GC-sparing Agent Research Articles

Faster steroid-free remission with tocilizumab compared to methotrexate in giant cell arteritis: a real-life experience in two reference centres.

Glucocorticoids (GCs) are still the mainstay of treatment of giant cell arteritis (GCA). Although GCs are highly effective in GCA, the high burden of toxicity of GCs as well as the disease relapse during GC tapering is well documented. To compare the efficacy and rapidity of TCZ and MTX as steroid-sparing agents in a real-life cohort of GCA patients. A retrospective analysis was conducted including patients with newly diagnosed GCA from the Rheumatology Units of Udine and Rome. The inclusion criterion was the treatment with TCZ or MTX as first steroid-sparing drug. 112 GCA patients (81 females) with a median age of 70 (IQ 65-75) years were collected. Thirty-one out of 112 (27.7%) patients were treated with TCZ (162mg/week), while 81/112 (72.3%) patients received MTX (up to 20mg/week) as a GC-sparing agent. At month 6 after GCA onset, 5/31 (16.1%) patients in TCZ group and none in MTX group were in GC-free sustained remission (p value = 0.001). Similarly, at month 12, 64.5% (20/31) and 11.1% (9/81) of patients were in sustained GC-free remission in TCZ and MTX group, respectively (p value <0.001). At month 24 of follow-up, at least one relapse of the disease occurred in 7/31 (22.6%) in TCZ-treated and 28/81 (34.6%) in MTX-treated patients, respectively (p value = 0.22). TCZ allowed a faster discontinuation of steroid therapy than MTX in GCA patients, without increasing the risk of relapse.

Current management of giant cell arteritis and its complications.

This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity. The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase-signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments. While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.

Glucocorticoid discontinuation rate and risk factors for relapses in a contemporary cohort of patients with giant cell arteritis

The rates of relapses and therapy discontinuation in patients with giant cell arteritis (GCA) in the modern therapeutic era have not been defined. We aimed to evaluate the glucocorticoid (GC) discontinuation rate and the factors associated with relapses in a contemporary GCA cohort. Patient and treatment data were collected cross-sectionally at first evaluation and 2 years later (second evaluation), in a multicenter, prospective GCA cohort. Predictors of relapses were identified by logistic regression analyses. 243 patients with GCA were initially included (67% women, mean age at diagnosis: 72.1 years, median disease duration: 2 years) while 2 years later complete data for 160 patients were available and analyzed. All patients had received GCs at diagnosis (mean daily prednisolone dose: 40 mg) while during follow-up, 37% received non-biologic and 16% biologic agents, respectively. At second evaluation, 72% of patients were still on therapy (GCs: 58% and/or GC-sparing agents: 29%). Relapses occurred in 27% of patients during follow-up; by multivariable logistic regression analysis, large vessel involvement at diagnosis [odds ratio (OR) = 4.22], a cardiovascular event during follow-up (OR = 4.60) and a higher initial GC daily dose (OR = 1.04), were associated with these relapses. In this large, real-life, contemporary GCA cohort, the rates of GC discontinuation and relapses were 40% and 27%, respectively. Large vessel involvement, a higher GC dose at diagnosis and new cardiovascular events during follow-up were associated with relapses.

The administration of methotrexate in patients with Still's disease, “real-life” findings from AIDA Network Still Disease Registry

ObjectivesTo describe clinical characteristics of patients with Still's disease treated with methotrexate (MTX) and to assess drug effectiveness evaluating change in disease activity, reduction of inflammatory markers, and glucocorticoid (GC)-sparing effect. MethodsPatients with Still's disease treated with MTX were assessed among those included in AIDA Network Still Disease Registry. ResultsIn this registry, 171 patients with Still's disease were treated with MTX (males 43.3%, age 37.1 ± 16.0 years). They were mainly characterised by joint features and fever without a prominent multiorgan involvement. MTX was administered with GCs in 68.4% of patients, with other conventional synthetic DMARDs in 6.4%, and with biologic DMARDs in 25.1%. A significant reduction of the modified systemic score was observed, and 38.6% patients were codified as being in clinical remission at the end of follow-up. The concomitant administration of a biologic DMARD resulted a predictor of the clinical remission. Furthermore, a reduction of inflammatory markers and ferritin levels was observed following the administration of MTX. Additionally, a marked reduction of the dosage of concomitant GCs was identified, while 36.7% discontinued such drugs. Male gender appeared as a predictor of GC discontinuation. MTX was discontinued in 12.3% of patients because of adverse effects, and in 12.3% for lack of efficacy. ConclusionsClinical characteristics of patients with Still's disease treated with MTX were described, mainly joint features and fever without a prominent multiorgan involvement. The clinical usefulness of MTX was reported in reducing the disease activity, decreasing the inflammatory markers, and as GC-sparing agent.

