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Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a heterogenous autoimmune disease. While traditionally stratified into two conditions, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the subclassification of ANCA-associated vasculitis is subject to continued debate. Here we aim to identify phenotypically distinct subgroups and develop a data-driven subclassification of ANCA-associated vasculitis, using a large real-world dataset., Methods: In the collaborative data reuse project FAIRVASC (Findable, Accessible, Interoperable, Reusable, Vasculitis), registry records of patients with ANCA-associated vasculitis were retrieved from six European vasculitis registries: the Czech Registry of ANCA-associated vasculitis (Czech Republic), the French Vasculitis Study Group Registry (FVSG; France), the Joint Vasculitis Registry in German-speaking Countries (GeVas; Germany), the Polish Vasculitis Registry (POLVAS; Poland), the Irish Rare Kidney Disease Registry (RKD; Ireland), and the Skåne Vasculitis Cohort (Sweden). We performed model-based clustering of 17 mixed-type clinical variables using a parsimonious mixture of two latent Gaussian variable models. Clinical validation of the optimal cluster solution was made through summary statistics of the clusters' demography, phenotypic and serological characteristics, and outcome. The predictive value of models featuring the cluster affiliations were compared with classifications based on clinical diagnosis and ANCA specificity. People with lived experience were involved throughout the FAIRVASVC project., Findings: A total of 3868 patients diagnosed with ANCA-associated vasculitis between Nov 1, 1966, and March 1, 2023, were included in the study across the six registries (Czech Registry n=371, FVSG n=1780, GeVas n=135, POLVAS n=792, RKD n=439, and Skåne Vasculitis Cohort n=351). There were 2434 (62·9%) patients with GPA and 1434 (37·1%) with MPA. Mean age at diagnosis was 57·2 years (SD 16·4); 2006 (51·9%) of 3867 patients were men and 1861 (48·1%) were women. We identified five clusters, with distinct phenotype, biochemical presentation, and disease outcome. Three clusters were characterised by kidney involvement: one severe kidney cluster (555 [14·3%] of 3868 patients) with high C-reactive protein (CRP) and serum creatinine concentrations, and variable ANCA specificity (SK cluster); one myeloperoxidase (MPO)-ANCA-positive kidney involvement cluster (782 [20·2%]) with limited extrarenal disease (MPO-K cluster); and one proteinase 3 (PR3)-ANCA-positive kidney involvement cluster (683 [17·7%]) with widespread extrarenal disease (PR3-K cluster). Two clusters were characterised by relative absence of kidney involvement: one was a predominantly PR3-ANCA-positive cluster (1202 [31·1%]) with inflammatory multisystem disease (IMS cluster), and one was a cluster (646 [16·7%]) with predominantly ear-nose-throat involvement and low CRP, with mainly younger patients (YR cluster). Compared with models fitted with clinical diagnosis or ANCA status, cluster-assigned models demonstrated improved predictive power with respect to both patient and kidney survival., Interpretation: Our study reinforces the view that ANCA-associated vasculitis is not merely a binary construct. Data-driven subclassification of ANCA-associated vasculitis exhibits higher predictive value than current approaches for key outcomes., Funding: European Union's Horizon 2020 research and innovation programme under the European Joint Programme on Rare Diseases., Competing Interests: Declaration of interests PL has received grants or contracts from the German Research Society, Federal Ministry of Education and Research, German Society for Rheumatology, John Grube Foundation, and Vifor Pharma; consulting fees from AbbVie, AstraZeneca, GSK, Novartis, UCB, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, GSK, Janssen, Novartis, Rheumaakademie, UCB, and Vifor Pharma; support for attending meetings or travel from Vifor Pharma; and has participated on Data Safety Monitoring Boards or Advisory Boards of AbbVie, AstraZeneca, GSK, and Vifor Pharma. XP has received grants as an investigator of academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma. MS has received consulting fees from Vifor Pharma, Otsuka, and Hansa Biopharma. BT has received consulting fees from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; support for attending meetings or travel from GSK, AstraZeneca, and Novartis; and participates on the Advisory Board for Amgen. KW is a member of the Advisory Board at CSL Vifor. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV., Methods: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis., Results: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019)., Conclusion: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests., Methods: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests., Results: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]., Conclusion: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: B-cell depletion induced by rituximab (RTX) in ANCA-associated vasculitis (AAV) is a risk factor for hypogammaglobulinemia. Aggregating data on gammaglobulin levels kinetics during RTX and its association with the risk of relapse and severe infection is of interest., Methods: Gammaglobulin levels were collected before induction therapy and during RTX maintenance therapy. We used different definitions of gammaglobulin decline: 1/gammaglobulin levels <6 g/L after induction; 2/>25 % decline in gammaglobulin levels between induction and maintenance, and 3/both. Our primary objective was the impact of gammaglobulin decline on the risk of relapse and severe infections., Results: We included 98 patients. Patients with gammaglobulin level <6 g/L after induction and gammaglobulin decline >25 % were older (OR 3.9; 95%CI 1.1-16.1), had more frequently baseline gammaglobulin levels <10 g/L (OR 6.0; 95%CI 1.7-25.8) and received more frequent pulses of methylprednisolone at induction (OR 4.6; 95%CI 1.3-18.5). Severe infection-free survival was significantly poorer in patients with both gammaglobulin <6 g/L and gammaglobulin decline >25 % (adjusted HR 2.3; 95%CI 1.0-5.1) and in those who received pulses of methylprednisolone (HR 5.6; 95%CI 2.3-13.4). Gammaglobulin decline was in contrast not associated with the risk of relapse., Conclusion: Older age, low gammaglobulin levels and pulses of methylprednisolone at induction increase the likelihood of gammaglobulin decline after induction therapy. Such decline was associated with an increased risk of severe infections but not lower risk of vasculitis relapse. Pulses of methylprednisolone at induction had an independent negative impact on gammaglobulin levels and the risk of severe infections., Competing Interests: Declaration of competing interest All authors have been involved in institutional randomized controlled trials for which rituximab was provided by Roche Inc., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy., Methods: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment., Results: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone., Conclusion: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes., Methods: Patients included in the MAINRITSAN2 trial (ClinicalTrials.gov identifier: NCT01731561) were randomized to receive a 500-mg fixed-schedule rituximab infusion or an individually tailored regimen. Rituximab plasma concentrations at month 3 (CM3) were assessed. DNA samples (n = 53) were genotyped for single-nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models., Results: One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/ml) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% versus 18.0%; P = 0.02, respectively). Low rituximab plasma concentration at 3 months (CM3 <4 μg/ml) was an independent risk factor for major relapse (odds ratio 6.56 [95% confidence interval (95% CI) 1.26-34.09]; P = 0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/ml as an independent risk factor for major relapse (hazard ratio [HR] 4.81 [95% CI 1.56-14.82]; P = 0.006) and relapse (HR 2.70 [95% CI 1.02-7.15]; P = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28., Conclusion: These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase., (© 2023 American College of Rheumatology.)

