Prevention of glucocorticoid morbidity in giant cell arteritis

Prevention of glucocorticoid morbidity in giant cell arteritis Abstract Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit–risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. giant cell arteritis, glucocorticoids, adverse events, morbidity Rheumatology key messages Patients with GCA require long-term glucocorticoid treatment, increasing their risk for glucocorticoid-related morbidity. Glucocorticoid dose and duration must be balanced against the risk for disease-related and treatment-related morbidity in GCA. Glucocorticoid sparing and other management strategies, including patient self-education, help mitigate the risk for glucocorticoid-related morbidity in GCA. Introduction Glucocorticoids remain the mainstay of therapy for GCA. Prompt diagnosis and initiation of glucocorticoids is critical to prevent complications associated with GCA, such as visual loss/blindness and other vascular complications [1–5]. There are wide variations across health care settings in the diagnosis and management of GCA. There is also a paucity of high-quality trials regarding the optimal dose, route of administration and tapering schedule of glucocorticoids in GCA. As a result, the standard of care for glucocorticoid use is not well defined [6, 7]. Long-term glucocorticoid use (3–6 months or more) may potentially be associated with numerous treatment-related adverse events (AEs), depending on both mean daily dose and cumulative dose [8, 9]. These AEs include skin, gastrointestinal, ophthalmological, skeletal muscle, bone, adrenal, cardiometabolic and neuropsychiatric complications [9–12]. The glucocorticoid-related AEs that patients and rheumatologists consider the most important or worrisome include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections [13]. Here we discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. Mechanism of action of glucocorticoids Mechanism of therapeutic effects The anti-inflammatory and immunosuppressive effects of glucocorticoids are mediated primarily by the cytosolic glucocorticoid receptor (cGR) through genomic mechanisms (Fig. 1) [14–16]. The classic genomic pathway is mediated by binding of glucocorticoids to this receptor. The cGR is a multiprotein complex that, in its native form, is associated with heat shock proteins and other co-chaperones in the cytoplasm [15, 17]. Glucocorticoids are lipophilic substances that easily pass through the cell membrane, where they bind with high affinity to the cGR, resulting in dissociation of the associated proteins and co-chaperones from the cGR [17]. The glucocorticoid–cGR complex is then translocated to the nucleus, where it forms homodimers that bind to DNA-binding sites termed glucocorticoid response elements (GREs) located in the promotor regions of target genes [15, 17]. Fig. 1 View largeDownload slide Genomic mechanisms of action of glucocorticoids 1: Direct binding of glucocorticoid–cGR complex to positive GREs. 2: Direct binding of glucocorticoid–cGR complex to negative GREs. 3: Glucocorticoid–cGR complex competition with transcription factors for co-activator binding, preventing transcription factors from binding to positive GREs. 4: Direct protein–protein interactions between glucocorticoid–cGR complex and transcription factors, preventing transcription factors from binding to positive GREs [15]. cGR: cytosolic glucocorticoid receptor; COX-2: cyclo-oxygenase 2; GILZ: glucocorticoid-induced leucine zipper; GRE: glucocorticoid response element; IκB; inhibitor of κB; MKP-1: mitogen-activated protein kinase phosphatase-1; PEPCK: phosphoenolpyruvate carboxykinase; TF: transcription factor. Fig. 1 View largeDownload slide Genomic mechanisms of action of glucocorticoids 1: Direct binding of glucocorticoid–cGR complex to positive GREs. 2: Direct binding of glucocorticoid–cGR complex to negative GREs. 3: Glucocorticoid–cGR complex competition with transcription factors for co-activator binding, preventing transcription factors from binding to positive GREs. 4: Direct protein–protein interactions between glucocorticoid–cGR complex and transcription factors, preventing transcription factors from binding to positive GREs [15]. cGR: cytosolic glucocorticoid receptor; COX-2: cyclo-oxygenase 2; GILZ: glucocorticoid-induced leucine zipper; GRE: glucocorticoid response element; IκB; inhibitor of κB; MKP-1: mitogen-activated protein kinase phosphatase-1; PEPCK: phosphoenolpyruvate carboxykinase; TF: transcription factor. The genomic effects of glucocorticoids can be divided into transactivation and transrepression. Transactivation results from binding of the glucocorticoid–cGR complex to positive GREs, resulting in transcription of anti-inflammatory and other regulatory proteins [15, 17]. Transrepression results from direct binding of the glucocorticoid–cGR complex to negative GREs, prevention of glucocorticoid–cGR binding to positive GREs through competition with transcription factors for co-activator binding or protein–protein interactions with the glucocorticoid–cGR complex, preventing the transcription of pro-inflammatory proteins [2, 15, 17]. However, some of the anti-inflammatory and immunosuppressive effects of glucocorticoids occur too rapidly to be attributable to genomic modes of action, particularly if high doses of glucocorticoids are used [15, 17]. These rapid effects of glucocorticoids, called non-genomic mechanisms of action, may be mediated by non-specific interactions with cell membranes, dissociation of proteins from the multiprotein–cGR complex or glucocorticoid interactions with membrane-bound GR [2, 15, 17]. Mechanism of adverse effects Glucocorticoid-related adverse effects are the result of on-target GR-mediated effects in that they are amplified manifestations of the normal effects of endogenous cortisol [18]. In general, it is thought that transactivation is responsible to a greater extent than transrepression for adverse effects, whereas transrepression is responsible to a greater extent for anti-inflammatory effects [2, 18]. However, this may be an oversimplification of glucocorticoid actions. Several AEs, including glaucoma, hypertension and diabetes, are indeed primarily attributable to transactivation, but hypothalamic–pituitary axis suppression and susceptibility to infections are caused primarily by transrepression (Table 1) [18–22]. Osteoporosis is the result of both transactivation and transrepression, whereas the mechanisms of other AEs are not fully elucidated [18]. Table 1 Glucocorticoid-related adverse events according to mechanism of action Transactivation  Partial transactivation  Transrepression  Arterial hypertension  Osteoporosis  Infections  Diabetes mellitus  Skin atrophy  Hypothalamic–pituitary axis suppression  Glaucoma  Growth retardation    Cushingoid appearance  Transactivation  Partial transactivation  Transrepression  Arterial hypertension  Osteoporosis  Infections  Diabetes mellitus  Skin atrophy  Hypothalamic–pituitary axis suppression  Glaucoma  Growth retardation    Cushingoid appearance  Glucocorticoid adverse events may be mediated by transactivation, transrepression or partial transactivation [18–22]. Glucocorticoid-induced osteoporosis results from direct effects of glucocorticoids on osteoblasts and osteoclasts [23], including decreased proliferation and activity of osteoblasts in conjunction with (at least during the initial treatment phase) increased activity of osteoclasts [18, 24, 25]. Osteoclast activity is stimulated by transactivation of osteoprotegerin ligand (OPG-L) and transrepression of OPG, shifting the OPG-L/OPG ratio in favour of bone resorption [18]. Furthermore, osteoclast apoptosis is reduced by glucocorticoids through the inhibition of OPG and increased expression of receptor activator of nuclear factor κB ligand [26]. Additionally, osteoclast activity is considered indirectly increased by glucocorticoid-induced reduction in intestinal calcium absorption and increased urinary calcium excretion. Decreased osteoblast activity results from a variety of mechanisms, including glucocorticoid-induced suppression of adrenal steroidal hormones, growth hormone, insulin-like growth factor-1 and TGF-β [18, 24]. Long-term treatment with glucocorticoids can also lead to hyperglycaemia and, consequently, to increased risk for diabetes [18, 24]. Glucocorticoids increase glucose synthesis through the transactivation of enzymes involved in gluconeogenesis (e.g. glucose-6-phosphatase and phosphoenolpyruvate carboxykinase); glucocorticoid-mediated activation of glycogen synthase results in increased glycogen storage in the liver [18, 24]. The primary mechanism underlying glucocorticoid-induced hypertension is sodium retention [18, 24]. Glucocorticoids increase epithelial sodium channel expression through transactivation effects and increase epithelial sodium channel activity through transactivation of serum- and glucocorticoid-regulated kinase [18, 24]. The risk for infection is increased during glucocorticoid therapy as a result of immunosuppression mediated by transrepression and transactivation effects on both the innate and the acquired immune systems [18, 