Low relapse rate in patients with giant cell arteritis in a multi-centre retrospective Turkish Registry.

Glucocorticoids (GC) are widely accepted as the standard first-line treatment for giant cell arteritis (GCA). However, relapse rates are reported up to 80% on GC-only protocol arms in controlled trials of tocilizumab and abatacept in 12-24 months. Herein, we aimed to assess the real-life relapse rates retrospectively in patients with GCA from Turkey. We assembled a retrospective cohort of patients with GCA diagnosed according to ACR 1990 criteria from tertiary rheumatology centres in Turkey. All clinical data were abstracted from medical records. Relapse was defined as any new manifestation or increased acutephase response leading to the change of the GC dose or use of a new therapeutic agent by the treating physician. The study included 330 (F/M: 196/134) patients with GCA. The mean age at disease onset was 68.9±9 years. The most frequent symptom was headache. Polymyalgia rheumatica was also present in 81 (24.5%) patients. Elevation of acute phase reactants (ESR>50 mm/h or CRP>5 mg/l) was absent in 25 (7.6%) patients at diagnosis. Temporal artery biopsy was available in 241 (73%) patients, and 180 of them had positive histopathological findings for GCA. For remission induction, GC pulses (250-1000 methylprednisolone mg/3-7 days) were given to 69 (20.9%) patients, with further 0.5-1 mg/kg/day prednisolone continued in the whole group. Immunosuppressives as GC-sparing agents were used in 252 (76.4%) patients. During a follow-up of a median 26.5 (6-190) months, relapses occurred in 49 (18.8%) patients. No confounding factor was observed in relapse rates. GC treatment could be stopped in only 62 (23.8%) patients. Additionally, GC-related side effects developed in 64 (24.6%) patients, and 141 (66.2%) had at least one Vasculitis Damage Index (VDI) damage item present during follow-up. In this first multi-centre series of GCA from Turkey, we observed that only one-fifth of patients had relapses during a mean follow-up of 26 months, with 76.4% given a GC-sparing IS agent at diagnosis. At the end of follow-up, GC-related side effects developed in one-fourth of patients. Our results suggest that patients with GCA had a low relapse rate in real-life experience of a multi-centre retrospective Turkish registry, however with a significant presence of GC-associated side effects during follow-up.

What is a response in randomised controlled trials in giant cell arteritis?

Glucocorticoids (GCs) are the gold standard for treatment of giant cell arteritis (GCA); however, there is a need for studies on GC-sparing agents, given that up to 85% of patients...

Relapses are common in severe hematologic systemic lupus erythematosus and may be prevented by early institution of immunosuppressive agents: Α real-life single-center study

Hematologic manifestations are common in systemic lupus erythematosus (SLE), either at initial presentation or during the course of the disease, but data regarding their natural history are scarce. To describe the characteristics, treatments, and outcomes of severe hematological manifestations in a large cohort of lupus patients. Retrospective cohort study of patients in the "Attikon" lupus cohort who had a history of a severe hematologic manifestation, defined as autoimmune hemolytic anemia (AIHA) with hemoglobin < 8g/dL, thrombocytopenia with platelet count < 30,000/mm3, Evans syndrome with hemoglobin < 8g/dL, and/or platelet count < 30,000/mm3, neutropenia with < 500 neutrophils/mm3, thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)-like syndrome, or macrophage activation syndrome (MAS). Demographic and clinical characteristics, treatments, and outcomes were recorded. From over 300 patients with hematologic manifestations, 41 qualified as severe (70.7% women, mean [SD] age at SLE diagnosis 42.6 [18.0] years). Hematologic manifestations preceded SLE diagnosis in 13 patients (31.7%), was concomitant to SLE diagnosis in 16 patients (39%), and occurred during the course of the disease in 12 (29.3%) patients, with a mean (SD) disease duration of 8.7 (5.5) years. Thrombocytopenia was the most common severe hematological manifestation (56.1%), followed by AIHA (17.1%) and TTP-like syndrome (12.2%). For initial treatment, all patients were treated with glucocorticoids (GC), while rituximab and cyclophosphamide were the most frequently used immunosuppressive agents. Following initial treatment, relapse occurred in 22 patients (53.7%). Compared to patients that did not relapse, those that relapsed had less often received concomitant immunosuppressive agents following treatment of initial episode (n = 17/23, 73.9% vs 5/17, 29.4%, p = 0.005). Severe hematologic disease in SLE has a high risk of relapse, which may be mitigated by the early institution of GC-sparing agents.