Objective: To assess the prevalence and impact on damage accrual of different levels of disease activity in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)., Methods: Patients with GPA and MPA followed for ≥5 years in 2 different centers were included. Disease activity and damage were assessed using the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), respectively. Three levels of remission were defined: complete remission (BVAS = 0, negative for antineutrophil cytoplasmic antibody [ANCA], off treatment), clinical remission off therapy (CROffT; BVAS = 0, positive for ANCA), and clinical remission on therapy (CROnT; BVAS = 0, negative or positive for ANCA, glucocorticoids ≤5 mg/day and/or immunosuppressant). A low disease activity state (LDAS) was defined as 0 < BVAS ≤3, low-dose glucocorticoids (≤7.5 mg/day), and/or immunosuppressant. Remission or LDAS were defined as prolonged when lasting ≥2 consecutive years., Results: A total of 167 patients were included: 128 (76.6%) with GPA, 39 (23.4%) with MPA, mean ± SD age 51.0 ± 16.7 years. During a 5-year follow-up, 10 patients (6.0%) achieved prolonged complete remission, 6 (3.6%) prolonged CROffT, 89 (53.3%) prolonged CROnT, 42 (25.1%) prolonged LDAS, and 20 (12.0%) never achieved LDAS. The VDI score at 5 years progressively worsened according to increasing levels of disease activity targets (complete remission, CROffT, CROnT, and LDAS). The mean ± SD 5-year VDI score was higher in patients not achieving prolonged remission compared to those who did (3.7 ± 2.0 versus 2.2 ± 1.9; P < 0.0001). By multivariate analysis, baseline ear, nose, and throat (P = 0.006), and lung involvement (P = 0.047) were negative predictors of prolonged remission., Conclusion: More than 60% of patients with GPA/MPA achieved prolonged remission, which was associated with better long-term outcomes. In contrast, prolonged LDAS correlated with increased damage accrual and was not a sufficient treatment target., (© 2022 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: ANCA-associated vasculitis (AAV) is an exceptional cause of small and large vascular aneurysms. Here, we present the phenotypic characteristics of patients with AAV associated with the presence of aneurysms., Methods: We conducted a retrospective multicenter study and a systematic review of the literature. Only AAV patients with positive ANCA results and > 1 aneurysm(s) were enrolled. Patients were recruited through a call of observations among the French Vasculitis Study Group (FVSG) and the French Internal Medicine Network. Patients with aneurysm rupture were compared to those without., Results: We enrolled 51 patients in the cohort, including 31 (67%) with granulomatosis with polyangiitis. The median Birmingham Vasculitis Activity Score was 18 [6-41]. A total of 92 aneurysms were noted, 74% of which involved medium-sized arteries, particularly the renal artery. During a follow-up of 24 [6-56] months, 22 (43%) patients experienced aneurysmal rupture, 91% of which involved medium-sized vessels. Patients with aneurysmal rupture showed significantly more pulmonary infiltrates and higher creatinine levels at baseline than patients without rupture. Initial treatments did not differ between the two groups. Ten (20%) patients died during the follow-up, including three from an aneurysmal rupture., Conclusion: Aneurysms were more frequently observed in GPA patients and predominantly affected medium-sized vessels, especially the renal arteries. The risk of rupture was high and occurred in >40% of patients. Because of their increased mortality, further studies are required to better manage this subset of patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: While myocardial impairment is a predictor of poor prognosis in antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), little is known about valvular involvement. This study aims at describing the clinical presentation, management, and outcome of endocarditis associated with AAV., Methods: We conducted a multicenter retrospective study in centers affiliated with the French Vasculitis Study Group. We included patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic GPA with endocardial impairment. A systematic review was then performed through PubMed, Embase, and Cochrane Library from inception up to September 2020., Results: The retrospective cohort included 9 patients (82%) with GPA, 1 (9%) with MPA, and 1 (9%) with unclassified AAV. Clinical presentation included acute valvular insufficiency (n = 7, 64%), cardiac failure (n = 3, 27%), dyspnea (n = 3, 27%), and no symptoms (n = 2, 18%). The aortic valve was the most frequently affected (n = 8/10, 80%), and vegetations were noted in 4 of 10 patients (40%). Six patients (55%) underwent surgical valvular replacement. No death from endocarditis was reported. The systematic review retrieved 42 patients from 40 references: 30 (71%) had GPA, 21 (50%) presented with vegetations, the aortic valve (n = 26, 62%) was the most frequently involved. Valvular replacement was required in 20 cases (48%) and 5 patients (13%) died from the endocarditic impairment., Conclusion: Endocarditis is a rare and potentially life-threatening manifestation of AAV. Acute valvular insufficiency may lead to urgent surgery. Implementing transthoracic echocardiography in standard assessment at baseline and follow-up of AAV might reduce the delay to diagnosis and allow earlier immunosuppressive treatment before surgery is needed., (Copyright © 2022 by the Journal of Rheumatology.)