24]. Additionally, glucocorticoid treatment results in reduced adhesion of neutrophils to epithelial monolayers and increased neutrophil counts [9]. Long-term treatment with glucocorticoids is also known to result in adrenal insufficiency, a condition in which the adrenal glands become incapable of generating sufficient cortisol once treatment with glucocorticoids has been stopped [27]. This occurs as a result of the negative feedback effect of exogenous glucocorticoids on the hypothalamic–pituitary axis through both transrepression and non-genomic effects [24, 28]. Inhibition at the level of the anterior hypothalamus results in suppression of the production of corticotrophin-releasing hormone and, consequently, adrenocorticotrophic hormone (ACTH), leading to adrenocortical hypoplasia and atrophy [24, 27]. Safety issues related to long-term glucocorticoid therapy in GCA The level of harm associated with glucocorticoid therapy is related to daily dose, total duration of intake and cumulative dose. In patients with RA treated with low-dose glucocorticoids in clinical trials of 2 years’ duration, adverse effects were usually modest and not necessarily different from those incurred with placebo treatment [29]. Nevertheless, it was suggested that AEs from glucocorticoids—including osteoporosis, Cushingoid symptoms, adrenal insufficiency and adrenal crisis upon glucocorticoid withdrawal, growth retardation in children, diabetes mellitus in at-risk patients and worsening glycaemic control in patients with diabetes mellitus, cataracts, glaucoma and hypertension—should be monitored and, if necessary, prevented or treated in patients with rheumatic diseases [29]. Long-term glucocorticoid therapy at dosages ⩽5 mg/day prednisone equivalent is associated with a low level of harm for most patients relative to its anticipated therapeutic effects; the exception is patients at high risk for cardiovascular disease, who may require preventive measures. In contrast, dosages ⩾10 mg/day prednisone equivalent are usually associated with a high level of harm [8]. Patients with GCA generally require higher starting doses and often longer durations of treatment with glucocorticoids than patients with other systemic inflammatory conditions [30, 31]. Guidelines uniformly recommend initial treatment with high-dose glucocorticoid regimens (40–60 mg/day prednisone or prednisone equivalent for 2–4 weeks) to achieve rapid resolution of inflammation. This recommendation must be balanced against the need to use the lowest effective dose to avoid AEs [5, 7, 31, 32]. Once the disease-related symptoms are under control and the inflammatory process has been satisfactorily suppressed (i.e. ESR and CRP levels are normalized), the goal is to taper glucocorticoid therapy to achieve a stable low maintenance dose or complete withdrawal [4, 5, 33]. The glucocorticoid dosage should be tapered gradually to avoid disease relapse [4]. The disease flare rate increases after reduction of the glucocorticoid dosage to 5–10 mg/day prednisone equivalent [32]. A substantial proportion of patients (30–50%) experience relapse, particularly during the glucocorticoid-tapering phase, and 20–30% of patients experience relapse after glucocorticoid withdrawal [6, 34–36]. The average duration of glucocorticoid therapy in GCA is ∼2–3 years, although lifelong treatment may be required in some patients [2, 6, 12, 37, 38]. Furthermore, trends over time in glucocorticoid use in patients with GCA suggest increasing cumulative doses and longer exposures in recent decades [37–39]. The reason for this trend is unknown. It has been postulated that increased recognition of the chronic nature of the disease, increased recognition of relapse and possibly overdiagnosis of relapse and greater use of imaging studies documenting persistent subclinical vascular inflammation may be contributing factors [37]. Recent claims-based data suggest that patients with GCA typically receive cumulative glucocorticoid doses of >5000 mg prednisone equivalent over the course of several years [38]. These extended periods of glucocorticoid use leading to higher cumulative doses may increase the risk for glucocorticoid-related complications, which places a substantial burden on the GCA population. Available data regarding the frequency of glucocorticoid-related AEs in patients with GCA are sparse, and it is difficult to distinguish the effects of glucocorticoids from those related to the disease itself, comorbid conditions and concomitant medications [2, 9]. Up to 90% of patients with GCA who receive long-term glucocorticoid treatment experience AEs [10, 12]. In a recent retrospective study of 2497 patients with GCA using medical claims data, glucocorticoid-related AEs were reported at an overall rate of 0.43 events per patient-year of exposure (Table 2) [38]. Apart from weight gain, the most frequent AEs were cataract (0.16 events per patient-year) and bone disease, including osteoporosis, fractures, hip replacement and aseptic necrosis (0.16 events per patient-year) [38]. Only AEs leading to direct claims were assessed in this study; these excluded weight gain, an AE of particular significance to patients and one that occurs in ∼70% of adults receiving long-term glucocorticoid treatment [10]. Compared with patients who did not experience AEs, those who did received glucocorticoids for longer durations (median 195 vs 102.5 days) and at higher cumulative doses (median 3400 vs 2145 mg prednisone equivalent) [38]. For each 1000 mg increase in cumulative glucocorticoid dose, the hazard ratio for AEs was increased by 3%, with the greatest increase observed for new-onset diabetes mellitus (5% per 1000 mg increase) [38]. Safety data such as these do not discriminate between glucocorticoid-related AEs and symptoms caused by GCA [39]. Furthermore, patients requiring higher doses of glucocorticoids are likely to be those with more active disease and higher inflammatory activity, factors that also contribute to the development of many AEs [40]. Table 2 Incidence of glucocorticoid-related adverse events based on claims data Adverse event  Events/patient-yeara  Hazard ratio per 1000 mgb increase in cumulative exposure (95% CI)  Percentage increase per 1000 mgb increase in cumulative exposure  Any  0.426  1.03 (1.02, 1.05)  3  Cataract  0.158  1.03 (1.02, 1.05)  3  Bone disease  0.156  1.05 (1.03, 1.06)  5      Osteoporosis  0.099  1.05 (1.03, 1.07)  5      Fracture  0.066  1.04 (1.03, 1.06)  4      Hip replacement  0.008  1.04 (0.99, 1.08)  4      Aseptic necrosis of bone  0.004  1.06 (1.01, 1.12)  6  Pneumonia  0.068  1.03 (1.01, 1.04)  3  Glaucoma  0.022  1.05 (1.01, 1.08)  5  Opportunistic infections  0.010  1.04 (1.00, 1.08)  4  Ulcer disease  0.006  1.00 (0.94, 1.06)  0  Adverse event  Events/patient-yeara  Hazard ratio per 1000 mgb increase in cumulative exposure (95% CI)  Percentage increase per 1000 mgb increase in cumulative exposure  Any  0.426  1.03 (1.02, 1.05)  3  Cataract  0.158  1.03 (1.02, 1.05)  3  Bone disease  0.156  1.05 (1.03, 1.06)  5      Osteoporosis  0.099  1.05 (1.03, 1.07)  5      Fracture  0.066  1.04 (1.03, 1.06)  4      Hip replacement  0.008  1.04 (0.99, 1.08)  4      Aseptic necrosis of bone  0.004  1.06 (1.01, 1.12)  6  Pneumonia  0.068  1.03 (1.01, 1.04)  3  Glaucoma  0.022  1.05 (1.01, 1.08)  5  Opportunistic infections  0.010  1.04 (1.00, 1.08)  4  Ulcer disease  0.006  1.00 (0.94, 1.06)  0  a Patients ≥50 years of age with two or more medical claims with GCA as a listed diagnosis, one or more filled oral corticosteroid prescription and no AEs before GCA diagnosis [38]. b Prednisone equivalent. The association between glucocorticoid use and AEs was also demonstrated in a large UK database of patients with GCA (n = 3074) and matched controls (n = 6148), in which 33% of patients each were treated with a cumulative dose of prednisone >10 000 mg [39]. Although causality cannot be ascertained in this type of study, AEs considered to be potentially related to glucocorticoid use included osteoporosis [relative risk (RR) = 2.9], osteopenia (RR = 2.5), angina pectoris (RR = 2.4), intermittent claudication (RR = 2.4) and diabetes mellitus (RR = 2.4). Adrenal insufficiency was not identified in the safety analyses described, but it is believed to occur frequently among patients treated with glucocorticoids. Although evidence from GCA-specific populations is rare, the results of one prospective study found that 49% of GCA patients receiving glucocorticoids did not respond to their first ACTH stimulation test, indicating impaired adrenal function [41]. Of these patients, 53% had not recovered their normal adrenal function after 12 months. This effect appeared temporary in most patients, with only 15% continuing to have a negative response in the ACTH stimulation test at 36 months and only 5% categorized as having definitive adrenal insufficiency. In this study, both total dose of glucocorticoid and duration of treatment were identified as risk factors for adrenal insufficiency [41]. Management of glucocorticoid-related complications Prophylaxis, monitoring and treatment of glucocorticoid-related complications are essential to the