R. Seror

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort.

OBJECTIVEnEarlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes.nnnMETHODSnA retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis.nnnRESULTSnWe identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean±SD of 66.8±62.5 months. At diagnosis, their mean±SD age was 50.3±15.7 years, and 91.1% had asthma (duration 9.3±10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA-negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8-74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse.nnnCONCLUSIONnThe characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.

Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome

Objective: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjögren’s syndrome (pSS), and changes in B cell biomarkers. Patients and methods: The records of 16 patients with pSS according to the American European consensus group criteria were reviewed retrospectively. Results: Patients, all women, had a median age of 58.5 (range 41–71) years and a disease duration of 9.5 (range 0–25) years. RTX was prescribed for lymphoma (nu200a=u200a5), refractory pulmonary disease with polysynovitis (nu200a=u200a2), severe polysynovitis (nu200a=u200a2), mixed cryoglobulinaemia (nu200a=u200a5), thrombocytopenia (nu200a=u200a1) and mononeuritis multiplex (nu200a=u200a1). The median follow-up duration was 14.5 (range 2–48) months. Three patients experienced adverse events, including one mild serum sickness-like reaction with the presence of human antichimeric antibodies. Efficacy of treatment was observed in 4 of 5 patients with lymphomas and in 9 of 11 patients with systemic involvement. Dryness was improved in only a minority of patients. Corticosteroid dose was reduced in 11 patients. RTX induced decreased rheumatoid factor, γ-globulin and β2-microglobulin levels, and the level of B cell activating factor of the tumour necrosis factor family (BAFF) increased concomitantly with B cell depletion. Five patients were re-treated, with good efficacy and tolerance, except for one with probable serum sickness-like reaction. Conclusion: This study shows good efficacy and fair tolerance of RTX for systemic features. In addition, RTX allows for a marked reduction in corticosteroid use. Except for BAFF, the level of which increases, serum B cell biomarker levels decrease after taking RTX. Controlled trials should be performed to confirm the efficacy of RTX in pSS.

Clinical features and outcomes in 348 patients with polyarteritis nodosa: A systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French vasculitis study group database

OBJECTIVEnPrevious studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with well-characterized PAN diagnoses.nnnMETHODSnWe conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status.nnnRESULTSnAt diagnosis, the mean +/- SD age was 51.2 +/- 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV-related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non-HBV-related PAN (n = 225). During a mean +/- SD followup of 68.3 +/- 63.5 months, 76 patients (21.8%) relapsed (63 with non-HBV-related PAN [28%] versus 13 with HBV-related PAN [10.6%]; P < 0.001); 86 patients (24.7%) died (44 with non-HBV-related PAN [19.6%] versus 42 with HBV-related PAN [34.1%]; P = 0.003). Five-year relapse-free survival rates were 59.4% (95% confidence interval [95% CI] 52.6-67.0) versus 67.0% (95% CI 58.5-76.8) for non-HBV-related PAN and HBV-related PAN, respectively. Multivariate analysis retained age >65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse.nnnCONCLUSIONnOur findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.

High frequency of venous thromboembolic events in Churg–Strauss syndrome, Wegener’s granulomatosis and microscopic polyangiitis but not polyarteritis nodosa: a systematic retrospective study on 1130 patients

Objective: To determine the frequency and risk factors of venous thromboembolic events (VTE) in Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and, the so far unstudied, Churg–Strauss syndrome (CSS) and polyarteritis nodosa (PAN). Methods: Retrospective, systematic analysis and comparisons were made between the characteristics of patients in the VTE group and non-VTE group. 1130 patients with WG, MPA, CSS or PAN were identified from the French Vasculitis Study Group cohort. Results: During a mean follow-up of 58.4 (45.8) months, 83 VTE occurred in 74 (6.5%) patients, with a median vasculitis–VTE diagnosis interval of 5.8 months (−3 to +156). VTE occurred in seven of 285 (2.5%) patients with PAN, 19 of 232 (8.2%) with CSS, 30 of 377 (8%) with WG and 18 of 236 (7.6%) with MPA. Multivariate analysis retained age, male sex or previous VTE or stroke with motor deficit as being associated with a higher VTE risk. The adjusted odds ratio (95% confidence interval) for VTE was 2.88 (1.27 to 6.50) for patients with WG, MPA or CSS compared with PAN (pu200a=u200a0.01). Conclusions: Our results suggest that, like WG and MPA, patients with CSS are at a greater risk of VTE, than those with PAN. The reasons for this difference remain to be elucidated.