Introduction: A two-stage therapeutic approach is now applied as standard-of-care to treat antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs): first, glucocorticoids (GCs) combined with cyclophosphamide (CYC) or rituximab (RTX) to induce remission, and then relapse prevention with remission-maintenance therapy. Nonetheless, a substantial risk of relapse persists., Areas Covered: The authors provide an overview of the current state of AAV remission-induction after relapse and maintenance therapies, and discuss new strategies recommended to prevent and treat relapses, focusing on granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)., Expert Opinion: For remission-induction after GPA or MPA relapse with organ-threatening manifestations, reintroduction or intensification of GCs in combination with CYC or RTX cycle is recommended; we prefer RTX in light of its superior responses obtained in patients with relapsing disease. Rapid tapering of GCs has been shown not to alter AAV evolution while decreasing the risk of serious infections. In contrast, for non-severe, active MPA, we recommend GCs alone as first-line therapy. For patients whose MPA remains uncontrolled by GCs alone, immunosuppressant adjunction can be a GC-sparing option or to counter GC intolerance. Once remission is achieved, we recommend prolonged maintenance therapy with preemptive low-dose (500 mg) RTX infusion biannually.

Objective: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC., Methods: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders., Results: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12., Conclusion: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes., Objectives: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease., Design: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab., Setting: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated., Participants: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m 2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis., Interventions: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician., Primary Outcome: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial., Results: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p  = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p  = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p  = 0.016)., Conclusions: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections., Future Work: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis., Limitations: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study., Trial Registration: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Importance: Older patients are underrepresented in studies of rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Little is known about outcomes and adverse events associated with the use of rituximab therapy among patients 75 years and older with ANCA-associated vasculitis., Objective: To examine outcomes and adverse events associated with the use of rituximab therapy in patients 75 years and older with ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)., Design, Setting, and Participants: This multicenter cohort study involved 93 patients 75 years and older with ANCA-associated vasculitis from 36 university and nonuniversity hospitals in France. Data were obtained from the French Vasculitis Study Group database between January 1, 2000, and July 1, 2018, and a call for observation sent to French Vasculitis Study Group members on June 6, 2019. Data analysis was performed from November 15 to December 31, 2021. Inclusion criteria included a diagnosis of GPA or MPA according to European Medicines Agency classification criteria and receipt of treatment with rituximab after age 75 years. Patients were excluded if they were missing relevant clinical or biological data. Data on race and ethnicity were not reported because inclusion of this information was not authorized by the ethics committee., Exposure: At least 1 infusion of rituximab as induction or maintenance therapy., Main Outcomes and Measures: Occurrence of remission, relapse, drug discontinuation, death, and serious infections (including types of serious infections)., Results: Of 238 patients screened, 93 were included (median [IQR] age, 79.4 [76.7-83.1] years; 51 women [54.8%]); 52 patients (55.9%) had a diagnosis of GPA, and 41 (44.1%) had a diagnosis of MPA. Thirty patients (32.3%) received rituximab as induction therapy in combination with high-dose glucocorticoid regimens, 27 (29.0%) received rituximab as maintenance therapy, and 36 (38.7%) received rituximab as both induction and maintenance therapy. The median (IQR) follow-up was 2.3 (1.1-4.0) years. Among 66 patients who received rituximab as induction therapy, 57 (86.4%) achieved remission, and 2 (3.0%) experienced relapses. The incidence of serious infection was significantly higher when rituximab was used as induction therapy vs maintenance therapy (46.6 [95% CI, 24.8-79.7] per 100 patient-years vs 8.4 [95% CI, 3.8-15.9] per 100 patient-years; P = .004). Most infections (12 of 22 [54.5%]) were gram-negative bacterial infections. The incidence of death was 19.7 (95% CI, 7.2-42.9) per 100 patient-years among those who received rituximab as induction therapy and 5.3 (95% CI, 1.9-11.6) per 100 patient-years among those who received rituximab as maintenance therapy., Conclusions and Relevance: In this cohort study, rituximab therapy was associated with achievement and maintenance of remission in most patients 75 years and older with ANCA-associated vasculitis. The incidence of serious infections and death was high when rituximab was used as induction therapy in combination with high-dose glucocorticoid regimens but not when rituximab was used as maintenance therapy. Efforts might focus on reducing serious infections during the first months of therapy.

