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Objectives: The need for glucocorticoid-sparing drugs (GCSD) remains an important issue and is an unmet need in the treatment of polymyalgia rheumatica (PMR). We therefore aimed to assess the effectiveness and safety of methotrexate (MTX) and of leflunomide (LEF) in daily clinical practice in PMR patients from Argentina. Methods: A multicentre and observational study (medical records review) of PMR patients seen between 2007 and 2023, who had at least three months of follow-up after starting a GCSD, either MTX or LEF, was performed. Results are expressed as medians and interquartile ranges [25th-75th (IQR)] for continuous variables and percentages for categorical ones. The two treatment groups were compared using χ2 test for categorical variables, Mann-Whitney U test for continuous variables and the log-rank test for time-to-event data. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression. In all cases, a p-value <0.05 was considered statistically significant. Results: One-hundred and eighty-six patients (79% female) with a median age of 72 years (IQR, 65-77 years) were included. One-hundred and forty-three patients (77%) were prescribed MTX (15, IQR 10-15) and 43 (23%) LEF (20 mg, fixed dose). Flare-ups (relapses and recurrences) occurred in 13 patients (7%) and were comparable between both groups. Persistent GCSD intake was observed in 145 patients (78%). Glucocorticoid (GC) withdrawal was achieved in 67 of these 145 patients (46%) and this occurred more frequently in the LEF group (P = 0.001). Furthermore, time until prednisone discontinuation was shorter in the LEF-treated patients (4.7 months, IQR 3-20 on LEF versus 31.8 months, IQR 10-82 on MTX, P = 0.000). Remission was found more frequently in the LEF group (P = 0.003). In the multivariate analysis, the probability of remission was higher with LEF therapy (P = 0.010) and this finding persisted in the subgroup analysis who were followed up < 40 months (OR 3.12, 95% CI = 1.30-7.47, P = 0.011). Conclusions: This study demonstrated the clinical effectiveness of LEF and even its superiority in achieving remission when compared with MTX as GCSD in PMR patients. Further research is needed to support these findings.

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OBJECTIVES: Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. MATERIAL AND METHODS: This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. RESULTS: Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. CONCLUSIONS: Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. STUDY REGISTRATION: ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.

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Monomodal systemic glucocorticoids remain the mainstay of treatment for bullous pemphigoid (BP). In this retrospective, single-arm study, we evaluated the feasibility (efficacy and tolerability) of the combination of methylprednisolone and low-dose (up to 12.5 mg/week) methotrexate (MP + MTX) for BP. At week 12, 53/55 (96.4%) patients initiated on MP + MTX during a five-year period (potential follow up time: ≥4 years) remained on treatment. At this time-point, BP remission was achieved in all compliant patients (including n = 24 cases of dipeptidyl peptidase-4 inhibitors-associated BP; 12-week remission rate: 100% [95% CI: 91.9-100.0%]; mean time to remission: 29.5 days, SEM: 2.3 days) at a mean cumulative MP dose to disease control of 678.4 mg (SEM = 49.4 mg). Eight patients relapsed during follow up (10.81 [95% CI: 5.16-21.72] relapses/100 person years, py), and seven manifested a severe adverse event (6.80 [95% CI: 3.00-14.28] severe adverse events/100 py); however, 73.4% (±7.9%) had suffered neither a relapse nor a SAE at the three-years follow up. Continuing low dose MP intake (≤8 mg/day) beyond week 12 in combination with MTX minimized the risk of a feasibility limiting event (p = 0.013). Conclusively, the combination of methylprednisolone with methotrexate is a promising, safe, and efficient modality for BP patients, which enables rapid glucocorticoid tapering.

