were given prophylactic TB treatment based on the clinician’s assessment and discretion before commencement of biologic therapy. We followed local guidelines by using isoniazid monotherapy for 9 months,28 and the biologics were not started until completing 1 month of isoniazid prophylaxis. Subjects were followed up every 4 months. At each visit, a detailed interview including history of fever, weight loss, chills, cough, and exposure to TB were obtained. All subjects had a CXR every 6–8 months, repeat IGRA every 4months, and a TST every 12 months during biolog therapy for up to 3 years. Any individual with a positive TST, IGRA, or CXR indicative of latent tuberculosis were screened for active TB, and referred to an infectious disease physician for management as necessary. This study was approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. Informed consent was signed by all participants before participation in this study. 2.2. Definitions 2.2.1. TB screening test IGRA was performed using the QFT-G assay [Cellestis, Melbourne, Australia] by a trained technician blinded to the results of the diagnosis and blood tests, in accordance with the manufacturer’s instructions. In brief, 1 mL aliquot of heparinised blood from each subject was incubated within 12 h of blood collection with stimulation antigens [ESAT-6, CFP-10, TB-7.7, and mitogen] and nil control for 16 to 24 h at 37°C. Plasma was then harvested for interferon gamma measurement using enzyme-linked immunoassay. The result was calculated using the QFT-G analysis software. The result was considered positive if ESAT/CFP-10 minus nil control were ≥0.35 IU/mL and ≥25% of nil, or negative if mitogen minus nil was ≥0.5 IU/mL, or indeterminate if mitogen minus nil was <0.5 IU/mL. TST was performed by injecting 0.1 mL [2 units] of tuberculin purified protein derivative RT23 [Statens Serum Institut, Copenhagen, Denmark] intradermally over the forearm. The induration was evaluated 48 to 72 h after the injection, by a trained physician. TST was considered positive if the diameter of induration was ≥5 mm in size. Postero-anterior CXRs were interpreted by an experienced radiologist [EH]. Findings were divided into three categories: normal, positive with suspicion of latent TB, or positive with suspicion of consolidation, malignancy, or other findings. Findings on CXR indicative of latent TB included apical or basal pleural thickening, fibrous scarring, calcified granuloma, or lymph nodes. 2.3. Latent TB infection and active TB LTBI was defined as having at least one screening test [TST, IGRA, or CXR] positive, whereas active TB was defined as having active symptoms consistent with TB with positive microbiological evidence of TB (positive acid-fast bacillus smear, TB culture, or polymerase chain reaction [PCR]). IGRA conversion was defined by a reproducibly positive result under biological therapy after a negative baseline test. TST conversion was defined by the negative baseline TST becoming positive [≥5 mm of induration] under biological therapy.29 CXR conversion was defined by new X-ray features indicating active TB after a normal CXR at baseline. Reversion was defined as a negative test result after a positive result in previous tests. 2.4. Biologic and immunosuppressive therapies The dosage, frequency, and route of administration of biologic therapies were given according to the standard prescription information of the respective drugs, and adjustments were made accordingly based on patients’ clinical conditions and clinicians’ discretion. Immunosuppressive medication was defined as ≥15 mg/day of prednisone or equivalent for 1 month or longer,29,30 or any dose of azathioprine, 6-mercaptopurine, or methotrexate and leflunomide. Biological therapies included infliximab, adalimumab, certolizumab, golimumab, etanercept, ustekinumab and tocilizumab. 2.5. Statistical analysis Data were presented as frequencies and percentages as mean and standard deviation or median values with range, respectively. Group data were compared using Student’s t test for quantitative variables and the chi-square [x2] test or Fisher’s exact test for categorical variables. Logistic regression analysis was performed to study the factors associated with conversion of LTBI tests. Statistical analysis was conducted using SPSS Statistics V.17.0 [SPSS, Chicago, IL, USA] and STATAV.11.1 [StataCorp, College Station, TX, USA]. Statistical significance was set at p <0.05. 