Raphaèle Seror

EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome

Objective To develop a disease activity index for patients with primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) Sjögrens syndrome disease activity index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true. Conclusions The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort.

The 1996 Five-Factor Score (FFS) for systemic necrotizing vasculitides (polyarteritis nodosa [PAN], microscopic polyangiitis [MPA], and Churg-Strauss syndrome [CSS]) is used to evaluate prognosis at diagnosis. In the current study we revisited the FFS, this time including Wegener granulomatosis (WG). We analyzed clinical, laboratory, and immunologic manifestations present at diagnosis of systemic necrotizing vasculitides for 1108 consecutive patients registered in the French Vasculitis Study Group database. All patients met the American College of Rheumatology and Chapel Hill nomenclature criteria. Univariable and multivariable analyses yielded the 2009 FFS for the 4 systemic necrotizing vasculitides. Overall mortality was 19.8% (219/1108); mortality for each of the SNV is listed in descending order: MPA (60/218, 27.5%), PAN (86/349, 24.6%), CSS (32/230, 13.9%), and WG (41/311, 13.2%) (p < 0.001). The following factors were significantly associated with higher 5-year mortality: age >65 years, cardiac symptoms, gastrointestinal involvement, and renal insufficiency (stabilized peak creatinine ≥150 &mgr;mol/L). All were disease-specific (p < 0.001); the presence of each was accorded +1 point. Ear, nose, and throat (ENT) symptoms, affecting patients with WG and CSS, were associated with a lower relative risk of death, and their absence was scored +1 point (p < 0.001). Only renal insufficiency was retained (not proteinuria or microscopic hematuria) as impinging on outcome. According to the 2009 FFS, 5-year mortality rates for scores of 0, 1, and ≥2 were 9%, 21% (p < 0.005), and 40% (p < 0.0001), respectively. The revised FFS for the 4 systemic necrotizing vasculitides now comprises 4 factors associated with poorer prognosis and 1 with better outcome. The retained items demonstrate that visceral involvement weighs heavily on outcome. The better WG prognosis for patients with ENT manifestations, even for patients with other visceral involvement, compared with the prognosis for those without ENT manifestations, probably reflects WG phenotype heterogeneity. Abbreviations ANCA = antineutrophil cytoplasmic antibodies, BVAS = Birmingham Vasculitis Activity Score, CNS = central nervous system, CSS = Churg-Strauss syndrome, ENT = ear, nose, and throat, FFS = Five-Factor Score, FVSG = French Vasculitis Study Group, HBV = hepatitis B virus, MPA = microscopic polyangiitis, NS = not significant, PAN = polyarteritis nodosa, SNV = systemic necrotizing vasculitides, WG = Wegener granulomatosis.

Central Nervous System Involvement in Wegener Granulomatosis

Abstract: Wegener granulomatosis (WG) is an antineutrophil cytoplasmic antibody (ANCA)-associated granulomatous vasculitis of small and medium-sized vessels. This vasculitis involves mainly the upper and lower respiratory tracts and kidneys, although WG may affect any organ. Central nervous system (CNS) involvement is an uncommon manifestation of WG, reported in 7%-11% of patients. Three major mechanisms have been incriminated as causing CNS disease in WG: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and CNS vasculitis. Herein we describe 6 patients with WG-related CNS involvement, 2 of whom had chronic hypertrophic pachymeningitis, 3 with pituitary involvement, and 1 with cerebral vasculitis. CNS involvement was present at disease onset in 2 patients and occurred 5-18 years after WG diagnosis in the remaining 4. Based on these observations and a review of the literature, we discuss the pathogenic mechanisms, clinical features, imaging findings, treatment, and outcome of meningeal, pituitary, and vascular involvement, with an emphasis on differential diagnoses, prognosis, and therapeutic management of WG-related CNS involvement. Abbreviations: ANCA = antineutrophil cytoplasmic antibody, C-ANCA = cytoplasmic ANCA, CHP = chronic hypertrophic pachymeningitis, CNS = central nervous system, CS = corticosteroids, CSF = cerebrospinal fluid, CYC = cyclophosphamide,DI = diabetes insipidus, ELISA= enzyme-linked immunosorbent assay, ENT = ear, nose and throat, ESR = erythrocyte sedimentation rate, PR3 = proteinase 3, WG = Wegener granulomatosis.

2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome A consensus and data-driven methodology involving three international patient cohorts

Objectives To develop and validate an international set of classification criteria for primary Sjögrens syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS. Methods We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgement. We then validated the performance of the classification criteria in a separate cohort of patients. Results The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2, each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmers test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert—derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively. Conclusion Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well suited as criteria for enrolment in clinical trials.

Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study

BACKGROUND Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögrens syndrome (pSS). OBJECTIVES To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. METHODS Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögrens syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. RESULTS Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögrens Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögrens Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmers test did not change. CONCLUSIONS These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

Rationale and efficacy of interleukin-1 targeting in Erdheim–Chester disease

Erdheim-Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-α therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1α levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD.

Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial

Objectives To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). Methods Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40 mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7 mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1 mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). Results Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). Conclusions In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1 mg/kg of corticosteroids at 6 months. Clinical trial registration number NCT00305539.

Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome: The JOQUER Randomized Clinical Trial

IMPORTANCE Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited. OBJECTIVE To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue. DESIGN, SETTING, AND PARTICIPANTS From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012. INTERVENTIONS Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48. MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue. RESULTS At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group. CONCLUSIONS AND RELEVANCE Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00632866.

Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls

OBJECTIVE Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence. METHODS Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls. RESULTS Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died. CONCLUSIONS Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.

Classification criteria for Sjögren's syndrome: we actually need to definitively resolve the long debate on the issue

A new approach for the classification of patients with Sjögrens syndrome (SS) has been recently proposed. Although these new criteria substantially differ from the American European Consensus Group criteria, which have represented the gold standard for the last decade, when compared with each other the two sets show a high statistical degree of agreement. However, the fact that two different criteria to classify patient with SS could be available may introduce some additional difficulties in the scientific communication, making cohorts of patients selected by using different methods less than completely equivalent, and the results of epidemiological studies and therapeutic trials not entirely comparable. Consequently, to reach a consensus agreement on universally accepted classification criteria for SS seems to be a very desirable objective.