Ophthalmologic Manifestations of Systemic Necrotizing Vasculitides at Diagnosis: A Retrospective Study of 1286 Patients and Review of the Literature

OBJECTIVEnTo determine the frequencies and types of ophthalmologic manifestations in patients with systemic necrotizing vasculitides (SNV), including polyarteritis nodosa (PAN) and ANCA-associated vasculitides (granulomatosis with polyangiitis (Wegeners, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA); Churg-Strauss syndrome (CSS)) and review the literature on eye involvement in these diseases.nnnMETHODSnThis retrospective analysis was conducted on the ophthalmologic manifestations of SNV patients entered into the French Vasculitis Study Group database between July 1955 and August 2008.nnnRESULTSnAmong the 1286 identified patients, 214 (16.6%) had ophthalmologic manifestations at diagnosis, significantly more often in GPA (117/343, 34.1%) than in EGPA (30/270, 11.1%; P = 0.0001), PAN (42/393, 10.7%; P = 0.0001) or MPA (25/280, 8.9%; P = 0.0001). The 3 most common recorded ophthalmologic manifestations were conjunctivitis (89, (7%)), episcleritis (56, (4%)), and/or blurred vision (44, (3%)), mainly caused by retinal vasculitis in 5, oculomotor nerve palsy in 4, uveitis in 4 and/or optic neuropathy in 3. Orbital inflammatory tumor, another common feature was rather specific to GPA (23/349, 6.6% (P = 0.0001)) compared to other SNV. The literature on ophthalmologic manifestations of SNV is limited to case reports except for GPA, in which the eye involvement frequency ranged from 29% to 57%.nnnCONCLUSIONSnEye manifestations were more common in GPA than MPA, PAN and EGPA, but can be sight-threatening in any SNV. Given the heterogeneity of ophthalmologic involvement in SNV, close collaboration between the ophthalmologists and internists is critical.

Central nervous system involvement of granulomatosis with polyangiitis: clinical–radiological presentation distinguishes different outcomes

OBJECTIVEnThe aim of this study was to describe the presentation and outcomes of patients with granulomatosis with polyangiitis (GPA) presenting with CNS involvement.nnnMETHODSnPatients were included in this nationwide retrospective study if they had GPA according to ACR criteria and/or the European Medicines Agency algorithm and CNS involvement.nnnRESULTSnThirty-five patients were included in the study. CNS involvement was observed in 51% of patients at GPA diagnosis. Headache (66%) was the main symptom, followed by sensory (43%) and motor impairment (31%). CNS involvement was characterized by pachymeningitis in 20, cerebral ischaemic lesions in 15 and haemorrhagic lesions in 2, with hypophyseal involvement in 2 patients. According to the clinical-radiological presentation, we distinguished granulomatous (G-CNS) and vasculitic (V-CNS) phenotypes. G-CNS patients more frequently had headaches, while V-CNS patients more frequently had motor impairment and renal involvement. Induction therapy produced clinical responses in 86% of patients. Baseline modified Rankin scale was higher for V-CNS than G-CNS patients (3 vs 2, P = 0.002). Initial spinal cord pachymeningitis was significantly associated with the need for a new induction regimen for relapsing/refractory disease (P = 0.01). Long-term neurological sequelae were noted in 51% of patients, including 35% with G-CNS and 69% with V-CNS (P = 0.08). Neurological sequelae were mainly noted in cases of spinal cord pachymeningitis (100%) and ischaemic or haemorrhagic lesions (73%).nnnCONCLUSIONnThe clinical-radiological phenotype distinguished different long-term outcomes in patients with GPA and CNS involvement. Long-term neurological sequelae persisted in half of patients, mainly those with spinal cord pachymeningitis and vasculitic lesions.

Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial

Objectives To study the efficacy of rescue treatment strategies and outcomes in patients with Wegeners granulomatosis (WG) and microscopic polyangiitis (MPA) not achieving remission with first-line induction with corticosteroids (CS) and intravenous cyclophosphamide (CYC). Methods 159 eligible patients in the Wegeners Granulomatosis-Entretien (WEGENT) trial newly diagnosed with systemic or renal WG or MPA with ≥1 poor prognosis factors were included in this prospective study. Rescue treatment strategies and outcomes in patients with induction-refractory disease were analysed and patient characteristics at diagnosis were compared with those of induction-responders. Results Most patients (n=126, 79.2%) achieved remission; 1 stopped induction because of allergy and 32 were induction-refractory (24 WG and 8 MPA); 11 died rapidly within a median of 2.5 months, 6 of uncontrolled disease, 1 of an infectious complication and 4 of both. Treatment was discontinued in 1 patient with MPA with end-stage renal disease. Induction was switched to oral CYC in 20 patients, combined with infliximab in 1; 15 (75%) achieved remission or low disease activity state, 3 subsequently died of uncontrolled disease and 2 entered remission using several other agents including biological agents. Alveolar haemorrhage and a creatinine level >200 μmol/l were independently associated with induction-refractory disease. Among patients with induction-refractory disease, massive alveolar haemorrhage was associated with higher mortality. Conclusion Switching to oral CYC can be an effective rescue treatment for patients with systemic forms of WG or MPA who fail to achieve remission with first-line CS and intravenous CYC. However, a more rapidly effective regimen remains to be identified for most severely affected patients whose outcomes can be rapidly fatal.