3. Results 3.1. Patient characteristics A total of 108 patients on biologics were recruited (70 Crohn’s disease [CD], 12 ulcerative colitis [UC], one IBD unclassified [IBDU], eigh rheumatoid arthritis [RA], two ankylosing spondylitis [AS], one psoriasis, and 14 psoriatic arthritis [PA]) [Table 1]. All subjects were of Chinese ethnicity apart from four subjects [three Caucasians; one Indo-Chinese]. Table 1. Patient characteristics. Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] aConverters are defined as patients with conversion of at least one screening assay. bNot mutually exclusive, four patients on two biologics. LTBI, latent tuberculosis infection; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. View Large Table 1. Patient characteristics. Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] Convertersa [n = 17] Non-converters [n = 73] Baseline LTBI [n = 18] Total [n = 108] Median age 35.0 [27.0–42.0] 36.0 [25.0–48.0] 54.5 [38.0–58.0] 36.5 [26.0–51.0] Sex [male]  Male 11 [64.7%] 43 [58.9%] 13 [72.2%] 67 [62.0%]  Female 6 [35.3%] 30 [41.1%] 5 [27.8%] 41 [38.0%] Smoking  Current 2 [11.8%] 6 [8.2%] 5 [27.8%] 13 [12.0%]  Ex 0 [0.0%] 5 [6.8%] 3 [16.7%] 8 [7.4%]  Never 15 [88.2%] 62 [85.0%] 10 [55.5%] 87 [80.6%] Alcohol  Current 0 [0.0%] 4 [5.5%] 5 [27.8%] 9 [8.4%]  Ex 0 [0.0%] 5 [6.8%] 0 [0.0%] 5 [4.6%]  Never 17 [100.0%] 64 [87.7%] 13 [72.2%] 94 [87.0%] Patient disease type  CD 15 [88.2%] 51 [69.9%] 4 [22.2%] 70 [64.8%]  UC 0 [0.0%] 11 [15.1%] 1 [5.6%] 12 [11.1%]  IBDU 0 [0.0%] 1 [1.3%] 0 [0.0%] 1 [0.9%]  Rheumatic disease 2 [11.8%] 10 [13.7%] 13 [72.2%] 25 [23.2%] Biological therapyb Anti-TNF  Infliximab 11 [64.7%] 48 [65.8%] 4 [22.2%] 63 [58.3%]  Adalimumab 6 [35.3%] 19 [26.0%] 3 [16.7%] 28 [25.9%]  Certolizumab 0 [0.0%] 3 [4.1%] 2 [11.1%] 5 [4.6%]  Golimumab 0 [0.0%] 2 [2.7%] 7 [38.9%] 9 [8.3%]  Etanercept 0 [0.0%] 0 [0.0%] 2 [11.1%] 2 [1.9%] Other  Ustekinumab 2 [11.8%] 1 [1.4%] 2 [11.1%] 5 [4.6%]  Tocilizumab 0 [0.0%] 2 [2.7%] 0 [0.0%] 2 [1.9%] aConverters are defined as patients with conversion of at least one screening assay. bNot mutually exclusive, four patients on two biologics. LTBI, latent tuberculosis infection; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. View Large Patients were treated with infliximab [n = 63], adalimumab [n = 28], certolizumab [n = 5], golimumab [n = 9], etanercept [n = 2], ustekinumab [n = 5], or tocilizumab [n = 2]. Among these patients, four were initially on infliximab and subsequently switched to adalimumab due to a loss of response, and two switched from etanercept to golimumab. At baseline, 18 patients [16.7%] tested positive for LTBI [three IGRA-positive, nine TST-positive, one CXR-positive, and five both IGRA- and TST-positive]. These patients positive for LTBI at baseline comprised one UC and two PA patients with IGRA positivity alone; three CD, three RA, one AS, and two PA patients with TST positivity alone; one CD patient with CXR positivity alone; and one RA, one psoriasis and three PA patients with both IGRA and TST positivity [Table 2]. Table 2. Positive latent tuberculosis infection screening tests at baseline. N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray. View Large Table 2. Positive latent tuberculosis infection screening tests at baseline. N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 N = 18 Only IGRA-positive Only TST-positive Only CXR-positive Both TST- and IGRA-positive CD 0 3 1 0 UC 1 0 0 0 IBDU 0 0 0 0 Rheumatoid arthritis 0 3 0 1 Ankylosing spondylitis 0 1 0 0 Psoriasis 0 0 0 1 Psoriatic arthritis 2 2 0 3 Other rheumatic diseases 0 0 0 0 Total 3 9 1 5 CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray. View Large A total of 14 out of 18 patients positive for latent TB infection were given isoniazid monotherapy before commencing biologic therapy. Three of the psoriasis patients [two IGRA-positive and one both IGRA- and TST-positive] were diagnosed with latent TB previously [between 2008 and 2010 and completed isoniazid prophylaxis] and one CD [with CXR suggestive of LTBI which showed right upper and middle zone fibrosis] had a history of mycobacterium avian complex disease in 2006 and had completed a full course of anti-mycobacterial treatment. All these four patients were not given any more isoniazid prophylaxis before initiation of biologic therapy. 