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BACKGROUND: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting people older than 50, resulting in pain and stiffness of the neck, shoulder, and pelvic girdle. To date, glucocorticoids (GC) remain the cornerstone of treatment, but these have several drawbacks. Firstly, a large proportion of patients do not achieve GC-free remission within either the first (over 70%) or second year of treatment (over 50%). Secondly, GC-related adverse events (AE) occur in up to 65% of patients and can be severe. The current EULAR/ACR guidelines for PMR recommend early introduction of methotrexate (MTX) as a GC sparing agent in patients at risk for worse prognosis. However, earlier trials of low to medium quality only studied MTX dosages of 7.5-10 mg/week with no to modest effect. These doses may be suboptimal as MTX is recommended in higher doses (25 mg/week) for other inflammatory rheumatic diseases. The exact role, timing, and dose of MTX in PMR remain unclear, and therefore, our objective is to study the efficacy of MTX 25 mg/week in recently diagnosed PMR patients. METHODS: We set up a double-blind, randomized, placebo-controlled superiority trial (PMR MODE) to assess the efficacy of MTX 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ACR criteria. All patients will receive prednisolone 15 mg/day, tapered to 0 mg over the course of 24 weeks. In case of primary non-response or disease relapse, prednisolone dose will be temporarily increased. Assessments will take place at baseline, 4, 12, 24, 32, and 52 weeks. The primary outcome is the difference in proportion of patients in GC-free remission at week 52. DISCUSSION: No relapsing PMR patients were chosen, since the possible benefits of MTX may not outweigh the risks at low doses and effect modification may occur. Accelerated tapering was chosen in order to more easily identify a GC-sparing effect if one exists. A composite endpoint of GC-free remission was chosen as a clinically relevant endpoint for both patients and rheumatologist and may reduce second order (treatment) effects. TRIAL REGISTRATION: Dutch Trial Registration, NL8366 . Registered on 10 February 2020.

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Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in the age group over 50 years. It requires prompt diagnostics and treatment to avoid severe complications, such as visual loss or stroke. The tendency to relapse makes a glucocorticoid (GC) treatment necessary for several years and sometimes lifelong, which increases the risk of GC-induced long-term side effects. Therefore, additive GC-sparing treatment is recommended in the majority of patients. For this purpose, the anti-IL­6 receptor antibody tocilizumab is available as an approved substance for subcutaneous application; alternatively, methotrexate (MTX) can be used (off-label).

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Guidelines on management of polymyalgia rheumatica (PMR) recommend early introduction of methotrexate (MTX), especially in patients with worse prognosis, although evidence on clinical efficacy of MTX in PMR is limited. Our objective was to assess MTX efficacy in real-world PMR care. Retrospective data of newly diagnosed PMR patients who started MTX were compared to control patients in whom MTX was not started at the first flare. Main outcomes were number of flares per year (Poisson regression) and weighted daily glucocorticoid (GC)-dose (linear regression), and flare incidence rate ratio in the MTX group only. 240 patients were selected; 39 patients in the MTX group and 201 in the control group. The yearly incidence rate ratio of flares in the MTX versus control group was 0.80 (95% CI 0.45-1.42). The yearly flare rate was 1.22 before and 0.43 after MTX initiation, resulting in an incidence ratio of 0.35 (95% CI 0.23-0.52). Adjusted time weighted daily GC dose was higher in the MTX versus control group (ratio 1.37, 95% CI 1.04-1.80). No clear effect of MTX on flares was found and time weighted daily GC dose was higher, possibly due to residual confounding by indication. However, the clearly reduced flare rate after MTX start might be suggestive for a beneficial effect of MTX.

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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, I 2 = 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, I 2 = 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.

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Giant cell arteritis is a systemic vasculitis of large vessels, manifesting mainly as temporal arteritis or large vessel vasculitis of the aorta and its branches. Glucocorticoid therapy is essential and so far had to be continued over a period of 1.5-2 years, resulting in relevant morbidity through adverse effects. With the approval of tocilizumab, an effective glucocorticoid sparing option is now available. In two randomized controlled trials, a profound reduction of cumulative glucocorticoid dose, prolonged relapse-free remission and reduced number of adverse events in the treatment groups have been demonstrated. Therefore, tocilizumab constitutes a novel therapeutic option in giant cell arteritis. Its differential role in different subgroups, timing of tocilizumab therapy and optimal treatment duration remain to be determined.

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Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

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BACKGROUND: 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. PATIENTS: 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. TREATMENT AND OUTCOMES: 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. CONCLUSIONS: 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.

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