management of GCA [2]. Different glucocorticoid-dosing schemes, including high-dose intravenous glucocorticoids, have been investigated with the objective of reducing glucocorticoid-related adverse effects [42]. The rationale for this approach was to make use of the non-genomic effects of glucocorticoids to lower inflammation rapidly and to decrease the overall dose burden of subsequent oral glucocorticoid whose genomic effects are responsible for adverse effects [8, 10–12, 31, 38]. In a small randomized controlled trial, initial treatment with high-dose intravenous glucocorticoid (methylprednisolone, 15 mg/kg of ideal body weight/day for 3 days followed by a starting dose of 40 mg/day with scheduled tapering) allowed for more rapid tapering of oral glucocorticoids with higher frequency of sustained remission after treatment discontinuation [42]. However, a second randomized study reported no benefit for pulse treatment (single intravenous pulse of 240 mg methylprednisolone followed by 0.5 or 0.7 mg/kg/day oral prednisone) over oral prednisone alone (0.7 mg/kg/day) [43]. Therefore, current evidence does not support routine use of pulse therapy, and additional research on this issue is required [1, 7]. Treatment with glucocorticoids on alternating days has also been proposed to reduce the risk for AEs, but in a randomized prospective study of GCA (n = 60), this approach was associated with a higher rate of treatment failure [44] than daily administration in GCA and is therefore not recommended [4, 32]. The risk–benefit ratio of glucocorticoid therapy may also be influenced by patient-specific factors, such as disease activity, disease-related complications (e.g. loss of sight), age and gender, and the risks for some AEs can be mitigated by lifestyle interventions [8, 30]. Management strategies for the four most worrisome glucocorticoid-related AEs are detailed in Table 3 [2, 8, 30, 45, 46]. For example, the risk for glucocorticoid-induced osteoporosis, with or without fractures, is elevated by increasing cumulative doses [23] and by patient-related factors such as older age, female sex, low body weight, low bone mineral density, prevalent fractures and family history of osteoporosis [8]. Where available, the Fracture Risk Assessment Tool® is recommended for assessment of osteoporosis risk [23, 30]. Table 3 Recommended glucocorticoid-related risk management strategies for the most worrisome adverse event Adverse event  Patient-related risk factors  Risk assessment  Lifestyle interventions  Management option  Possibly included in monitoring  Osteoporosis  Older age Female sex Low body weight Low bone mineral density Prevalent fractures Family history of osteoporosis  Dose and fracture history FRAX tool  Physical exercise (weight-bearing exercise, strength training) Smoking cessation Limiting alcohol intake Dietary calcium intake  Preventive therapy and treatment with calcium and vitamin D supplementation Preventive therapy and treatment with bisphosphonates in patients with ongoing high-dose glucocorticoid therapy Teriparatide in patients with fractures  BMD before and during treatment Vitamin D levels  Hyperglycaemia  Genetic disposition Age Obesity Chronic inflammation    Weight reduction Healthful diet Exercise    Pretreatment screening Regular blood/urine glucose monitoring  Cardiovascular complications  Older age Male sex Obesity Hypertension Diabetes Dyslipidaemia Higher disease activity  SCORE model, or per national guidelines  Healthful diet (low in saturated fat and calories) Physical exercise Weight loss Sodium restriction Smoking cessation  Preventive therapy with statins or angiotensin-converting enzyme inhibitors in patients at high risk  Regular monitoring of blood pressure, cardiac insufficiency and serum lipid profile before and after initiation of glucocorticoids  Infection  Comorbidities History of serious infection Concomitant immunosuppressive treatments    Appropriate wound care Hand washing  Vaccination (influenza, pneumococcal, varicella zoster) in appropriate patients Trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii in patients receiving high- dose glucocorticoid therapy  Specific infection screening  Adverse event  Patient-related risk factors  Risk assessment  Lifestyle interventions  Management option  Possibly included in monitoring  Osteoporosis  Older age Female sex Low body weight Low bone mineral density Prevalent fractures Family history of osteoporosis  Dose and fracture history FRAX tool  Physical exercise (weight-bearing exercise, strength training) Smoking cessation Limiting alcohol intake Dietary calcium intake  Preventive therapy and treatment with calcium and vitamin D supplementation Preventive therapy and treatment with bisphosphonates in patients with ongoing high-dose glucocorticoid therapy Teriparatide in patients with fractures  BMD before and during treatment Vitamin D levels  Hyperglycaemia  Genetic disposition Age Obesity Chronic inflammation    Weight reduction Healthful diet Exercise    Pretreatment screening Regular blood/urine glucose monitoring  Cardiovascular complications  Older age Male sex Obesity Hypertension Diabetes Dyslipidaemia Higher disease activity  SCORE model, or per national guidelines  Healthful diet (low in saturated fat and calories) Physical exercise Weight loss Sodium restriction Smoking cessation  Preventive therapy with statins or angiotensin-converting enzyme inhibitors in patients at high risk  Regular monitoring of blood pressure, cardiac insufficiency and serum lipid profile before and after initiation of glucocorticoids  Infection  Comorbidities History of serious infection Concomitant immunosuppressive treatments    Appropriate wound care Hand washing  Vaccination (influenza, pneumococcal, varicella zoster) in appropriate patients Trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii in patients receiving high- dose glucocorticoid therapy  Specific infection screening  Recommendations for the most worrisome adverse events are summarized [2, 8, 30, 45, 46]. BMD: bone mineral density; FRAX: Fracture Risk Assessment; SCORE: Systematic Coronary Risk Evaluation. Lifestyle interventions to reduce the risk for osteoporosis include physical exercise (including weight-bearing exercise and strength training), smoking cessation, limiting alcohol intake and maintaining an adequate intake of dietary calcium [8, 30]. All patients receiving glucocorticoids should receive bone protective therapy in the absence of contraindications [4]. Preventive therapy should include calcium and vitamin D supplementation. Prevention of fractures with anti-osteoporotic therapies such as bisphosphonates and teriparatide may be indicated, depending on glucocorticoid dose and actual fracture risk [23, 30, 47]. Regular monitoring of bone mineral density during glucocorticoid treatment is recommended [5, 23]. The risk for diabetes during treatment with glucocorticoids is dependent on potency of treatment, length of treatment and absolute dose [8, 9, 48]. Patient-related risk factors include genetic disposition, age, obesity and chronic inflammation [8]. Recommended lifestyle interventions include weight loss, healthful diet and appropriate exercise [8]. Blood glucose monitoring before and every 3 months during treatment is suggested for all patients receiving glucocorticoids, and patients who have diabetes or pre-diabetes before starting treatment should be carefully monitored [5, 9, 30]. Assessing the risk for cardiovascular events in GCA patients is complicated by the fact that they may be caused by the disease itself [9]. Risk factors for cardiovascular events include older age, male sex, obesity, hypertension, diabetes, dyslipidaemia and higher disease activity [8]. Risk can be assessed with generic risk assessment tools used in the general population. The EULAR recommends the Systematic Coronary Risk Evaluation model for assessing risk [46]. Lifestyle interventions that may modify the risk for cardiovascular events include healthful diet (low in saturated fat and calories), physical activity, weight normalization, sodium restriction and cessation of smoking [8]. Treatment with statins or angiotensin-converting enzyme inhibitors is recommended for patients at high risk. Although it has been suggested that patients receiving glucocorticoids should start treatment at a lower threshold than the general population, current EULAR guidelines recommend they be initiated according to national guidelines for the general population [9, 46]. In contrast to the risk for osteoporosis, which is influenced primarily by the cumulative glucocorticoid dose, the risk for infections does not appear to be related to cumulative glucocorticoid dose and is instead dependent on the actual dose of glucocorticoids [8, 49]. The risk for infection is highest during the first year of treatment, when patients are typically receiving initial treatment with high-dose glucocorticoids; after the first 12 months, a dosage of >10 mg/day prednisone equivalent is associated with an increased risk for severe infection and death [49]. Patient-related risk factors include high disease activity, comorbidities (including chronic heart, lung