C. Francès

Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients

Objectives: To describe presentation and outcome of patients with scleroderma renal crisis (SRC). Methods: SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension occurring during the course of systemic sclerosis (SSc). Chronic dialysis-free survival was analysed using multivariate Cox proportional hazards regression models. The risk for developing SRC associated with corticosteroid (CS) exposure during the preceding 1- or 3-month periods was analysed according to a case–crossover design. Results: A total of 50 SSc patients aged 53.3 (14.5) (mean (SD)) years were included in the study. SRC occurred between 1979 and 2003, after a mean (SD) disease duration of 27.7 (49.1) months. A total of 43 (86%) patients had diffuse SSc, 5 (10%) had limited cutaneous SSc and 2 (4%) had SSc sine scleroderma. At the time of SRC, 10 (20%) patients were taking angiotensin converting enzyme inhibitors, and mean creatininaemia was 468 (293) μmol/l. A total of 28 (56%) patients required haemodialysis. In all, 11 patients underwent a renal biopsy, all of them had specific vascular lesions of SRC. Multivariate analyses retained age >53 years and normal blood pressure as independent predictors of decreased dialysis-free survival. Exposure to CS prior to SRC was identified in 30 (60%) patients. The odds ratios for developing SRC associated with CS exposure during the preceding 1- or 3-month periods were 24.1 (95% CI 3.0–193.8) and 17.4 (95% CI 2.1–144.0), respectively. Conclusion: SRC remains associated with severe morbidity and mortality. CS might increase the risk of developing SRC. Further studies are needed to confirm these results.

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study).

Introduction Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares. Patients and methods [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up. Results Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12). Conclusions Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up. ClinicalTrials.gov NCT00413361

Association of the CD226 Ser307 variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis

OBJECTIVE The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis.

OBJECTIVE Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc. METHODS The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed. RESULTS Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset. CONCLUSION These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.

Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor

The first large genome-wide association (GWA) study of systemic sclerosis (SSc) recently included 2296 SSc patients and 5014 healthy controls from four case–control series of Caucasian individuals and involved the analysis of about 280 000 single nucleotide polymorphisms (SNPs).1 Outside the HLA region, SNPs mapping to the known TNPO3 - IRF5 and STAT4 regions showed the strongest association but three other loci reached genome-wide significance (namely CD247 locus in 1q22–23, CDH7 in 18q22 and EXOC2 - IRF4 near 6p25) although only one ( CD247 ) could be replicated in the second set of samples. Given the major challenge of separating the many false-positive associations from the few true-positive associations with disease in GWA studies, resulting in a stratification bias, a critical strategy is replication of results in independent samples.2 Therefore, we herein provide an attempt of …

Cutaneous lesions of the digits in systemic lupus erythematosus: 50 cases

The objective of this study was to observe the clinical and pathologic features of digital lesions in a cohort of 50 patients with systemic lupus erythematosus (SLE). Biopsy and pictures of digital lesions were performed in 50 consecutive patients with SLE and digital lesions. A clinical diagnosis of vasculitis was previously suggested in 36% of cases. Pictures were reviewed by three dermatologists and all the tissue sections were analysed by the same pathologist. Files of patients were reviewed retrospectively. Activity of SLE was established according to the lupus activity index (LAI). Digital lesions in SLE were frequently painful (60%) with a finger-pulp inflammation (70%). According to clinical and pathological correlation, five patients had acute cutaneous lupus, five subacute cutaneous lupus, 21 discoid lupus and 15 chilblain lupus. Two patients presented vasculitis: one had an urticarial vasculitis concomitantly to a lupus flare, the other had an erythema elevatum diutinum, independent of SLE evolution. Thrombosis of dermal vessels was present in two patients with SLE-associated antiphospholipid syndrome and in two patients with chilblain lupus. LAI was > 1.5 in only seven patients. These results highlight the tendency to clinically overestimate the prevalence of cutaneous vasculitis of the fingers in patients without active SLE. Clinical features of cutaneous lupus of the digits are polymorphous. So, a pathological examination of the lesions is often necessary for diagnosis and proper management.

Presence of gelatinase A and etalloelastase type protease at the plasma membrane of human skin fibroblasts. Influence of cytokines and growth factors on cell‐associated metalloendopeptidase levels

Gelatinase A and elastase type proteinase (Homsy, et al., 1988) present at plasma membranes of human skin fibroblasts (HSF) were separated by anion exchange chromatography on a DEAE Tris acryl M column. Elastase type proteinase (HSFE1) was able to convert 72 kDa progelatinase A to a lower 66 kDa M.W. active enzyme. Several cytokines (IL‐1β, 1L4, IL6), interferon γ (IFN γ) and tumor growth factor β (TGFβ) were studied for their ability to modify the levels of those plasma membrane associated proteinases. Among these mediators, only IL‐1β was found to enhance the amounts of HSF membrane‐bound HSFE1 and Gelatinase A.

IgA antineutrophil cytoplasmic antibodies in cutaneous vasculitis

Background Antineutrophil cytoplasmic antibodies (ANCA) of the IgA isotype have, for the most part, been detected in patients with Henoch–Schönlein purpura (HSP) or inflammatory bowel disease. Objectives We have evaluated the prevalence of IgA ANCA in a series of patients with different causes of cutaneous vasculitis. Methods Forty consecutive patients with histologically proven leucocytoclastic vasculitis were included in the study: 18 had systemic vasculitis as well as cutaneous lesions, 10 of whom were diagnosed as having HSP, and 22 had only cutaneous vasculitis (with no identified cause in 10 cases). IgA ANCA were sought by indirect immunofluorescence using ethanol‐fixed human neutrophil preparations as the substrate. Results IgA ANCA were detected in six of 40 patients (15%) (one each with HSP, ulcerative colitis, Sjögren’s syndrome, hypergammaglobulinaemia associated with Castelman’s disease, erythema elevatum diutinum and bacterial endocarditis). Three of these patients also had IgG ANCA whose target antigen remained unidentified. Conclusions IgA ANCA are rarely observed in HSP (10%) and can be detected in a wide variety of other cutaneous vasculitides.

Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide.

CONTEXT Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients. OBJECTIVE We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide. DESIGN AND SETTING We conducted a matched cohort study in referral centers for SLE. PATIENTS Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study. MAIN OUTCOME MEASURES AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status. RESULTS The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5-4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH. CONCLUSION We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels.

Manifestations dermatologiques du lupus

Various dermatologic manifestations are observed in the different lupus subsets. Lupus lesions are most frequently characterized by a dermoepidermal dermatitis. Other lesions, vascular or nonvascular, are essentially present in association with systemic lupus erythematosus. Acute, subacute and chronic lupus erythematosus are distinguishable according to their clinical aspects, pathological features and their evolution. Acute lesions are either localized to the midface or widespread. Subacute lesions may be annular or psoriasiform. Chronic lupus erythematosus includes localized or widespread discoid lupus, lupus tumidus, chilblain lupus and panniculitis. Therapy of cutaneous lupus is mainly based on antimalarials and avoidance of sun exposure. In refractory cutaneous lupus, no universal guidelines are available. Except for acrosyndromes and urticaria-like lesions, vascular lesions may be due to vasculitis or thrombosis. An accurate diagnosis is necessary, since therapeutic management is quite different in these two conditions. Nonvascular and nonlupus lesions are numerous and some of them require specific treatment, such as dapsone for bullous lupus.