3.2. Conversion of LTBI tests Patients were followed up for a median of 16 months (interquartile range [IQR]: 6–24). Among patients with a negative baseline test for LTBI [n = 90; 18 patients with IBD, 12 with rheumatic diseases patients with rheumatic diseases], 17 [18.9%] had a conversion with one or more of the TB tests from negative to positive [Table 3]. Fourteen of these patients with conversion of LTBI tests received isoniazid prophylaxis during their course of biologic treatment which was not interrupted. One patient with CD had conversion of TST and IGRA, and later developed active TB despite completion of isoniazid treatment. One CD patient had only IGRA conversion 5 months after stopping the biologic treatment [biologic treatment was stopped earlier, as patient achieved mucosal healing and was in deep remission]. Another two CD patients with TST conversion were not given isoniazid, based on the discretion of the treating doctors. Table 3. Characteristics of patients who converted at least one screening test during biological therapy. Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab M, male; F, female; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray; CD, Crohn’s disease; PsA, psoriatic arthritis aPreviously on infliximab. View Large Table 3. Characteristics of patients who converted at least one screening test during biological therapy. Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab Age/ gender Diagnosis IGRA TST CXR Active TB Anti-TB prophylaxis Biologics 1 45/M CD [+] after 46 months [-] Adalimumaba 2 23/M CD [+] after 33 months [-] Infliximab 3 37/M CD [+] after 14 months [-] Infliximab 4 26/M CD [+] after 23 months [-] Infliximab 5 32/F CD [+] after 28 months [-] [-] Infliximab 6 37/M CD [+] after 14 months [-] [-] Infliximab 7 27/M CD [+] after 34 months [-] [-] Infliximab 8 20/M CD [+] after 4 months [-] Infliximab 9 25/M CD [+] after 4 months [+] after 4 months [+] Infliximab 10 53/M CD [+] after 17 months [+] after 12 months [-] Infliximab 11 33/F CD [+] after 13 months [-] Adalimumab 12 47/M CD [+] after 5 months [+] after 15 months [-] Infliximab 13 33/F CD [+] after 24 months [-] Adalimumab 14 40/M CD [+] after 16 months [-] Adalimumab 15 35/F CD [+] after 12 months [-] Adalimumab 16 42/F PsA [+] after 2 months [-] Ustekinumab 17 51/F PsA [+] after 12 months [-] Ustekinumab M, male; F, female; TST, tuberculin skin test; IGRA, interferon gamma release assays; CXR, chest X-ray; CD, Crohn’s disease; PsA, psoriatic arthritis aPreviously on infliximab. View Large 3.3. Factors associated with TB test conversion Univariate analysis was performed to examine factors associated with LTBI conversion. None of the factors, including age, sex, smoking status, alcohol, travel history to high TB-burden countries, type of disease, type of biologic treatments [anti-TNF or non anti-TNF], or changes of immunosuppressive therapies after initiation of biologic treatment, was significantly associated with LTBI conversion in univariate analysis [Table 4]. There were nor significant association factors in terms of IGRA conversion [Table 5]. Table 4. Univariate analysis of factors associated with conversion of at least one screening assay during anti-TNF therapy. OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference cAddition of immunosuppressnats or increase in dose View Large Table 4. Univariate analysis of factors associated with conversion of at least one screening assay during anti-TNF therapy. OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR [95% CI] p-Value Age 1.00 [0.96–1.05] 0.975 Sex, male 0.72 [0.20–2.59] 0.614 Smoking  Current 0.45 [0.79–2.53] 0.363  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 1.12 [0.21–5.89] 0.894  UCa - -  IBDUa - -  Rheumatic fisease reference Anti-TNFb 