or renal disease, peripheral vascular disease, diabetes, hepatitis C, leucopenia and certain neurological diseases) and a history of serious infection [8]. It has also been suggested that infection risk (including tuberculosis) be evaluated before treatment is started [8, 50]. Appropriate wound care and good hygiene, especially hand washing, may help to reduce the risk for infection [8]. Prophylactic vaccination should be considered according to EULAR and national guidelines for patients with autoimmune inflammatory rheumatic diseases [51, 52]. Vaccination against influenza and pneumococcal pneumonia is strongly recommended for all patients, but vaccination against herpes zoster should be considered only in patients who are less severely immunosuppressed [51]. Antibacterial treatment should be initiated promptly at suspicion of bacterial infection. Prophylaxis against Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole should be considered for patients receiving high-dose glucocorticoids [2, 53]. Specific infection screening (particularly for tuberculosis) before the initiation of glucocorticoid treatment, and the prompt initiation of antimicrobial therapy when required, may reduce the risk for severe infection [49]. The primary management strategy for the prevention of adrenal insufficiency is to use a tapering regimen to ensure the adrenal glands return to an adequate level of function [41]. Tapering is a standard technique recommended for all patients to stop treatment or to reduce glucocorticoid exposure, and therefore it is widely used; however, a more gradual taper and ACTH stimulation testing may be appropriate for patients at high risk [4, 5, 41]. Optimal tapering regimens with regard to length of exposure and degree of adrenal suppression have thus far not been defined. Glucocorticoid-sparing treatment strategies Given the substantial morbidity associated with long-term glucocorticoid therapy, guidelines (EULAR and British Society for Rheumatology/British Health Professionals in Rheumatology) recommend that early initiation of MTX or other immunosuppressive agents be considered for patients with GCA [4, 5]. The usefulness of immunosuppressive agents, such as AZA and CYC, has not been uniformly demonstrated for the treatment of patients with GCA, but a benefit from methotrexate has been suggested [7, 54]. In a meta-analysis of individual patient data from three randomized controlled trials in GCA, it was found that adjunctive low-dose MTX reduced both relapse risk and glucocorticoid exposure, though the frequency and severity of AEs were not reduced [55]. Adjunctive MTX may reduce cumulative glucocorticoid doses by ∼20% [56] and relapses by 35% [55] in GCA [7]. Based on systematic analysis of clinical trial data, use of methotrexate as a glucocorticoid-sparing strategy can be considered for patients at high risk for glucocorticoid-induced AEs at disease outset and for patients whose disease course is protracted and who are at risk for recurrent relapses and glucocorticoid-induced AEs [7, 31]. A Cochrane review of methotrexate in GCA is ongoing. Overall, no clear benefit has been observed with TNF-α inhibitors such as infliximab in randomized controlled trials; therefore, the use of these agents is not recommended in GCA [1, 4, 30, 57, 58]. In a randomized, double-blind, placebo-controlled, phase 2 trial, the IL-6 receptor-alpha inhibitor tocilizumab demonstrated efficacy in the induction and maintenance of remission in patients with GCA [59]. Recently, blockade of IL-6 signalling with tocilizumab has been demonstrated to have clinical efficacy and a glucocorticoid-sparing effect in patients with GCA in a randomized, placebo-controlled, phase 3 trial with blinded glucocorticoid regimens of variable dose and duration (GiACTA trial) [60]. Tocilizumab combined with a 26-week prednisone taper was superior to placebo combined with 26-week and 52-week prednisone tapers for achieving sustained glucocorticoid-free remission [60]. Cumulative prednisone exposure over the 52-week trial was significantly lower in patients treated with tocilizumab plus a 26-week prednisone taper than in those treated with a 52-week prednisone taper: 43.5 and 51.2% reductions occurred in the cumulative prednisone dose arms compared with the 26- and 52-week prednisone taper arms, respectively. The 26-week prednisone taper implemented in GiACTA [60] allows for faster glucocorticoid tapering than current recommended glucocorticoid-tapering schedules (Fig. 2) [5]. A higher rate of serious AEs was observed in the placebo plus prednisone taper groups than in the tocilizumab plus prednisone taper groups, which might have been driven by glucocorticoid-related toxicity [60]. Abatacept, a modulator of T cell costimulation, and ustekinumab, an anti-IL-12 and anti-IL-23 mAb, have also shown initial promise [61–63]. Fig. 2 View largeDownload slide Glucocorticoid tapering schedule in GiACTA vs BSR tapering schedule GiACTA glucocorticoid tapering occurred in combination with tocilizumab treatment [60]. BSR tapering schedule is as recommended [5]. BSR: British Society for Rheumatology. Fig. 2 View largeDownload slide Glucocorticoid tapering schedule in GiACTA vs BSR tapering schedule GiACTA glucocorticoid tapering occurred in combination with tocilizumab treatment [60]. BSR tapering schedule is as recommended [5]. BSR: British Society for Rheumatology. Future perspectives A clear need to improve the benefit–risk ratio of glucocorticoid therapy has led to the development of novel formulations of existing glucocorticoids and of novel cGR ligands [15]. Novel formulations that have been investigated in inflammatory rheumatic diseases include modified/delayed-release prednisone, liposome encapsulation and coupling of glucocorticoids to nitrogen oxide (nitrosteroids) [15, 64]. Modified/delayed-release prednisone has been incorporated into clinical practice for RA, but it is yet to be evaluated in GCA [64]. Liposomal glucocorticoids accumulate at the site of inflammation, resulting in high local concentrations and reduced impact on non-target tissues; thus, liposome encapsulation is expected to enhance the anti-inflammatory action of glucocorticoids while limiting AEs [17, 64]. Early results with liposomal dexamethasone appear promising in patients with RA [64]. Based on the theory that genetic transactivation by the glucocorticoid–receptor complex causes most glucocorticoid-related adverse effects whereas transrepression mediates anti-inflammatory and immunomodulatory effects, selective glucocorticoid receptor agonists (SEGRAs) have been developed [15]. Data are pending for SEGRAs now in phase 2 clinical development for rheumatic diseases [64]. The fact that some glucocorticoid-related adverse effects may be partially mediated by transrepression should also be considered. Recent data also suggest that important anti-inflammatory effects of glucocorticoids are mediated by transactivation of inhibitor of the NF-κB kinase, mitogen-activated protein kinase phosphatase-1, IL-10 and glucocorticoid-induced leucine zipper [18, 64]. The clinical relevance of these effects is unclear, however, and must be investigated in future clinical trials. Other initiatives to improve the management of GCA and to reduce the need for and the risk from glucocorticoids include study of various anti-cytokine and anti-cellular therapies and refinement of currently promising regimens, including anti-IL-6 inhibitory agents. Conclusions Patients with GCA often require long-term treatment with glucocorticoids; therefore, the challenge is to maximize the benefit–risk ratio for each patient by administering as much glucocorticoid treatment as necessary to control the disease initially and to prevent subsequent relapses, but as little as possible to reduce the occurrence of glucocorticoid-related AEs. Glucocorticoid-sparing strategies should be considered in each patient, and comorbidity risk management should be used as recommended by international and national guidelines. Effective prevention or management of complications associated with long-term glucocorticoid therapy is essential to reduce morbidity and mortality in patients with GCA. Patients require detailed education about their disease and lifestyle factors that may reduce the burden of glucocorticoid-related morbidity. Data on the efficacy and tolerability of the SEGRAs, DMARDs such as LEF, biological agents including cytokine inhibitors and co-stimulatory blockade and Janus kinase inhibitors are awaited with interest in view of their potential to limit cumulative glucocorticoid exposure and to mitigate osteoporotic and cardiometabolic risks patients consider the most worrisome. Acknowledgements Medical writing assistance in the preparation of this manuscript was provided by Melanie Sweetlove and Sara Dugan, PhD, of ApotheCom (Yardley, PA, USA). Support for this assistance was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Supplement: This supplement was funded by F. Hoffmann-La Roche Ltd. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. 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Prevention of glucocorticoid morbidity in giant cell arteritis