How to taper glucocorticoids in inflammatory rheumatic diseases? A narrative review of novel evidence in rheumatoid arthritis, systemic lupus erythematosus, and giant cell arteritis.

Glucocorticoids (GCs) remain regularly used drugs in patients with chronic inflammatory rheumatic diseases. As long-term intake at high dosages is associated with harm, it is generally advised that GCs be tapered and stopped. However, most recommendations concerning tapering have been eminence- or consensus-based. In this narrative review, we present novel data from recent studies (SEMIRA, CORTICOLUP, and GiACTA) shedding light from different angles on the effects of tapering GCs in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and giant cell arteritis (GCA). In RA and SLE, our main findings comprise that (a) the majority of RA and SLE patients can successfully taper their GC, but that (b) tapering increases the risk of flare. In GCA, tocilizumab was shown to be a potent GC-sparing agent. Finally, we also present exemplary tapering schemes for RA, SLE, and GCA, although different tapering regimens have not yet been sufficiently compared in randomized trials.

Abatacept as Adjunctive Therapy in Refractory Polymyalgia Rheumatica.

Glucocorticoids (GCs) are the mainstay of treatment for patients with polymyalgia rheumatica (PMR).1 Despite their efficacy, GCs are associated with well-known adverse events and a substantial proportion of patients with PMR do not respond adequately, or are refractory, to initial GC treatment. GC-sparing agents in PMR are limited to methotrexate (MTX).1.

Treatment of Giant Cell Arteritis and Takayasu Arteritis-Current and Future.

Purpose of ReviewGuidelines for the management of large vessel vasculitides have been recently updated by several scientific societies. We have evaluated the current recommendations for treatment of giant cell arteritis (GCA) and Takayasu arteritis (TA) and addressed potential future therapeutic strategies.Recent FindingsWhile glucocorticoids (GCs) remain the gold standard for induction of remission, many patients relapse and acquire high cumulative GC exposure. Thus, GC-sparing therapies such as methotrexate are recommended for selected patients with GCA and all patients with TA. Recent high-quality evidence shows that tocilizumab is an effective GC-sparing agent in GCA. Non-biologic and biologic immunomodulators also appear to have GC-sparing properties in TA.SummaryTocilizumab is now considered to be part of the standard treatment for GCA, particularly with relapsing disease, but questions on its use such as length of treatment and monitoring of disease activity remain open. High-quality evidence to guide treatment of TA is still lacking.

The reduction of concomitant glucocorticoids dosage following treatment with IL-1 receptor antagonist in adult onset Still's disease. A systematic review and meta-analysis of observational studies.

Background:Despite being burdened by significant adverse events, glucocorticoids (GCs) are frequently employed in managing adult onset Still’s disease (AOSD), prompting the need for GC-sparing agents. In this work, we performed a systematic review and meta-analysis to synthesize the evidence about the reduction of concomitant GCs dosage and the rate of GCs discontinuation in patients with AOSD who were treated with anakinra, a recombinant IL-1 receptor antagonist.Methods:A systematic review of the literature was completed to identify all available data concerning the reduction of concomitant GCs dosage following anakinra in AOSD and a meta-analysis was thus performed using a random-effects model.Results:A significant reduction of the GCs dosage was detected by pooled analysis with mean difference of –22.4 mg/day [95% confidence interval (CI): –28.8 to –16.1, p < 0.0001] at the last follow-up; the heterogeneity was moderate (Q = 11.67 with df = 7.00, p < 0.0001, I2 = 40.01%). Furthermore, the pooled analysis under a random effects model showed an overall rate of GCs discontinuation of 0.35 (95% CI: 0.28–0.41, p < 0.0001); the heterogeneity was low (Q = 5.99 with df = 6.00, p < 0.0001, I2 = 0.00%).Discussion:Taking together all these findings, the reduction of concomitant GCs dosage following anakinra could be suggested, leading to a further improvement of AOSD therapeutic strategy.Conclusion:In conclusion, the present systematic review and meta-analysis suggests the reduction of concomitant GCs dosage following treatment with anakinra. A percentage of patients are no longer required to be treated with GCs, discontinuing these drugs without a flare of the disease.