5.00 [0.74–33.66] 0.098 Immunosuppressantsc 0.66 [0.20–2.23] 0.503 Travel to high-risk area 0.75 [0.22–2.57] 0.650 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference cAddition of immunosuppressnats or increase in dose View Large Table 5. Univariate analysis of factors associated with IGRA conversion during anti-TNF therapy. OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference. cAddition of immunosuppressant or increase in dose. View Large Table 5. Univariate analysis of factors associated with IGRA conversion during anti-TNF therapy. OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR [95% CI] p-Value Age 1.02 [0.96–1.08] 0.553 Sex, male 0.31 [0.35–2.75] 0.293 Smoking  Current 0.73 [0.08–6.81] 0.732  Exa - -  Never reference Alcohol  Currenta - -  Exa - -  Never reference Disease type  CD 0.54 [0.60–4.89] 0.584  UCa - -  IBDUa - -  Rheumatic disease reference  Anti-TNFb 3.20 [0.32–31.92] 0.322 Immunosuppressantc 0.30 [0.05–1.70] 0.172 Travel to high-risk area 0.21 [0.02–1.84] 0.158 OR, odds ratio; CI, confidence interval; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, inflammatory bowel disease unclassified; TNF, tumour necrosis factor. aFactor is constant. bNon anti-TNF as reference. cAddition of immunosuppressant or increase in dose. View Large 3.4. Patient developing active tuberculosis Out of 108 patients, one CD patient [male, aged 27] developed active TB at 20 months after commencement of infliximab. Initial screening for TB was negative. This patient had IGRA seroconversion 4 months after initiation of infliximab. He received isoniazid prophylaxis for 9 months. Seven months after completion of LTBI treatment, he presented with fever and cough with whitish sputum. His chest radiography showed right upper zone consolidation. Bronchoscopy was performed, and bronchoalveolar lavage was positive for acid-fast bacillus [AFB] smear and culture yielded Myobacterium tuberculosis. He was started on isoniazid [H], rifampicin [R], ethambutol [M], and pyrazinamide [Z]. Infliximab was stopped after the diagnosis of active TB. His IGRA level became negative at the end of TB treatment and remained negative on subsequent tests. His CD was under control with weekly methotrexate. 3.5. Pattern of changes of IGRA levels for baseline LTBI-positive patients and those with LTBI tests conversion Eight subjects [one UC; seven rheumatic diseases] had a positive IGRA at baseline [three with IGRA alone and five with both IGRA and TST] at baseline. All patients with rheumatic diseases were on methotrexate. Three of the patients with rheumatic diseases did not receive isoniazid prophylaxis. They all showed fluctuating levels of IGRA, and one patient had persistent low positive IGRA levels <4 [0.47–0.65] with spontaneous reversion in between. The other two had intermittent levels of >4 [Figure 1]. None of these patients developed active TB during the study period. Figure 1. View largeDownload slide Pattern of changes of IGRA levels for baseline IGRA-positive patients. Figure 1. View largeDownload slide Pattern of changes of IGRA levels for baseline IGRA-positive patients. For those with IGRA conversion [n = 6; three with IGRA alone, three with both IGRA and TST], their IGRA at conversion was in the range of 0.57–20.57. Most of them [4/6, 66.7%] had conversion during the first 6 months of initiation of biologic treatment. Among those who were treated with isoniazid [four CD and one psoriasis; one CD was not treated, as mentioned earlier], the IGRA was negative at the end of isoniazid treatment [Figure 2] except one [IGRA of 20.57 during conversion, remaining elevated at 7.58 after 3 months’ completion of isoniazid prophylaxis] who subsequently developed active TB. Figure 2. View largeDownload slide Pattern of changes of IGRA levels for IGRA-conversion patients. Figure 2. View largeDownload slide Pattern of changes of IGRA levels for IGRA-conversion patients. 