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Abstract

Abstract Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit–risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. giant cell arteritis, glucocorticoids, adverse events, morbidity Rheumatology key messages Patients with GCA require long-term glucocorticoid treatment, increasing their risk for glucocorticoid-related morbidity. Glucocorticoid dose and duration must be balanced against the risk for disease-related and treatment-related morbidity in GCA. Glucocorticoid sparing and other management strategies, including patient self-education, help mitigate the risk for glucocorticoid-related morbidity in GCA. Introduction Glucocorticoids remain the mainstay of therapy for GCA. Prompt diagnosis and initiation of glucocorticoids is critical to prevent complications associated with GCA, such as visual loss/blindness and other vascular complications [1–5]. There are wide variations across health care settings in the diagnosis and management of GCA. There is also a paucity of high-quality trials regarding the optimal dose, route of administration and tapering schedule of glucocorticoids in GCA. As a result, the standard of care for glucocorticoid use is not well defined [6, 7]. Long-term glucocorticoid use (3–6 months or more) may potentially be associated with numerous treatment-related adverse events (AEs), depending on both mean daily dose and cumulative dose [8, 9]. These AEs include skin, gastrointestinal, ophthalmological, skeletal muscle, bone, adrenal, cardiometabolic and neuropsychiatric complications [9–12]. The glucocorticoid-related AEs that patients and rheumatologists consider the most important or worrisome include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections [13]. Here we discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. Mechanism of action of glucocorticoids Mechanism of therapeutic effects The anti-inflammatory and immunosuppressive effects of glucocorticoids are mediated primarily by the cytosolic glucocorticoid receptor (cGR) through genomic mechanisms (Fig. 1) [14–16]. The classic genomic pathway is mediated by binding of glucocorticoids to this receptor. The cGR is a multiprotein complex that, in its native form, is associated with heat shock proteins and other co-chaperones in the cytoplasm [15, 17]. Glucocorticoids are lipophilic substances that easily pass through the cell membrane, where they bind with high affinity to the cGR, resulting in dissociation of the associated proteins and co-chaperones from the cGR [17]. The glucocorticoid–cGR complex is then translocated to the nucleus, where it forms homodimers that bind to DNA-binding sites termed glucocorticoid response elements (GREs) located in the promotor regions of target genes [15, 17]. Fig. 1 View largeDownload slide Genomic mechanisms of action of glucocorticoids 1: Direct binding of glucocorticoid–cGR complex to positive GREs. 2: Direct binding of glucocorticoid–cGR complex to negative GREs. 3: Glucocorticoid–cGR complex competition with transcription factors for co-activator binding, preventing transcription factors from binding to positive GREs. 4: Direct protein–protein interactions between glucocorticoid–cGR complex and transcription factors, preventing transcription factors from binding to positive GREs [15]. cGR: cytosolic glucocorticoid receptor; COX-2: cyclo-oxygenase 2; GILZ: glucocorticoid-induced leucine zipper; GRE: glucocorticoid response element; IκB; inhibitor of κB; MKP-1: mitogen-activated protein kinase phosphatase-1; PEPCK: phosphoenolpyruvate carboxykinase; TF: transcription factor. Fig. 1 View largeDownload slide Genomic mechanisms of action of glucocorticoids 1: Direct binding of glucocorticoid–cGR complex to positive GREs. 2: Direct binding of glucocorticoid–cGR complex to negative GREs. 3: Glucocorticoid–cGR complex competition with transcription factors for co-activator binding, preventing transcription factors from binding to positive GREs. 4: Direct protein–protein interactions between glucocorticoid–cGR complex and transcription factors, preventing transcription factors from binding to positive GREs [15]. cGR: cytosolic glucocorticoid receptor; COX-2: cyclo-oxygenase 2; GILZ: glucocorticoid-induced leucine zipper; GRE: glucocorticoid response element; IκB; inhibitor of κB; MKP-1: mitogen-activated protein kinase phosphatase-1; PEPCK: phosphoenolpyruvate carboxykinase; TF: transcription factor. The genomic effects of glucocorticoids can be divided into transactivation and transrepression. Transactivation results from binding of the glucocorticoid–cGR complex to positive GREs, resulting in transcription of anti-inflammatory and other regulatory proteins [15, 17]. Transrepression results from direct binding of the glucocorticoid–cGR complex to negative GREs, prevention of glucocorticoid–cGR binding to positive GREs through competition with transcription factors for co-activator binding or protein–protein interactions with the glucocorticoid–cGR complex, preventing the transcription of pro-inflammatory proteins [2, 15, 17]. However, some of the anti-inflammatory and immunosuppressive effects of glucocorticoids occur too rapidly to be attributable to genomic modes of action, particularly if high doses of glucocorticoids are used [15, 17]. These rapid effects of glucocorticoids, called non-genomic mechanisms of action, may be mediated by non-specific interactions with cell membranes, dissociation of proteins from the multiprotein–cGR complex or glucocorticoid interactions with membrane-bound GR [2, 15, 17]. Mechanism of adverse effects Glucocorticoid-related adverse effects are the result of on-target GR-mediated effects in that they are amplified manifestations of the normal effects of endogenous cortisol [18]. In general, it is thought that transactivation is responsible to a greater extent than transrepression for adverse effects, whereas transrepression is responsible to a greater extent for anti-inflammatory effects [2, 18]. However, this may be an oversimplification of glucocorticoid actions. Several AEs, including glaucoma, hypertension and diabetes, are indeed primarily attributable to transactivation, but hypothalamic–pituitary axis suppression and susceptibility to infections are caused primarily by transrepression (Table 1) [18–22]. Osteoporosis is the result of both transactivation and transrepression, whereas the mechanisms of other AEs are not fully elucidated [18]. Table 1 Glucocorticoid-related adverse events according to mechanism of action Transactivation  Partial transactivation  Transrepression  Arterial hypertension  Osteoporosis  Infections  Diabetes mellitus  Skin atrophy  Hypothalamic–pituitary axis suppression  Glaucoma  Growth retardation    Cushingoid appearance  Transactivation  Partial transactivation  Transrepression  Arterial hypertension  Osteoporosis  Infections  Diabetes mellitus  Skin atrophy  Hypothalamic–pituitary axis suppression  Glaucoma  Growth retardation    Cushingoid appearance  Glucocorticoid adverse events may be mediated by transactivation, transrepression or partial transactivation [18–22]. Glucocorticoid-induced osteoporosis results from direct effects of glucocorticoids on osteoblasts and osteoclasts [23], including decreased proliferation and activity of osteoblasts in conjunction with (at least during the initial treatment phase) increased activity of osteoclasts [18, 24, 25]. Osteoclast activity is stimulated by transactivation of osteoprotegerin ligand (OPG-L) and transrepression of OPG, shifting the OPG-L/OPG ratio in favour of bone resorption [18]. Furthermore, osteoclast apoptosis is reduced by glucocorticoids through the inhibition of OPG and increased expression of receptor activator of nuclear factor κB ligand [26]. Additionally, osteoclast activity is considered indirectly increased by glucocorticoid-induced reduction in intestinal calcium absorption and increased urinary calcium excretion. Decreased osteoblast activity results from a variety of mechanisms, including glucocorticoid-induced suppression of adrenal steroidal hormones, growth hormone, insulin-like growth factor-1 and TGF-β [18, 24]. Long-term treatment with glucocorticoids can also lead to hyperglycaemia and, consequently, to increased risk for diabetes [18, 24]. Glucocorticoids increase glucose synthesis through the transactivation of enzymes involved in gluconeogenesis (e.g. glucose-6-phosphatase and phosphoenolpyruvate carboxykinase); glucocorticoid-mediated activation of glycogen synthase results in increased glycogen storage in the liver [18, 24]. The primary mechanism underlying glucocorticoid-induced hypertension is sodium retention [18, 24]. Glucocorticoids increase epithelial sodium channel expression through transactivation effects and increase epithelial sodium channel activity through transactivation of serum- and glucocorticoid-regulated kinase [18, 24]. The risk for infection is increased during glucocorticoid therapy as a result of immunosuppression mediated by transrepression and transactivation effects on both the innate and the acquired immune systems [18, 24]. Additionally, glucocorticoid treatment results in