Objectives: Coxiella and Bartonella spp. display particular tropism for endothelial or endocardial tissues and an abnormal host response to infections with induced autoimmunity. We aimed, through a case series combined with a comprehensive literature review, to outline characteristics of Coxiella and Bartonella infections presenting as systemic vasculitis., Methods: We retrospectively included cases of definite Coxiella and Bartonella infections presenting with vasculitis features and performed a comprehensive literature review., Results: Six cases of Bartonella infections were added to 18 cases from literature review. Causative pathogens were mainly B. henselae. Bartonella infection mimicked ANCA-associated vasculitis in 83% with PR3-ANCA and presented as cryoglobulinaemic vasculitis in 8%. GN was present in 92%, and 88% had endocarditis. Complement fractions were low in 82% and rheumatoid factor positive in 85%. Kidney biopsies showed cell proliferation, mostly crescentic, with pauci-immune GN in 29%. Outcome was favourable, with the use of antibiotics alone in one-third. Five cases of Coxiella infections were added to 16 from literature review. Sixteen had small-vessel vasculitides, mainly cryoglobulinaemia vasculitis in 75%. One patient had polyarteritis nodosa-like vasculitis and four large-vessel vasculitis. Outcome was good except for one death. A highly sensitive next generation sequencing analysis on three Coxiella- and two Bartonella-related vasculitides biopsies did not find any bacterial DNA., Conclusion: Coxiella and Bartonella are both able to induce vasculitis but display distinct vasculitis features. Bartonella mimics PR3-ANCA-associated vasculitis in the setting of endocarditis, whereas Coxiella may induce vasculitis involving all vessel sizes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Little is known about antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years., Methods: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively., Results: The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65-75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause-specific hazards ratio [CSHR] 0.54, 95% CI [0.33-0.89], p = 0.016, Cox model; subdistribution hazard ratio [SHR] 0.46, 95% CI [0.29-0.74], p = 0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI [0.11-0.68], p = 0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95% [CI 0.24-0.67], p < 0.001)., Conclusions: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

Background: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX., Methods: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12)., Results: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%., Conclusions: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making., (Copyright © 2022 by the American Society of Nephrology.)

Objective: To report on a large series of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and bronchiectasis, with a specific focus on the timeline of occurrence of both features., Methods: Retrospective nationwide multicenter study of patients diagnosed with both AAV and bronchiectasis., Results: Sixty-one patients were included, among whom 27 (44.25%) had microscopic polyangiitis (MPA), 27 (44.25%) had granulomatosis with polyangiitis (GPA), and 7 (11.5%) had eosinophilic GPA. Thirty-nine (64%) had myeloperoxidase (MPO)-ANCA and 13 (21%) had proteinase 3-ANCA. The diagnosis of bronchiectasis either preceded (n = 25; median time between both diagnoses: 16 yrs, IQR 4-54 yrs), was concomitant to (n = 12), or followed (n = 24; median time between both diagnoses: 1, IQR 0-6 yrs) that of AAV. Patients in whom bronchiectasis precedes the onset of AAV (B-AAV group) have more frequent mononeuritis multiplex, MPA, MPO-ANCA, and a 5-fold increase of death. The occurrence of an AAV relapse tended to be protective against bronchiectasis worsening (HR 0.6, 95% CI 0.4-0.99, P = 0.049), while a diagnosis of bronchiectasis before AAV (HR 5.8, 95% CI 1.2-28.7, P = 0.03) or MPA (HR 18.1, 95% CI 2.2-146.3, P = 0.01) were associated with shorter survival during AAV follow-up., Conclusion: The association of bronchiectasis with AAV is likely not accidental and is mostly associated with MPO-ANCA. Patients in whom bronchiectasis precedes the onset of AAV tend to have distinct clinical and biological features and could carry a worse prognosis.

Objective: The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter's titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12., Methods: MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV., Results: At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV., Conclusions: We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV)., Objective: To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen., Design: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522)., Setting: 39 clinical centers in France., Patients: 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy., Intervention: Rituximab or placebo infusion every 6 months for 18 months (4 infusions)., Measurements: The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0., Results: From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) ( P  = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) ( P  = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group., Limitation: Potential selection bias based on previous rituximab response and tolerance., Conclusion: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy., Primary Funding Source: French Ministry of Health and Hoffmann-La Roche.

Background: The analysis of the main features of randomized controlled trials (RCTs) on ANCA-associated vasculitis (AAV) can inform future study design., Methods: We searched within the International Clinical Trials Registry Platform all registered RCTs on AAV from October 2008 to December 2018. Two reviewers selected studies according to pre-specified eligibility criteria. We retrieved information including countries, funding, design, sample sizes, eligibility criteria, primary outcomes (POs), and treatments., Results: Among the 40 RCTs identified, 22 (55%) were conducted in Europe, 29 (72,5%) in a single country, 14 (35%) were industry-funded. The median number of patients planned to enrol was 68 (IQR 36-138). Only 28% of RCTs targeted a single vasculitis, and ANCA negative patients were not included in about 40% of studies. Interventions investigated were mainly drugs given to induce (40%) or maintain (32.5%) remission. Eighty-five percent of POs were considered being 'patient-important', but discrepancies in definition of disease states, such as remission or relapse were observed. Glucocorticoids use was part of the PO in < 25% of studies. The number of trials targeting a single disease, non-industry funded, incorporating glucocorticoids in PO, as well as the planned sample size increased over time., Conclusion: Despite the important achievements in the field, a better harmonization of eligibility, and outcome criteria across studies is an important objective to pursue in next future.