3.6. Pattern of changes of tuberculin tests for baseline LTBI=positive patients and those with LTBI tests conversion There were 14 patients with baseline positive tuberculin tests. Twelve of these received isoniazid and the other two had completed isoniazid prophylaxis before recruitment into the study. After completion of isoniazid, seven had persistently positive tuberculin tests at 1 year as per protocol. Three other patients had subsequent negative tuberculin tests. For those not treated with isoniazid, one had persistently positive tests and one had negative tuberculin tests upon repeated testing. Overall, the reversion rate of those with baseline positive tuberculin tests after completion of isoniazid was 30% [3/10 excluding two subjects who had not yet repeated their tuberculin tests]. On the other hand, nine patients had conversion of their tuberculin tests, all of whom received isoniazid prophylaxis. For those with conversion of tuberculin tests upon completion of LTBI treatment, three had reversion, two remained positive, and another four had yet to repeat their tuberculin tests. 4. Discussion In this prospective study comprising mainly IBD patients followed up for a median of 2 years, we found that latent TB tests conversion is common in a region of intermediate to high TB incidence. During the follow-up, none of the subjects who had positive LTBI tests at baseline developed active TB during or after treatment with isoniazid prophylaxis. Furthermore, in those who had LTBI test conversion after initiation of biologic therapy, one patient with IBD developed active TB despite isoniazid prophylaxis. Overall, 16.7% patients had baseline positive latent TB before biologic treatment [most of whom received isoniazid] and 18.9% of the remaining patients had conversion of any one of the latent TB tests during biologic therapy. Isoniazid monotherapy showed effective protection in 96% [27/28] of subjects against the development of active TB in our IMID cohort with LTBI. Our findings were slightly higher compared with an earlier study reporting an incidence of active TB of 1.65% despite LTBI screening and treatment, and the majority of cases appeared within the first 4 months after starting therapy.31 All six patients who had IGRA conversion were on other immunosuppressive medications, which may explain the possibility of false-negative results at baseline. We repeated TST on an annual basis rather than at shorter intervals, in order to reduce the ‘boosting phenomenon’ due to repeated TST. Boosting is maximal if the interval between the first and second test is between 1 and 5 weeks32,33 and is much less frequent if the interval is only 48 h34 or more than 60 days.32 Hence in this group of patients, even though the IGRAs were negative, we believe the TST conversion was genuinely representative of latent TB due to likely re-exposure in this country after initiation of biologic therapy. The lower prevalence of LTBI among IBD patients could be due to false-negative results secondary to steroid use which is common in IBD patients before escalation to immunomodulators or biologics. In contrast, steroids are less commonly used in the rheumatological cohorts comprising mostly patients with psoriasis. The exact cause for the higher conversion on biologics in CD [most of whom were on infliximab] compared with UC or rheumatology patients is unclear, but may relate to disease and patient factors whereby CD patients require more frequent visits or hospitalisation and are more likely to be exposed. The value of monitoring IGRA during treatment of both active and latent TB has been controversial. However, we believe that IGRA in addition to CXR has an important role in detection of TB, since more than 50% of reactivation occurred at extrapulmonary sites. A recent meta-analysis showed that IGRA quantitatively dropped with treatment but with substantial variation among studies, and hence it may not be useful in clinical practice.35 Our cohort showed that IGRA levels dropped in those who had conversion but not in those with baseline IGRA positivity after treatment with isoniazid. Besides, all three psoriasis patients with baseline IGRA positivity, yet not treated with isoniazid [background history of past latent TB and completed treatment many years ago], demonstrated great variation in changes of IGRA level during biologic treatment. One recent study had shown that conversion at interferon gamma values