reduced adhesion of neutrophils to epithelial monolayers and increased neutrophil counts [9]. Long-term treatment with glucocorticoids is also known to result in adrenal insufficiency, a condition in which the adrenal glands become incapable of generating sufficient cortisol once treatment with glucocorticoids has been stopped [27]. This occurs as a result of the negative feedback effect of exogenous glucocorticoids on the hypothalamic–pituitary axis through both transrepression and non-genomic effects [24, 28]. Inhibition at the level of the anterior hypothalamus results in suppression of the production of corticotrophin-releasing hormone and, consequently, adrenocorticotrophic hormone (ACTH), leading to adrenocortical hypoplasia and atrophy [24, 27]. Safety issues related to long-term glucocorticoid therapy in GCA The level of harm associated with glucocorticoid therapy is related to daily dose, total duration of intake and cumulative dose. In patients with RA treated with low-dose glucocorticoids in clinical trials of 2 years’ duration, adverse effects were usually modest and not necessarily different from those incurred with placebo treatment [29]. Nevertheless, it was suggested that AEs from glucocorticoids—including osteoporosis, Cushingoid symptoms, adrenal insufficiency and adrenal crisis upon glucocorticoid withdrawal, growth retardation in children, diabetes mellitus in at-risk patients and worsening glycaemic control in patients with diabetes mellitus, cataracts, glaucoma and hypertension—should be monitored and, if necessary, prevented or treated in patients with rheumatic diseases [29]. Long-term glucocorticoid therapy at dosages ⩽5 mg/day prednisone equivalent is associated with a low level of harm for most patients relative to its anticipated therapeutic effects; the exception is patients at high risk for cardiovascular disease, who may require preventive measures. In contrast, dosages ⩾10 mg/day prednisone equivalent are usually associated with a high level of harm [8]. Patients with GCA generally require higher starting doses and often longer durations of treatment with glucocorticoids than patients with other systemic inflammatory conditions [30, 31]. Guidelines uniformly recommend initial treatment with high-dose glucocorticoid regimens (40–60 mg/day prednisone or prednisone equivalent for 2–4 weeks) to achieve rapid resolution of inflammation. This recommendation must be balanced against the need to use the lowest effective dose to avoid AEs [5, 7, 31, 32]. Once the disease-related symptoms are under control and the inflammatory process has been satisfactorily suppressed (i.e. ESR and CRP levels are normalized), the goal is to taper glucocorticoid therapy to achieve a stable low maintenance dose or complete withdrawal [4, 5, 33]. The glucocorticoid dosage should be tapered gradually to avoid disease relapse [4]. The disease flare rate increases after reduction of the glucocorticoid dosage to 5–10 mg/day prednisone equivalent [32]. A substantial proportion of patients (30–50%) experience relapse, particularly during the glucocorticoid-tapering phase, and 20–30% of patients experience relapse after glucocorticoid withdrawal [6, 34–36]. The average duration of glucocorticoid therapy in GCA is ∼2–3 years, although lifelong treatment may be required in some patients [2, 6, 12, 37, 38]. Furthermore, trends over time in glucocorticoid use in patients with GCA suggest increasing cumulative doses and longer exposures in recent decades [37–39]. The reason for this trend is unknown. It has been postulated that increased recognition of the chronic nature of the disease, increased recognition of relapse and possibly overdiagnosis of relapse and greater use of imaging studies documenting persistent subclinical vascular inflammation may be contributing factors [37]. Recent claims-based data suggest that patients with GCA typically receive cumulative glucocorticoid doses of >5000 mg prednisone equivalent over the course of several years [38]. These extended periods of glucocorticoid use leading to higher cumulative doses may increase the risk for glucocorticoid-related complications, which places a substantial burden on the GCA population. Available data regarding the frequency of glucocorticoid-related AEs in patients with GCA are sparse, and it is difficult to distinguish the effects of glucocorticoids from those related to the disease itself, comorbid conditions and concomitant medications [2, 9]. Up to 90% of patients with GCA who receive long-term glucocorticoid treatment experience AEs [10, 12]. In a recent retrospective study of 2497 patients with GCA using medical claims data, glucocorticoid-related AEs were reported at an overall rate of 0.43 events per patient-year of exposure (Table 2) [38]. Apart from weight gain, the most frequent AEs were cataract (0.16 events per patient-year) and bone disease, including osteoporosis, fractures, hip replacement and aseptic necrosis (0.16 events per patient-year) [38]. Only AEs leading to direct claims were assessed in this study; these excluded weight gain, an AE of particular significance to patients and one that occurs in ∼70% of adults receiving long-term glucocorticoid treatment [10]. Compared with patients who did not experience AEs, those who did received glucocorticoids for longer durations (median 195 vs 102.5 days) and at higher cumulative doses (median 3400 vs 2145 mg prednisone equivalent) [38]. For each 1000 mg increase in cumulative glucocorticoid dose, the hazard ratio for AEs was increased by 3%, with the greatest increase observed for new-onset diabetes mellitus (5% per 1000 mg increase) [38]. Safety data such as these do not discriminate between glucocorticoid-related AEs and symptoms caused by GCA [39]. Furthermore, patients requiring higher doses of glucocorticoids are likely to be those with more active disease and higher inflammatory activity, factors that also contribute to the development of many AEs [40]. Table 2 Incidence of glucocorticoid-related adverse events based on claims data Adverse event  Events/patient-yeara  Hazard ratio per 1000 mgb increase in cumulative exposure (95% CI)  Percentage increase per 1000 mgb increase in cumulative exposure  Any  0.426  1.03 (1.02, 1.05)  3  Cataract  0.158  1.03 (1.02, 1.05)  3  Bone disease  0.156  1.05 (1.03, 1.06)  5      Osteoporosis  0.099  1.05 (1.03, 1.07)  5      Fracture  0.066  1.04 (1.03, 1.06)  4      Hip replacement  0.008  1.04 (0.99, 1.08)  4      Aseptic necrosis of bone  0.004  1.06 (1.01, 1.12)  6  Pneumonia  0.068  1.03 (1.01, 1.04)  3  Glaucoma  0.022  1.05 (1.01, 1.08)  5  Opportunistic infections  0.010  1.04 (1.00, 1.08)  4  Ulcer disease  0.006  1.00 (0.94, 1.06)  0  Adverse event  Events/patient-yeara  Hazard ratio per 1000 mgb increase in cumulative exposure (95% CI)  Percentage increase per 1000 mgb increase in cumulative exposure  Any  0.426  1.03 (1.02, 1.05)  3  Cataract  0.158  1.03 (1.02, 1.05)  3  Bone disease  0.156  1.05 (1.03, 1.06)  5      Osteoporosis  0.099  1.05 (1.03, 1.07)  5      Fracture  0.066  1.04 (1.03, 1.06)  4      Hip replacement  0.008  1.04 (0.99, 1.08)  4      Aseptic necrosis of bone  0.004  1.06 (1.01, 1.12)  6  Pneumonia  0.068  1.03 (1.01, 1.04)  3  Glaucoma  0.022  1.05 (1.01, 1.08)  5  Opportunistic infections  0.010  1.04 (1.00, 1.08)  4  Ulcer disease  0.006  1.00 (0.94, 1.06)  0  a Patients ≥50 years of age with two or more medical claims with GCA as a listed diagnosis, one or more filled oral corticosteroid prescription and no AEs before GCA diagnosis [38]. b Prednisone equivalent. The association between glucocorticoid use and AEs was also demonstrated in a large UK database of patients with GCA (n = 3074) and matched controls (n = 6148), in which 33% of patients each were treated with a cumulative dose of prednisone >10 000 mg [39]. Although causality cannot be ascertained in this type of study, AEs considered to be potentially related to glucocorticoid use included osteoporosis [relative risk (RR) = 2.9], osteopenia (RR = 2.5), angina pectoris (RR = 2.4), intermittent claudication (RR = 2.4) and diabetes mellitus (RR = 2.4). Adrenal insufficiency was not identified in the safety analyses described, but it is believed to occur frequently among patients treated with glucocorticoids. Although evidence from GCA-specific populations is rare, the results of one prospective study found that 49% of GCA patients receiving glucocorticoids did not respond to their first ACTH stimulation test, indicating impaired adrenal function [41]. Of these patients, 53% had not recovered their normal adrenal function after 12 months. This effect appeared temporary in most patients, with only 15% continuing to have a negative response in the ACTH stimulation test at 36 months and only 5% categorized as having definitive adrenal insufficiency. In this study, both total dose of glucocorticoid and duration of treatment were identified as risk factors for adrenal insufficiency [41]. Management of glucocorticoid-related complications Prophylaxis, monitoring and treatment of glucocorticoid-related complications are essential to the management of GCA [2]. Different glucocorticoid-dosing