Background: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis., Methods: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m 2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD)., Results: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups., Conclusions: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: To identify the role of Staphylococcus aureus (SA) or its intracellular small-colony variant phenotype (SCV) with co-trimoxazole (CTX) or ANCA-associated vasculitis (AAV) activity., Methods: All consecutive AAV patients with granulomatosis with polyangiitis (GPA), eosinophilic GPA or microscopic polyangiitis, followed at the French National Vasculitis Referral Center (09/2012-05/2013), and hospitalized non-AAV controls, exclusively for SA/SCV carriage comparisons, were enrolled. All had bilateral anterior nasal swab cultures. Nasal SA or SCV carriage was determined and associations with relapse(s), BVAS, ANCA-positivity, anti-staphylococcal and immunosuppressant use, were analysed ⩾4 years post-inclusion., Results: Nasal SA carriage rates did not differ among AAVs (P = 0.53): GPA (24/80; 30%), EGPA (7/28; 25%) and microscopic polyangiitis (3/11; 27.3%); and the rate was less frequent in controls than in GPA patients not taking CTX (P = 0.04). AAV patients taking CTX prophylaxis had less nasal SA carriage (8.7% vs 36.2%; P = 0.02). Nasal SA carriage or CTX use did not modify relapse rates, BVAS or ANCA-positivity at inclusion or during follow-up. Nasal SCV carriage, found in 15/207 (7.2%) patients, was similar for GPA (10/24; 41.7%), microscopic polyangiitis (2/7; 28.6%) and eosinophilic GPA (2/3; 66.7%), but higher (P = 0.02) than controls (1/14; 7.1%). SCV carriage by AAV groups did not modify relapse rates or ANCA positivity at inclusion or during follow-up; a trend towards higher BVAS was observed only for anti-PR3 ANCA patients., Conclusion: Nasal SA or SCV carriage was comparable among AAVs but more frequent than in controls. Nasal SA or SCV carriage and CTX use did not modify AAV relapse rates., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Progressive fibrosing interstitial lung disease (ILD) is rarely associated with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). This study focused on the outcomes of ILD patients with associated AAV (AAV-ILD)., Methods: AAV-ILD (cases: microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) with ILD) were compared to AAV patients without ILD (controls). ILD was defined as a usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP) pattern. Two controls were matched to each case for age (>or ≤65 years), ANCA status (PR3-or MPO-positive) and creatininemia (≥or <150 μmol/L)., Results: Sixty-two cases (89% MPO-ANCA+) were included. Median age at AAV diagnosis was 66 years. ILD (63% UIP), was diagnosed before (52%) or simultaneously (39%) with AAV. Cases versus 124 controls less frequently had systemic vasculitis symptoms. One-, 3- and 5-year overall survival rates, respectively, were: 96.7%, 80% and 66% for cases versus 93.5%, 89.6% and 83.8% for controls (p = 0.008). Multivariate analyses retained age >65 years (hazard ratio (HR) 4.54; p < 0.001), alveolar haemorrhage (HR 2.25; p = 0.019) and UIP (HR 2.73; p = 0.002), but not immunosuppressant use, as factors independently associated with shorter survival., Conclusion: For AAV-ILD patients, only UIP was associated with poorer prognosis. Immunosuppressants did not improve the AAV-ILD prognosis. But in analogy to idiopathic pulmonary fibrosis, anti-fibrosing agents might be useful and should be assessed in AAV-ILD patients with a UIP pattern., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Targeted immunotherapy is substantially improving the management of ANCA-associated vasculitides (AAV), which include granulomatosis with polyangiitis (GPA, Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). This article reviews the current role for targeted immunotherapy in AAV, its validated indications, and avenues for further development. Rituximab is a validated induction treatment for GPA and severe MPA. Rituximab in these indications is not less effective than cyclophosphamide and is particularly useful in patients with refractory or relapsing disease, women of childbearing potential, and patients previously treated with cyclophosphamide. Rituximab is more effective than cyclophosphamide for treating relapses. For remission maintenance therapy, which is indispensable, rituximab has been proven superior over conventional immunosuppressive treatment. Rituximab is licensed in the USA and in Europe for the induction treatment of severe forms of GPA and MPA. An extension study for remission maintenance therapy is ongoing. In EGPA, although maintenance treatment with the interleukin-5 antagonist mepolizumab is effective in decreasing glucocorticoid requirements and in alleviating asthma and sinonasal symptoms, its efficacy on the vasculitis remains somewhat unclear. Mepolizumab is licensed for use in EGPA, and rituximab is also being evaluated as an induction and maintenance agent. Immunoglobulins can be helpful as an adjuvant treatment for active AAV with severe immunedepression, notably when infections occur. Plasma exchange is indicated in AAV with advanced renal dysfunction and, perhaps, in the event of alveolar hemorrhage, a possibility that will be assessed in 2018 in a large international study., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs)., Methods: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group., Results: Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations., Conclusion: AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions., Trial Registration Number: NCT01731561; Results., Competing Interests: Competing interests: BT has received consulting and speaking fees (Roche, LFB, Grifols, GSK). MH has received personal fees from Roche. AK has received personal fees and non-financial support from Roche. XP has received speaking fees and honoraria (Pfizer, LFB, Roche) and a research grant (Pfizer)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides., Methods: The 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary endpoint was the major-relapse rate at month 60. Relapse and serious adverse event-free survival were also assessed., Results: Among the 115 enrolled patients, only one was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4% (95% CI 38.0% to 64.3%) and 71.9% (95% CI 61.2% to 84.6%) (p=0.003); minor and major relapse-free survival rates were 37.2% (95% CI 26.5% to 52.2%) and 57.9% (95% CI 46.4% to 72.2%) (p=0.012); overall survival rates were 93.0% (95% CI 86.7% to 99.9%) and 100% (p=0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p<0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse. HRs of positive ANCA to predict relapse increased over time., Conclusion: The rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival., Trial Registration Number: NCT00748644., Competing Interests: Competing interests: BT has received lecture fees from Roche/Genentech and advisory board fees from ChemoCentryx. CP has received research grants and lecture fees from Roche/Genentech and advisory board fees from ChemoCentryx and Sano., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To investigate differences between childhood-onset ANCA-associated vasculitides (cAAVs) and matched adult-onset controls (aAAVs)., Methods: cAAV clinical pictures at onset and outcomes were compared to a randomly selected sample of aAAV patients from the French Vasculitis Study Group Registry. Cases and controls were matched for AAV (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA] or eosinophilic granulomatosis with polyangiitis [EGPA]), sex and year of enrollment. Medications, disease activity and damage were prospectively recorded. Kaplan-Meier curves and the log-rank test were used to analyze case-vs.-control differences for predefined outcomes., Results: Comparing 35 cAAVs (25 GPA, 4 MPA, 6 EGPA) to 151 aAAVs (106 GPA, 17 MPA, 28 EGPA), their respective median follow-up durations were 71 and 64months (P=0.49), and, at baseline, children had less frequent myalgias (P=0.005) and peripheral neuropathy (P<0.001) but were more frequently febrile (P<0.05). Rates of renal involvement were comparable (13 [37%] cAAVs vs. 73 [48%] aAAVs; P=0.31). Initial GPA-associated ischemic abdominal pain and nasal cartilage damage were more common in cAAVs than aAAVs (P<0.05). During follow-up, the cAAV relapse rate was higher (24.5 vs. 18.7 flares per 100 patient-years; P<0.05) and, at last visit, cases had accumulated more damage, mostly ear, nose & throat sequelae (P=0.001), associated with longer maintenance therapy (P=0.03), than aAAV controls. Four (11.4%) cAAV and 13 (8.6%) aAAV patients died (P=0.53)., Conclusion: cAAVs are severe diseases, characterized by a higher relapse rate, more accrued damage and longer maintenance therapy than for aAAVs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up., Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months., Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative)., Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: Improved therapeutic strategies for ANCA-associated vasculitis (AAV) have transformed acute and life-threatening diseases into chronic ones responsible for marked morbidity that could impact employment, work disability and quality of life (QoL). We aimed to analyse work, handicaps and QoL of AAV patients and identify their determinants., Methods: Patients with AAV were included in a cross-sectional study assessing employment, work disability and QoL. Specific and non-specific questionnaires, including SF-36, were sent to patients, and clinical-biological data that could affect QoL and their determinants were analysed., Results: Questionnaires were completed by 189 patients. Among 94 working-age (<60 years) patients, 57% had jobs, consistent with their qualifications for 81%, 77% were stably employed; 23% of workers felt that their disease qualitatively limited the nature of their work, while 43% felt it limited the quantity of work they could do; 50% thought their disease had hindered their careers and 43% that it had led to a salary reduction. These results were comparable for the different vasculitides. QoL was significantly impaired for AAV patients compared to the general population (p<0.0001). Physical health determinants for our population were diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA), long disease duration and its neurological involvement, whereas mental health determinants tended to be ear, nose and throat and cardiovascular involvement, and unemployment., Conclusions: Our findings showed that AAV patients' QoL was impaired compared to the general population, mainly for patients with EGPA and long-standing disease. In contrast, normal employment seemed to be preserved for the majority of the patients.