higher than 4.00 IU/mL was linked to a more than 40 times higher risk of developing tuberculous disease in the following 6 to 24 months (incidence rate ratio [IRR] 42.2, 95% confidence onterval [CI] 17.2–99.7, p <0.001]. In contrast, conversion values in the range of 0.35–4.00 IU/mL had low predictive value for tuberculous disease [IRR of 3.7; 2.5 per 100 person-years as compared with 0.7 person-year in IGRA-negative subjects] and were associated with high rates [77%] of reversion.36 Our data were consistent with this observation, even though the number of IGRA conversions was small. Five out of the six IGRA converters had levels below 4 IU/ml, and none of them developed active TB after isoniazid prophylaxis. Papay et al. showed that in patients with negative LTBI at baseline, IGRA conversion during biologic therapy occurred but was usually transient and results generally turned negative upon repeated testing. Although no was isoniazid given, none of the subjects developed active TB after a median of 39 months’ follow-up.26 However, in our cohort, the decision to initiate isoniazid prophylaxis was based on a single IGRA conversion result rather than repeated samples. In contrast, the one patient who had IGRA levels persistently higher than 4 IU/ml developed active TB despite completion of isoniazid prophylaxis. The most reassuring observation from this study is that none of the patients with negative IGRA tests during biologic treatment developed TB during follow-up. These data suggest that false-negative results during therapy are less likely. In addition, our study showed that serial IGRAs have a meaningful role in monitoring subjects who had LTBI test conversion during biologic therapy. Subjects with persistently high IGRAs of more than 4 IU/ml upon completion of isoniazid prophylaxis may be at an increased risk of development of active TB, and require closer observation or intensive workup for active TB. In contrast, in subjects with a positive baseline latent TB tests, the role of serial IGRA monitoring during biologic treatment remains to be defined by longer and larger prospective studies. The main limitation of our study is a modest sample size and a relatively short period of follow-up for patients with baseline IGRA positive results, who may develop active TB later. It is also likely that monitoring with yearly CXR and IGRA will be sufficient for latent TB monitoring. In clinical practice, we often face the conundrum of indeterminate IGRA results, especially in patients on immunosuppressive treatments. Studies have shown that indeterminate results are associated with steroid and immunosuppressants use.37,38 Hence we recommend latent TB testing before initiation of immunosuppressants in patients at high risk in anticipation of escalation of treatment.23 In conclusion, latent TB tests conversion is common and occurs early during biologic treatment. Isoniazid monotherapy prophylaxis is effective in prevention of active TB. Serial IGRAs may have a role in monitoring those with latent TB tests conversion. Funding We would like to acknowledge the funding from the Food and Health Bureau [CU-15-A6]. Conflict of Interest None declared. Author Contributions CKL, SHW, GL, WT, LST, MI, EH, MC, JCW: study design, patient identification, data collection, and manuscript revision. SCN: study design, supervision of the study,. SCN had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. References 1. Hanauer SB , Feagan BG , Lichtenstein GR , et al. ; ACCENT I Study Group . Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial . Lancet 2002 ; 359 : 1541 – 9 . Google Scholar CrossRef Search ADS PubMed 2. Braun J , Brandt J , Listing J , et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial . Lancet 2002 ; 359 : 1187 – 93 . Google Scholar CrossRef Search ADS PubMed 3. Saag KG , Teng GG , Patkar NM , et al. ; American College of Rheumatology . 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Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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Journal of Crohn's and ColitisOxford University Press

Published: Aug 1, 2018

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