schemes, including high-dose intravenous glucocorticoids, have been investigated with the objective of reducing glucocorticoid-related adverse effects [42]. The rationale for this approach was to make use of the non-genomic effects of glucocorticoids to lower inflammation rapidly and to decrease the overall dose burden of subsequent oral glucocorticoid whose genomic effects are responsible for adverse effects [8, 10–12, 31, 38]. In a small randomized controlled trial, initial treatment with high-dose intravenous glucocorticoid (methylprednisolone, 15 mg/kg of ideal body weight/day for 3 days followed by a starting dose of 40 mg/day with scheduled tapering) allowed for more rapid tapering of oral glucocorticoids with higher frequency of sustained remission after treatment discontinuation [42]. However, a second randomized study reported no benefit for pulse treatment (single intravenous pulse of 240 mg methylprednisolone followed by 0.5 or 0.7 mg/kg/day oral prednisone) over oral prednisone alone (0.7 mg/kg/day) [43]. Therefore, current evidence does not support routine use of pulse therapy, and additional research on this issue is required [1, 7]. Treatment with glucocorticoids on alternating days has also been proposed to reduce the risk for AEs, but in a randomized prospective study of GCA (n = 60), this approach was associated with a higher rate of treatment failure [44] than daily administration in GCA and is therefore not recommended [4, 32]. The risk–benefit ratio of glucocorticoid therapy may also be influenced by patient-specific factors, such as disease activity, disease-related complications (e.g. loss of sight), age and gender, and the risks for some AEs can be mitigated by lifestyle interventions [8, 30]. Management strategies for the four most worrisome glucocorticoid-related AEs are detailed in Table 3 [2, 8, 30, 45, 46]. For example, the risk for glucocorticoid-induced osteoporosis, with or without fractures, is elevated by increasing cumulative doses [23] and by patient-related factors such as older age, female sex, low body weight, low bone mineral density, prevalent fractures and family history of osteoporosis [8]. Where available, the Fracture Risk Assessment Tool® is recommended for assessment of osteoporosis risk [23, 30]. Table 3 Recommended glucocorticoid-related risk management strategies for the most worrisome adverse event Adverse event  Patient-related risk factors  Risk assessment  Lifestyle interventions  Management option  Possibly included in monitoring  Osteoporosis  Older age Female sex Low body weight Low bone mineral density Prevalent fractures Family history of osteoporosis  Dose and fracture history FRAX tool  Physical exercise (weight-bearing exercise, strength training) Smoking cessation Limiting alcohol intake Dietary calcium intake  Preventive therapy and treatment with calcium and vitamin D supplementation Preventive therapy and treatment with bisphosphonates in patients with ongoing high-dose glucocorticoid therapy Teriparatide in patients with fractures  BMD before and during treatment Vitamin D levels  Hyperglycaemia  Genetic disposition Age Obesity Chronic inflammation    Weight reduction Healthful diet Exercise    Pretreatment screening Regular blood/urine glucose monitoring  Cardiovascular complications  Older age Male sex Obesity Hypertension Diabetes Dyslipidaemia Higher disease activity  SCORE model, or per national guidelines  Healthful diet (low in saturated fat and calories) Physical exercise Weight loss Sodium restriction Smoking cessation  Preventive therapy with statins or angiotensin-converting enzyme inhibitors in patients at high risk  Regular monitoring of blood pressure, cardiac insufficiency and serum lipid profile before and after initiation of glucocorticoids  Infection  Comorbidities History of serious infection Concomitant immunosuppressive treatments    Appropriate wound care Hand washing  Vaccination (influenza, pneumococcal, varicella zoster) in appropriate patients Trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii in patients receiving high- dose glucocorticoid therapy  Specific infection screening  Adverse event  Patient-related risk factors  Risk assessment  Lifestyle interventions  Management option  Possibly included in monitoring  Osteoporosis  Older age Female sex Low body weight Low bone mineral density Prevalent fractures Family history of osteoporosis  Dose and fracture history FRAX tool  Physical exercise (weight-bearing exercise, strength training) Smoking cessation Limiting alcohol intake Dietary calcium intake  Preventive therapy and treatment with calcium and vitamin D supplementation Preventive therapy and treatment with bisphosphonates in patients with ongoing high-dose glucocorticoid therapy Teriparatide in patients with fractures  BMD before and during treatment Vitamin D levels  Hyperglycaemia  Genetic disposition Age Obesity Chronic inflammation    Weight reduction Healthful diet Exercise    Pretreatment screening Regular blood/urine glucose monitoring  Cardiovascular complications  Older age Male sex Obesity Hypertension Diabetes Dyslipidaemia Higher disease activity  SCORE model, or per national guidelines  Healthful diet (low in saturated fat and calories) Physical exercise Weight loss Sodium restriction Smoking cessation  Preventive therapy with statins or angiotensin-converting enzyme inhibitors in patients at high risk  Regular monitoring of blood pressure, cardiac insufficiency and serum lipid profile before and after initiation of glucocorticoids  Infection  Comorbidities History of serious infection Concomitant immunosuppressive treatments    Appropriate wound care Hand washing  Vaccination (influenza, pneumococcal, varicella zoster) in appropriate patients Trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii in patients receiving high- dose glucocorticoid therapy  Specific infection screening  Recommendations for the most worrisome adverse events are summarized [2, 8, 30, 45, 46]. BMD: bone mineral density; FRAX: Fracture Risk Assessment; SCORE: Systematic Coronary Risk Evaluation. Lifestyle interventions to reduce the risk for osteoporosis include physical exercise (including weight-bearing exercise and strength training), smoking cessation, limiting alcohol intake and maintaining an adequate intake of dietary calcium [8, 30]. All patients receiving glucocorticoids should receive bone protective therapy in the absence of contraindications [4]. Preventive therapy should include calcium and vitamin D supplementation. Prevention of fractures with anti-osteoporotic therapies such as bisphosphonates and teriparatide may be indicated, depending on glucocorticoid dose and actual fracture risk [23, 30, 47]. Regular monitoring of bone mineral density during glucocorticoid treatment is recommended [5, 23]. The risk for diabetes during treatment with glucocorticoids is dependent on potency of treatment, length of treatment and absolute dose [8, 9, 48]. Patient-related risk factors include genetic disposition, age, obesity and chronic inflammation [8]. Recommended lifestyle interventions include weight loss, healthful diet and appropriate exercise [8]. Blood glucose monitoring before and every 3 months during treatment is suggested for all patients receiving glucocorticoids, and patients who have diabetes or pre-diabetes before starting treatment should be carefully monitored [5, 9, 30]. Assessing the risk for cardiovascular events in GCA patients is complicated by the fact that they may be caused by the disease itself [9]. Risk factors for cardiovascular events include older age, male sex, obesity, hypertension, diabetes, dyslipidaemia and higher disease activity [8]. Risk can be assessed with generic risk assessment tools used in the general population. The EULAR recommends the Systematic Coronary Risk Evaluation model for assessing risk [46]. Lifestyle interventions that may modify the risk for cardiovascular events include healthful diet (low in saturated fat and calories), physical activity, weight normalization, sodium restriction and cessation of smoking [8]. Treatment with statins or angiotensin-converting enzyme inhibitors is recommended for patients at high risk. Although it has been suggested that patients receiving glucocorticoids should start treatment at a lower threshold than the general population, current EULAR guidelines recommend they be initiated according to national guidelines for the general population [9, 46]. In contrast to the risk for osteoporosis, which is influenced primarily by the cumulative glucocorticoid dose, the risk for infections does not appear to be related to cumulative glucocorticoid dose and is instead dependent on the actual dose of glucocorticoids [8, 49]. The risk for infection is highest during the first year of treatment, when patients are typically receiving initial treatment with high-dose glucocorticoids; after the first 12 months, a dosage of >10 mg/day prednisone equivalent is associated with an increased risk for severe infection and death [49]. Patient-related risk factors include high disease activity, comorbidities (including chronic heart, lung or renal disease, peripheral vascular