The aim of the study was to report the clinical, biological, and pathological characteristics of patients with glomerulonephritis (GN) secondary to systemic lupus erythematosus (SLE)/antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) overlap syndrome.A nationwide survey was conducted to identify cases of SLE/AAV overlap syndrome. Data were collected from SLE and AAV French research groups. Inclusion criteria were diagnosis of both SLE and AAV according to international classification criteria and biopsy-proven GN between 1995 and 2014. Additional cases were identified through a systematic literature review. A cohort of consecutive biopsy-proven GN was used to study the prevalence of overlapping antibodies and/or overlap syndrome.The national survey identified 8 cases of SLE/AAV overlap syndrome. All patients were female; median age was 40 years. AAV occurred before SLE (n = 3), after (n = 3), or concomitantly (n = 2). Six patients had rapidly progressive GN and 3/8 had alveolar hemorrhage. All patients had antinuclear antibodies (ANA); 7/8 had p-ANCA antimyeloperoxidase (MPO) antibodies. Renal biopsies showed lupus nephritis (LN) or pauci-immune GN. Remission was obtained in 4/8 patients. A literature review identified 31 additional cases with a similarly severe presentation. In the GN cohort, ANCA positivity was found in 30% of LN, ANA positivity in 52% of pauci-immune GN, with no correlation with pathological findings. The estimated prevalence for SLE/AAV overlap syndrome was 2/101 (2%).In patients with GN, SLE/AAV overlap syndrome may occur but with a low prevalence. Most patients have an aggressive renal presentation, with usually both ANA and anti-MPO antibodies. Further studies are needed to assess shared pathogenesis and therapeutic options.