OP0217 Defining Disease Activity Sates and Minimal Clinically Important Improvement (MCII) with the EULAR Primary SjÖGren's Syndrome Disease Activity Index (ESSDAI)

Objectives To determine disease activity levels and clinically important changes with the recently developed and validated [1] EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI), and to assess their relevance for conducting clinical trials. Methods Patients from 2 large prospective cohorts (EULAR [multicenter international] n=395, ASSESS [multicenter French] n=395), have been followed for 6 months and 1 year, respectively. Physician completed ESSDAI, evaluated disease activity according to a 4 point scale, and assessed if the patients were in minimal disease activity (MDA). A ROC curve analysis and an anchoring method using MDA definition was used to determine disease activity levels of ESSDAI. At follow-up visit, physicians assessed whether disease activity has improved or not. An anchoring method based on this evaluation of change was used to estimate the minimum clinically important improvement (MCII) of ESSDAI. Data from recent clinical trials evaluating biologics [2-4] were used to assess the relevance of these thresholds. Results According to data from the 2 cohorts, low (ESSDAI <5), moderate (5 ≤ ESSDAI ≤13) and high (ESSDAI≥14) activity levels were defined. Fifty-four and 37% of patients from EULAR and ASSESS real life cohorts and 70 to 77% of patients from recent trials had at least moderately active disease (ESSDAI≥5). The MCII of the ESSDAI was defined as an improvement of at least 3 to 4 points. Based on recent trial data, the cutoff of 3 could be retained, because it was the best to discriminate between patients from placebo and treated arms. Conclusions In conclusion, this study, involving 2 independent large cohorts of primary SS patients allows determining disease activity levels and clinically relevant changes with ESSDAI. We hope that the results of this study will help to conduct more effectively clinical trials for evaluation of biologics in primary SS. Our proposal is to use the threshold of moderate activity as entry criteria (patients with ESSDAI≥5), and to define response to treatment as a significant improvement of ESSDAI (at least 3 points). References Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjogrens syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2014. Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjogrens syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 2013. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjogrens syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960-8. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Tolerance and efficacy of Rituximab in primary Sjögrens syndrome (TEARS): Results of a randomized controlled trial. Ann Rheum Dis 2012;71:75. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4399

Characteristics, prognosis, and outcomes of cutaneous ischemia and gangrene in systemic necrotizing vasculitides: A retrospective multicenter study

OBJECTIVESnTo describe the prevalence, characteristics, and outcome of cutaneous ischemia, and whether it can occur in systemic necrotizing vasculitides (SNVs), i.e., polyarteritis nodosa, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis.nnnMETHODSnWe conducted a retrospective analysis of all patients with SNV who were included in the French Vasculitis Study Group cohort database between March 1963 and September 2007. We compared characteristics and outcomes for patients with and without cutaneous ischemia (digital necrosis and/or isolated necrotic cutaneous ulcers).nnnRESULTSnAmong the 1304 patients with a diagnosis of SNVs, 40 (3.1%) had digital necrosis and 25 (1.9%) had isolated necrotic cutaneous ulcers, with an equal distribution among SNVs. Presence of cutaneous ischemia was associated with past and/or current smoking [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.02-2.95] and history of coronary artery disease (2.40; 1.01-6.00), as well as with other cutaneous manifestations (6.54; 3.21-8.67), gastrointestinal tract perforations (4.29; 1.41-13.07), and arthralgias (1.84; 1.10-3.07) during diagnosis. Ten patients with digital necrosis underwent extremity amputation, but no patient with isolated necrotic cutaneous ulcers (p = 0.007) underwent it. Smoking was the main risk factor of amputation (OR, 9.1; 1.7-48.9). At a mean follow-up of 10 years, cutaneous ischemia was identified as an independent predictor of vasculitis relapse (hazard ratio, 1.47; 95% CI, 1.05-2.05) and all-cause death (1.66; 1.01-2.74).nnnCONCLUSIONSnCutaneous ischemia is a rare manifestation of SNVs but is associated with an increased risk of relapse and mortality. Tobacco use is associated with amputation, which emphasizes the importance of managing conventional cardiovascular risk factors in SNV patients.

Remittent non-destructive polysynovitis in P-ANCA-positive vasculitis patients with anti-CCP antibodies.

Patients with antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AASV) commonly suffer from arthralgias and, sometimes, polyarthritis during disease flares. Although rheumatoid factor (RF) can be detected in up to 37-50% of AASV patients, anti-cyclic citrullinated peptide (anti-CCP) antibodies are rare. Herein, we describe the clinical features of five P-ANCA-positive vasculitis patients, who had persistent and/or high anti-CCP levels and, more importantly, suffered from remittent non-destructive arthralgias and polysynovitis, independently of the vasculitis course and without evidence of RA. Two were initially thought to have RA rather than microscopic polyangiitis and, at AASV diagnosis, all had kidney involvement and three had alveolar hemorrhages. With a median follow-up of 30 months, one suffered vasculitis relapses, preceded by polysynovitis, and others had remittent arthralgias and polysynovitis, while their vasculitides remained in remission. None of these patients had radiological destructive arthritis. We discuss the challenge of diagnosing these patients positive for anti-CCP and ANCA, and with dominant articular manifestations. AASV patients with anti-CCP antibodies may experience relapsing polysynovitis and non-erosive polyarthritis prior to vasculitis flares, but also independently of the vasculitis course, which is uncommon in AASV, and might represent a small subgroup of AASV patients.