Factors Associated with Relapse and Dependence on Glucocorticoids in Giant Cell Arteritis.

To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in patients with giant cell arteritis (GCA). We retrospectively analyzed 326 consecutive patients with GCA followed for at least 12 months. Factors associated with relapse and GC dependence were identified in multivariable analyses. The 326 patients (73% women) were followed up for 62 (12-262) months. During followup, 171 (52%) patients relapsed, including 113 (35%) who developed GC dependence. Relapsing patients had less history of stroke (p = 0.01) and presented large-vessel vasculitis (LVV) more frequently on imaging (p = 0.01) than patients without relapse. During the first months, therapeutic strategy did not differ among relapsing and nonrelapsing patients. GC-dependent patients were less likely to have a history of stroke (p = 0.004) and presented LVV on imaging more frequently (p = 0.005) than patients without GC-dependent disease. In multivariable analyses, LVV was an independent predictive factor of relapse (HR 1.49, 95% CI 1.002-2.12; p = 0.04) and GC dependence (OR 2.19, 95% CI 1.19-4.05; p = 0.01). Conversely, stroke was a protective factor against relapse (HR 0.21, 95% CI 0.03-0.68; p = 0.005) and GC-dependent disease (OR 0.10, 95% CI 0.001-0.31; p = 0.0005). Patients with a GC-dependent disease who received a GC-sparing agent had a shorter GC treatment duration than those without (p = 0.008). In this study, LVV was an independent predictor of relapse and GC dependence. Further prospective studies are needed to confirm these findings and to determine whether patients with LVV require a different treatment approach.

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes

AbstractHypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/μL and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ≥50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

Update on treatment of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease in the elderly after rheumatoid arthritis. It is clinically characterised by pain and stiffness in the neck, proximal shoulder and hip girdle. Glucocorticoids (GCs) are the cornerstone of PMR treatment, but they are associated with potentially severe side effects. Among GC-sparing agents, methotrexate revealed a modest benefit in clinical trials, and recently, there have been promising reports from tocilizumab. In this review, we summarize the available evidence on the treatment of PMR and the possible role in the future of other agents under investigation.

Steroid-sparing effect and toxicity of dapsone treatment in giant cell arteritis: A single-center, retrospective study of 70 patients.

Although a glucocorticoid (GC)-sparing strategy is needed for patients with giant cell arteritis (GCA) suffering from refractory disease or serious treatment-related complications, evidence of efficacy in this setting of immunosuppressive drugs and biotherapies is lacking. Herein, we evaluated the GC-sparing effects and tolerability of addition of dapsone (DDS) to prednisone therapy in patients with GCA. We retrospectively assessed data on 18 GCA patients who received DDS as a first-line treatment (DDS-1 group) and 52 patients who received it as a second- or third-line treatment for refractory GCA, with or without excessive GC-related toxicity (DDS-2 group). Of these 70 patients, 63 belonged to an inception cohort of 478 patients, whereas the remaining 7 were referred to our department for resistant GCA. In all, 52 patients were assessable for DDS efficacy. The baseline characteristics of the DDS-1 patients were similar to those of 395 GCA patients (control group) who received prednisone alone. DDS-1 patients had a more sustained decrease in GC dose with a lower mean prednisone dose at 12 months, and they comprised higher proportions who achieved GC withdrawal within the first year, who stopped prednisone treatment, and who recovered from GCA (P < 0.001 for each variable). Patients in the DDS-2 group achieved a mean rate of prednisone reduction of 65% and a prednisone dose reduction of 16.9 ± 13.3 mg/d. The monthly decreases in the prednisone dose were 2.4 and 1.25 mg in DDS-1 and DDS-2 patients, respectively. DDS-induced side effects were recorded in 44 (64%) assessable patients. These side effects led to lowering of the DDS dose by 25 mg/d in 11 (16%) patients and permanent cessation of DDS in 14 patients (20%), due to allergic skin rash in 7, agranulocytosis in 2, icteric hepatitis in 2, and excessive hemolysis in 2 patients. DDS is a potent GC-sparing agent in GCA that should be evaluated in prospective studies. However, DDS use should be restricted to refractory GCA patients due to its toxicity, and close clinical and laboratory monitoring for 3 months is necessary.