Objectives: To investigate the effects on health-related quality of life (HRQOL) and functional capability of rituximab vs azathioprine for ANCA-associated vasculitis (AAV) maintenance therapy., Methods: In a 24-month phase III randomised-controlled trial, 115 patients over time received rituximab or azathioprine for AAV maintenance therapy. Mean changes of 36-item Short-form Health Survey (SF-36) and Health Assessment Questionnaire (HAQ) scores from baseline were analysed., Results: Mean improvements of HAQ scores, from baseline to month 24 were significantly better for the rituximab (0.16 points lower) than the azathioprine group (p=0.038). As demonstrated by SF-36, study patients' baseline HRQOL was significantly impaired compared with age- and sex-matched US norms. At month 24, mean changes from baseline of SF-36 physical component score tended to be better for the rituximab group (+3.95 points, p=0.067) whereas mean changes from baseline of the SF-36 mental component score were significantly better for the azathioprine group (+4.23 points, p=0.041)., Conclusions: Azathioprine-treated patients' for AAV maintenance therapy showed a decline in physical abilities when compared to RTX at M24 in the MAINRITSAN trial., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00748644.

A few reports suggest combination of ANCA-associated vasculitis (AAV) and neutrophilic dermatoses (ND). We aimed to describe the main characteristics of patients presenting with both AAV and ND in a French cohort and through a systematic literature review, and to discuss the possible common pathogenic process involved. We conducted a retrospective study of patients with both conditions. Patients were selected via the French Internal Medicine Society (SNFMI) and the French Vasculitis Study Group (FVSG). A literature review focusing on a combination of both conditions, concentrated only on publications with well-established diagnoses and individual detailed data. Seventeen patients diagnosed with AAV and ND were identified in this cohort. Twelve patients had granulomatosis with polyangiitis (GPA), 4 had microscopic polyangiitis (MPA) and one had eosinophilic GPA (EGPA). Eight patients, all with GPA, displayed pyoderma gangrenosum (PG). Sweet's syndrome was observed in 6 patients (4 with MPA, one with GPA and one with EGPA) and erythema elevatum diutinum in the other three (2 with GPA and 1 with MPA). The literature review identified 33 additional patients with both conditions, including 26 with GPA. Altogether, of the 50 patients (17 from our study and 33 from the literature review), 33 (66%) patients presented with PG associated with GPA in 29 cases (89%). Corticosteroids were the first-line treatment in conjunction with an immunosuppressive agent in most cases. Outcomes were good and a total of 15 patients experienced a relapse. Patients who relapsed were more likely to have ear, nose and throat manifestation than patients who did not [12/15 (80%) relapsing patients vs. 15/35 (43%) non-relapsing patients; p = 0.03)]. In our stud, the most frequent association concerned GPA and PG. ND should be considered and specifically researched within the spectrum of cutaneous manifestations observed in AAV.

Objective: Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV., Methods: We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV., Results: A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1-156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%., Conclusion: This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease., (© 2016, American College of Rheumatology.)

Objectives: Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients., Methods: Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs., Results: Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p<0.001) and, interestingly, in 7 of 14 MPO and PR3 ANCA negative AAV patients. Moreover, by indirect immunofluorescence on fixed neutrophils, anti-PTX3 aAbs gave rise to a specific cytoplasmic fluorescence pattern distinct from the classical cytoplasmic (c-ANCA), perinuclear (p-ANCA), and atypical (a-ANCA) pattern. Anti-PTX3 aAbs levels were higher in patients with active AAV as compared to patients with inactive disease., Conclusion: Our work suggests that PTX3 is as a novel ANCA antigen. Anti-PTX3 aAbs appear thus as a promising novel biomarker in the diagnosis of AAV, including in patients without detectable MPO and PR3 ANCA.

