Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy: A Randomized Clinical Trial.

Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica. Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day. Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone. Main Outcomes and Measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone. Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group. Conclusions and Relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms. Trial Registration: ClinicalTrials.gov Identifier: NCT02908217.

Concordance and agreement between different activity scores in polymyalgia rheumatica.

OBJECTIVE: The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs. METHOD: Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots. RESULTS: A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time. CONCLUSION: The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used. TRIAL REGISTRATION NUMBER: NTC02908217.

Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey.

OBJECTIVE: To determine the pattern of demyelinating disorders (DDs) occurring during anti-TNF-α therapy. METHODS: Between June 2005 and April 2008, 1800 French rheumatologists and internists were contacted to report cases of DDs occurring in patients treated with anti-TNF-α. RESULTS: After a median of 10.2 (1.5-39.9) months of treatment, 33 patients developed DDs: 22 had CNS and 11 peripheral nervous system (PNS) involvement. Underlying diseases were RA (n = 16), AS (n = 11), PsA (n = 4), JIA (n = 1) and PM (n = 1). Anti-TNF-α was infliximab (n = 15), etanercept (n = 12) or adalimumab (n = 6). CNS involvement was encephalic lesions (n = 16), transverse myelitis (n = 8) or retrobulbar optic neuritis (n = 5). Cerebrospinal fluid (CSF) analysis in 16 patients and MRI in 20 patients were abnormal. All patients discontinued anti-TNF-α. Fifteen patients required steroids. Twenty patients initially improved. Five patients developed multiple sclerosis. PNS involvement was chronic (n = 9) or acute inflammatory demyelinating polyneuropathy (n = 2). CSF analysis revealed an increased protein level in nine patients. Nerve conduction studies confirmed DD in all these patients. Anti-TNF-α was discontinued in 10 patients and 8 received i.v. immunoglobulins. Two patients relapsed after introduction of another anti-TNF-α. Overall, a causal relationship between anti-TNF-α and DD was considered as probable in 31 patients and definite in 2 who had positive rechallenge. CONCLUSION: Causal relationship between anti-TNF-α and induction of DD remains unclear, but in some cases the chronology of clinical events is suggestive. Nevertheless, DD might persist despite treatment discontinuation, suggesting that anti-TNF-α could trigger the demyelinating process, which further evolves independently.

Association between hidradenitis suppurativa and spondyloarthritis.

OBJECTIVES: We aimed to investigate the existence of an association between hidrosadenitis suppurativa and spondyloarthritis. METHODS: We performed a single-centre, cross-sectional study in patients with hidrosadenitis suppurativa followed in a tertiary care center, and in healthy volunteers without dermatological disease, matched for age (±5years) and gender. For each subject included, clinical examinations, HLA-B27 testing and sacro-iliac MRI were performed in order to diagnose spondyloarthritis according to the Assessment of SpondyloArthritis international Society (ASAS) criteria. RESULTS: In total, 39 subjects were included in each group (70% women in each group, mean age 35.6±11.1 in the hidrosadenitis suppurativa group and 36.0±11.1 in the control group). Eleven (28.2%) patients in the hidrosadenitis suppurativa group were diagnosed with spondyloarthritis (in 4 of these, spondyloarthritis was already previously documented), and in 1 (2.6%) subject in the control group (OR 11.0; 95% CI 4.1-83.3; P=0.02). Axial spondyloarthritis was the most common form of spondyloarthritis, observed in 9/11 patients in the hidrosadenitis suppurativa group, the remainder were peripheral spondyloarthritis. In the hidrosadenitis suppurativa group, only HLA B27 was found to be associated with a diagnosis of spondyloarthritis. CONCLUSIONS: Our results indicate that hidrosadenitis suppurativa is significantly associated with an increased risk of spondyloarthritis, independently of age and sex. Patients with hidrosadenitis suppurativa presenting osteoarticular symptoms, specially low back pain or dactylitis, should be monitored for spondyloarthritis.

Discitis and sacroiliitis diagnosed 15 years after iatrogenic Mycobacterium xenopi inoculation.

A patient was diagnosed with discitis and sacroiliitis due to Mycobacterium xenopi. He had a history of percutaneous nucleotomy performed 15 years earlier (in 1992) at the Clinique du Sport, Paris, France, during an outbreak of nosocomial M. xenopi infection at that institution. In 1997, magnetic resonance imaging performed as part of the routine follow-up program for patients who had surgery at the Clinique du Sport during the outbreak was not interpreted as indicating discitis; this assessment was confirmed by our review of the images. Bone and joint infections due to atypical mycobacteria are rare and can develop very slowly. To our knowledge, this is the first reported case of M. xenopi discitis with secondary extension to the sacroiliac joint in an immunocompetent patient.

New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases.

UNLABELLED: Uveitis may be associated with various inflammatory diseases. Previous reports suggested that tumor necrosis factor (TNF) blockers, especially anti-TNF monoclonal antibodies, may reduce the incidence of uveitis flares in some inflammatory diseases. Under these circumstances, de novo occurrence, ie, new onset of the first episode of uveitis under anti-TNF therapy, is uncommon. OBJECTIVES: The aim of this study was to collect cases of new onset of uveitis under anti-TNF therapy, using a nationwide network, to describe these cases, and to gather with cases reported in the literature. METHODS: All French rheumatologists, pediatric rheumatologists, and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were contacted in an attempt to declare the cases of new onset of uveitis, diagnosed by an ophthalmologist, in patients treated with TNF blockers. The analysis of the literature was performed through PubMed database and manual research. RESULTS: Thirty-one cases were recorded, 19 men, mean age 43 (5-70) years, occurring in ankylosing spondylitis (19 cases), psoriatic arthritis (4 cases), rheumatoid arthritis (6 cases), juvenile idiopathic arthritis (2 cases). The TNF blocker at the time of uveitis was etanercept 23 times, adalimumab 3 times, infliximab 5 times, with a mean total duration of exposure to anti-TNF agents of 27 (4-96) months at uveitis occurrence. Most of the patients were good responders to TNF blockers at the time of uveitis onset. Analysis of the literature revealed 121 similar cases published in English. CONCLUSION: Uveitis occurs de novo under anti-TNF therapy mainly in spondyloarthropathies, but also in rheumatoid arthritis and juvenile idiopathic arthritis patients and more frequently under etanercept.