STEROID-INDUCED PEDIATRIC DIABETES MELLITUS – LITERATURE REVIEW AND CASE REPORT

Glucocorticoids (GCs), one of the principal drug classes used in rheumatology, are known for their fast onset and powerful action, but also for their multiple adverse effects, the most feared ones being osteoporosis, steroidinduced diabetes (SID), cardiovascular diseases and, in children, the decrease of linear growth rate. Due to data scarcity, most SID treatment recommendations are not evidence-based. Using the minimum dose and shortest possible treatment are preventive measures generally recommended, which are frequently not followed, due to fear of GC-sparing immunosuppressive agents’ side effects (DMARDs). Physiologic dose splitting, whenever possible, can be efficient in preventing at least some of the GCs’ adverse effects, mainly the suppression of the hypothalamic-pituitary axis and SID. These are depicted by a case presentation, of a 12-year-old female patient with SID caused by high dose GC treatment for juvenile dermatomyositis (JDM), in whom this method was sufficient to control glycaemia.

Rituximab for minimal change disease in adults: long-term follow-up

Minimal change nephropathy or disease (MCD) accounts for 10-15% of cases of the nephrotic syndrome in adults with frequent relapses occurring in up to 25% of cases. The drug of choice is glucocorticoids (GCs), but GC-dependence is seen in 25-30%. Treatment with rituximab has been found to be effective in relapsing and GC-dependent cases, but little data are available regarding long-term outcome in adults. We present nine female and seven male patients, ranging from 19 to 73 years of age with multirelapsing, GC-dependent or GC-resistant disease with a kidney biopsy consistent with MCD. Twelve patients were steroid-dependent with a lowest daily GC dose between 5 and 20 mg/day. Rituximab with a total dose 1000-2800 mg divided in two to four doses was given together with GC achieving B-cell depletion before the second dose. No major side-effects occurred. Thirteen of the patients responded with complete remission enabling discontinuation or tapering of GC significantly below levels, where relapses had occurred in the past (P < 0.001). Two patients reached partial remission and one had no response to therapy. Follow-up was 12-70 months (median 44). Eight patients have remained in remission, whereas relapses occurred in seven patients after 9-28 months with repeated rituximab treatment in four of these. Our study reinforces the role of rituximab as a GC-sparing agent in the challenging GC-dependent and multirelapsing MCD patients. In this emerging therapeutic field randomized studies with extended follow-up will add important information regarding optimal treatment, relapse and safety.

Substantial practice variation exists in the management of childhood nephrotic syndrome

Practice variation is common for nephrotic syndrome (NS) treatment. A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS. Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4 weeks by 26 %, and 10 % prescribed 'other'. Alternate-day GC was continued for 6 weeks by 63 % of respondents and for >6 and <6 weeks by 32 and 6 %, respectively. For biopsy-confirmed minimal change disease, 65 and 46 % of respondents chose oral cyclophosphamide for frequently relapsing and steroid-dependent phenotypes, respectively; calcineurin inhibitors or mycophenolate were the second most popular choices. Kidney biopsy was 'always' performed by 16, 39, and 97 % of respondents for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Rituximab had been administered by 60 % of respondents; 22, 56, and 72 % reported that they would consider rituximab for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Most notable differences between practice and Guideline recommendations were first presentation GC duration, GC-sparing agent choices in frequently relapsing and steroid-dependent patients, and biopsy practices. There is substantial Canadian practice variation in NS treatment. Assessment of factors driving variation and strategies to implement Guideline recommendations are needed.

THU0214 Treatment of refractory giant cell arteritis with cyclophosphamide. A retrospective analysis of 35 patients from three tertiary care centers

BackgroundPatients with giant cell arteritis (GCA) refractory to standard immunosuppressive therapy including glucocorticoids (GC) and GC-sparing agents (methotrexate, azathioprine) may comprise a significant clinical problem with a high risk of...

Glucocorticoids in autoimmune connective tissue diseases

: Glucocorticoids (GCs) are occasionally required for the cutaneous manifestations of autoimmune connective tissue diseases. In general, good therapeutic alternatives with fewer side effects than GCs are available, including anti-inflammatory agents such as antimalarials or dapsone, or immunosuppressives such as azathioprine or methotrexate, and these can serve as GC-sparing agents or can substitute for the use of GCs. When GC use cannot be avoided, it is important to implement a number of recommendations and improvements in dosing and prevention of side effects in order to optimize care. These include using appropriate and adequate doses of GCs initially, appropriate tapering regimens, and proper monitoring, prophylaxis, and treatment for infections, osteoporosis, avascular necrosis, hyperglycemia, hypertension, hyperlipidemia, and glaucoma.