The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Coexistence of ANCA-associated vasculitis (AAV) and IBD is a rare condition that is rarely described in the literature. The aim of the study was to describe the main characteristics of patients presenting with both IBD and AAV., Methods: A retrospective study of AAV patients in the French Vasculitis Study Group cohort who also had a diagnosis of IBD was conducted. We reviewed the medical records and outcomes of these patients., Results: We identified 11 patients with AAV and IBD. Four patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) also had ulcerative colitis and seven patients with granulomatosis with polyangiitis (GPA) had Crohn's disease. No Crohn's disease was observed in eosinophilic GPA and no ulcerative colitis in GPA. IBD started before AAV manifestations in six cases, simultaneously in two cases and after AAV manifestations in three cases., Conclusion: Coexistence of IBD and AAV is a rare condition. The therapeutic management of these patients includes corticosteroids in all cases and immunosuppressive drugs in some patients. Coexistence of IBD and AAV might be explained by common underlying inflammatory responses and cytokine profiles polarized towards either Th1 or Th2. Finally, in the presence of digestive manifestations in the context of AAV, the hypothesis of IBD should be assessed., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To describe the clinical presentation, management and prognosis of patients diagnosed with both primary Sjögren's syndrome (pSS) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: French nation-wide survey completed by a systematic literature review., Results: This work identified 7 new cases of coexisting pSS and AAV: 2 microscopic polyangiitis (MPA), 2 granulomatosis with polyangiitis (GPA), 2 anti-myeloperoxidase (MPO)-ANCA renal-limited AAV, and 1 eosinophilic granulomatosis with polyangiitis (EGPA). The systematic literature search identified 15 previously published cases. Among the 22 patients, 19 were females. Mean age at diagnosis of AAV was 63.9±9.8years. All individuals with available information experienced at least one extra-glandular manifestation attributable to pSS. p-ANCA with anti-MPO specificity were found in 76.2% (16/21), c-ANCA with anti-PR3 specificity in 14.3% (3/21) and isolated c-ANCA in 13.6% (3/22). Vasculitis involved kidneys (n=13), lungs (n=8), skin (n=6), peripheral nerves (n=5), central nervous system (n=2), small bowel (n=1), muscle (n=1), ear chondritis (n=1) and sinuses (n=1). The mean AAV follow-up was 73.5 (±120.0) months. While on treatment, disease remission occurred in 77.3% of cases, and one death was reported in the first 6months after diagnosis., Conclusion: This work shows that AAV may occur in patients with pSS. These are most commonly p-ANCA associated vasculitis with anti-MPO specificity. AAV may reveal an underlying pSS or arise during its evolution, but did not precede pSS in any of these cases. AAV occurrence appears to be correlated with extra-glandular manifestations of pSS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To describe the initial features and long-term outcomes of childhood-onset small vessel and medium vessel systemic necrotizing vasculitides (SNVs), including antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) and polyarteritis nodosa (PAN)., Methods: Data on patients with childhood-onset SNV registered in the French Vasculitis Study Group database were reviewed for demographic characteristics, clinical, laboratory, and histologic features, and outcomes. Disease activity was assessed with the Birmingham Vasculitis Activity Score and the Paediatric Vasculitis Activity Score, and damage was scored using the Vasculitis Damage Index. Relapse and survival rates and causes of death were analyzed., Results: Fifty-six patients (35 with AAV and 21 with PAN) (median age at database enrollment 14 years [range 2-17]) were included in the study. The median duration of followup was 96 months (range 1-336); two-thirds of the patients were followed up beyond 18 years of age. Six patients (11%) died, mostly of SNV-related causes. Relapse rates ranged from 33% for microscopic polyangiitis to 50% for eosinophilic granulomatosis with polyangiitis (Churg-Strauss) and 83% for granulomatosis with polyangiitis (Wegener's), with similar rates among AAV and PAN patients (76% and 75%, respectively); neither overall survival nor relapse-free survival differed significantly between the 2 disease groups. Rates of relapse increased after 18 years of age, both among patients with AAV and among patients with PAN. At the last followup evaluation, AAV patients had more major flares and more severe accrued damage compared with PAN patients., Conclusion: Despite similar relapse rates, patients with childhood-onset AAVs experienced more major flares with more cumulative damage than those with pediatric PAN. Treatments aimed at reducing the rates of mortality and relapse in this patient group need to be developed and assessed., (© 2015, American College of Rheumatology.)

Background: The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission., Methods: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both)., Results: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer)., Conclusions: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).

Increasing rituximab prescription for ANCA-associated necrotizing vasculitides justifies the publication of recommendations for clinicians. Rituximab is approved in the United States to induce and maintain remission. In Europe, rituximab was recently approved for remission induction. However, governmental agencies' approvals cannot replace clinical practice guidelines. Herein, the French Vasculitis Study Group Recommendations Committee, comprised of physicians with extensive experience in the treatment of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience., (Copyright © 2013. Published by Elsevier Masson SAS.)

Background: Dendritic cells (DC) and regulatory cells (Treg) play pivotal roles in controlling both normal and autoimmune adaptive immune responses. DC are the main antigen-presenting cells to T cells, and they also control Treg functions. In this study, we examined the frequency and phenotype of DC subsets, and the frequency and function of Treg from patients with ANCA-associated vasculitis (AAV)., Methodology/principal Findings: Blood samples from 19 untreated patients with AAV during flares and before any immunosuppressive treatment were analyzed, along with 15 AAV patients in remission and 18 age-matched healthy controls. DC and Treg numbers, and phenotypes were assessed by flow cytometry, and in vitro suppressive function of Treg was determined by co-culture assay. When compared to healthy volunteers, absolute numbers of conventional and plasmacytoid DC were decreased in AAV patients. During the acute phase this decrease was significantly more pronounced and was associated with an increased DC expression of CD62L. Absolute numbers of Treg (CD4(+)CD25(high)CD127(low/-) Tcells) were moderately decreased in patients. FOXP3 and CD39 were expressed at similar levels on Treg from patients as compared to controls. The suppressive function of Treg from AAV patients was dramatically decreased as compared to controls, and this defect was more pronounced during flares than remission. This Treg functional deficiency occurred in the absence of obvious Th17 deviation., Conclusion: In conclusion, these data show that AAV flares are associated with both a decrease number and altered phenotype of circulating DC and point to a role for Treg functional deficiency in the pathogenesis of AAV.