disease, diabetes, hepatitis C, leucopenia and certain neurological diseases) and a history of serious infection [8]. It has also been suggested that infection risk (including tuberculosis) be evaluated before treatment is started [8, 50]. Appropriate wound care and good hygiene, especially hand washing, may help to reduce the risk for infection [8]. Prophylactic vaccination should be considered according to EULAR and national guidelines for patients with autoimmune inflammatory rheumatic diseases [51, 52]. Vaccination against influenza and pneumococcal pneumonia is strongly recommended for all patients, but vaccination against herpes zoster should be considered only in patients who are less severely immunosuppressed [51]. Antibacterial treatment should be initiated promptly at suspicion of bacterial infection. Prophylaxis against Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole should be considered for patients receiving high-dose glucocorticoids [2, 53]. Specific infection screening (particularly for tuberculosis) before the initiation of glucocorticoid treatment, and the prompt initiation of antimicrobial therapy when required, may reduce the risk for severe infection [49]. The primary management strategy for the prevention of adrenal insufficiency is to use a tapering regimen to ensure the adrenal glands return to an adequate level of function [41]. Tapering is a standard technique recommended for all patients to stop treatment or to reduce glucocorticoid exposure, and therefore it is widely used; however, a more gradual taper and ACTH stimulation testing may be appropriate for patients at high risk [4, 5, 41]. Optimal tapering regimens with regard to length of exposure and degree of adrenal suppression have thus far not been defined. Glucocorticoid-sparing treatment strategies Given the substantial morbidity associated with long-term glucocorticoid therapy, guidelines (EULAR and British Society for Rheumatology/British Health Professionals in Rheumatology) recommend that early initiation of MTX or other immunosuppressive agents be considered for patients with GCA [4, 5]. The usefulness of immunosuppressive agents, such as AZA and CYC, has not been uniformly demonstrated for the treatment of patients with GCA, but a benefit from methotrexate has been suggested [7, 54]. In a meta-analysis of individual patient data from three randomized controlled trials in GCA, it was found that adjunctive low-dose MTX reduced both relapse risk and glucocorticoid exposure, though the frequency and severity of AEs were not reduced [55]. Adjunctive MTX may reduce cumulative glucocorticoid doses by ∼20% [56] and relapses by 35% [55] in GCA [7]. Based on systematic analysis of clinical trial data, use of methotrexate as a glucocorticoid-sparing strategy can be considered for patients at high risk for glucocorticoid-induced AEs at disease outset and for patients whose disease course is protracted and who are at risk for recurrent relapses and glucocorticoid-induced AEs [7, 31]. A Cochrane review of methotrexate in GCA is ongoing. Overall, no clear benefit has been observed with TNF-α inhibitors such as infliximab in randomized controlled trials; therefore, the use of these agents is not recommended in GCA [1, 4, 30, 57, 58]. In a randomized, double-blind, placebo-controlled, phase 2 trial, the IL-6 receptor-alpha inhibitor tocilizumab demonstrated efficacy in the induction and maintenance of remission in patients with GCA [59]. Recently, blockade of IL-6 signalling with tocilizumab has been demonstrated to have clinical efficacy and a glucocorticoid-sparing effect in patients with GCA in a randomized, placebo-controlled, phase 3 trial with blinded glucocorticoid regimens of variable dose and duration (GiACTA trial) [60]. Tocilizumab combined with a 26-week prednisone taper was superior to placebo combined with 26-week and 52-week prednisone tapers for achieving sustained glucocorticoid-free remission [60]. Cumulative prednisone exposure over the 52-week trial was significantly lower in patients treated with tocilizumab plus a 26-week prednisone taper than in those treated with a 52-week prednisone taper: 43.5 and 51.2% reductions occurred in the cumulative prednisone dose arms compared with the 26- and 52-week prednisone taper arms, respectively. The 26-week prednisone taper implemented in GiACTA [60] allows for faster glucocorticoid tapering than current recommended glucocorticoid-tapering schedules (Fig. 2) [5]. A higher rate of serious AEs was observed in the placebo plus prednisone taper groups than in the tocilizumab plus prednisone taper groups, which might have been driven by glucocorticoid-related toxicity [60]. Abatacept, a modulator of T cell costimulation, and ustekinumab, an anti-IL-12 and anti-IL-23 mAb, have also shown initial promise [61–63]. Fig. 2 View largeDownload slide Glucocorticoid tapering schedule in GiACTA vs BSR tapering schedule GiACTA glucocorticoid tapering occurred in combination with tocilizumab treatment [60]. BSR tapering schedule is as recommended [5]. BSR: British Society for Rheumatology. Fig. 2 View largeDownload slide Glucocorticoid tapering schedule in GiACTA vs BSR tapering schedule GiACTA glucocorticoid tapering occurred in combination with tocilizumab treatment [60]. BSR tapering schedule is as recommended [5]. BSR: British Society for Rheumatology. Future perspectives A clear need to improve the benefit–risk ratio of glucocorticoid therapy has led to the development of novel formulations of existing glucocorticoids and of novel cGR ligands [15]. Novel formulations that have been investigated in inflammatory rheumatic diseases include modified/delayed-release prednisone, liposome encapsulation and coupling of glucocorticoids to nitrogen oxide (nitrosteroids) [15, 64]. Modified/delayed-release prednisone has been incorporated into clinical practice for RA, but it is yet to be evaluated in GCA [64]. Liposomal glucocorticoids accumulate at the site of inflammation, resulting in high local concentrations and reduced impact on non-target tissues; thus, liposome encapsulation is expected to enhance the anti-inflammatory action of glucocorticoids while limiting AEs [17, 64]. Early results with liposomal dexamethasone appear promising in patients with RA [64]. Based on the theory that genetic transactivation by the glucocorticoid–receptor complex causes most glucocorticoid-related adverse effects whereas transrepression mediates anti-inflammatory and immunomodulatory effects, selective glucocorticoid receptor agonists (SEGRAs) have been developed [15]. Data are pending for SEGRAs now in phase 2 clinical development for rheumatic diseases [64]. The fact that some glucocorticoid-related adverse effects may be partially mediated by transrepression should also be considered. Recent data also suggest that important anti-inflammatory effects of glucocorticoids are mediated by transactivation of inhibitor of the NF-κB kinase, mitogen-activated protein kinase phosphatase-1, IL-10 and glucocorticoid-induced leucine zipper [18, 64]. The clinical relevance of these effects is unclear, however, and must be investigated in future clinical trials. Other initiatives to improve the management of GCA and to reduce the need for and the risk from glucocorticoids include study of various anti-cytokine and anti-cellular therapies and refinement of currently promising regimens, including anti-IL-6 inhibitory agents. Conclusions Patients with GCA often require long-term treatment with glucocorticoids; therefore, the challenge is to maximize the benefit–risk ratio for each patient by administering as much glucocorticoid treatment as necessary to control the disease initially and to prevent subsequent relapses, but as little as possible to reduce the occurrence of glucocorticoid-related AEs. Glucocorticoid-sparing strategies should be considered in each patient, and comorbidity risk management should be used as recommended by international and national guidelines. Effective prevention or management of complications associated with long-term glucocorticoid therapy is essential to reduce morbidity and mortality in patients with GCA. Patients require detailed education about their disease and lifestyle factors that may reduce the burden of glucocorticoid-related morbidity. Data on the efficacy and tolerability of the SEGRAs, DMARDs such as LEF, biological agents including cytokine inhibitors and co-stimulatory blockade and Janus kinase inhibitors are awaited with interest in view of their potential to limit cumulative glucocorticoid exposure and to mitigate osteoporotic and cardiometabolic risks patients consider the most worrisome. Acknowledgements Medical writing assistance in the preparation of this manuscript was provided by Melanie Sweetlove and Sara Dugan, PhD, of ApotheCom (Yardley, PA, USA). Support for this assistance was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Supplement: This supplement was funded by F. Hoffmann-La Roche Ltd. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. 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RheumatologyOxford University Press

Published: Feb 1, 2018

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