BACKGROUND Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. The objective of this study was to evaluate the efficacy and safety of thalidomide in ...severe cutaneous sarcoidosis. METHODS This study consisted of a randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicenter trial lasting 3 months and an open-label study from month 3 to month 6. Adults with a clinical and histologic diagnosis of cutaneous sarcoidosis were included in nine hospital centers in France. Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for 3 months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide, 100 mg to 200 mg daily. The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement in three target lesions scored for area and infiltration, were compared across randomization groups. RESULTS The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients in the thalidomide group (20%) vs four out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of −1% 95% CI, −26% to +24% for thalidomide vs placebo, P = 1.0). Eight patients with side effects were recorded in the thalidomide group vs three in the placebo group. We observed a large number of adverse event-related discontinuations in patients taking thalidomide in the first 3 months (four patients with thalidomide, zero with placebo) and in the 3 following months (five patients). CONCLUSIONS At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT0030552; URL: www.clinicaltrials.gov
To assess the value of major histocompatibility complex (MHC) class II antigen (HLA-DR) expression to distinguish anti-synthetase myopathy (ASM) from dermatomyositis (DM).
Muscle biopsies from ...patients with ASM (n = 33), DM without anti-synthetase antibodies (ASAb) (n = 17), and normal muscle biopsy (n = 10) were first reviewed. ASAb included anti-Jo1 (26/33), anti-PL12 (4/33), anti-PL7 (2/33), and anti-EJ (1/33). Immunohistochemistry was performed for MHC-I/HLA-ABC, MHC-II/HLA-DR, membrane attack complex (C5b-9), neural cell adhesion molecule (NCAM)/CD56 expression, and inflammatory cell subsets. Twenty-four ASM and 12 DM patients from another center were added for HLA-DR evaluation.
Ubiquitous myofiber HLA-ABC expression was equally observed in ASM and DM (93.9% vs 100%, NS). In contrast, myofiber HLA-DR expression was found in 27/33 (81.8%) ASM (anti-Jo1: 23/26, 88.5%; others: 5/7, 71.4%) vs 4/17 (23.5%) DM patients (p < 0.001). HLA-DR was perifascicular in ASM, a pattern not observed in DM. In addition, C5b-9 deposition was observed on sarcolemma of non-necrotic perifascicular fibers in ASM, while, in DM, C5b-9was mainly detected in endomysial capillaries. CD8 cells were more abundant in ASM than in DM (p < 0.05), and electively located in perimysium or in perifascular endomysium. HLA-DR expression correlated positively with the CD8+ cells infiltrates. Strictly similar observations were made in the confirmatory study.
ASM is characterized by strong myofiber MHC-II/HLA-DR expression with a unique perifascicular pattern, not described so far. HLA-DR detection must be included for routine myopathological diagnosis of inflammatory/dysimmune myopathies. HLA-DR expression in ASM may indicate a specific immune mechanism, possibly involving IFNγ.
The main component of the first-line treatment of pemphigus vulgaris is high doses of systemic corticosteroids, but adverse effects of these drugs are frequent and sometimes severe. Rituximab has ...shown effectiveness as a corticosteroid-sparing agent or in case of relapse. To our knowledge, the effectiveness of rituximab as a first-line treatment without systemic corticosteroids has not been evaluated.
Five women in their 50s, 60s, or 70s with pemphigus vulgaris (Pemphigus Disease Area Index score, 15-84 at diagnosis) and contraindications to systemic corticosteroid treatment received rituximab with high-potency topical corticosteroids as first-line treatment. All patients experienced a favorable response, with a mean time to healing of skin and mucosal lesions of 15 weeks. Two patients, with 42- and 48-month follow-up evaluations, did not experience relapse. Three patients developed 2 to 4 relapses, with effective retreatment achieved using rituximab and topical corticosteroids. No severe adverse effects were observed.
Considering the high rate of severe adverse effects induced by prolonged administration of high doses of systemic corticosteroids, new therapeutic options are warranted in the treatment of pemphigus vulgaris. The combination of rituximab and topical corticosteroids could be considered in mild to severe cutaneous disease. Larger long-term studies are needed to evaluate the optimal treatment strategies according to the severity of the disease and the benefit-risk ratio of rituximab.
Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases.
We sought to ...investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia.
We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network.
The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist IL-1RA) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213.
We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin’s key role in the complex molecular network of innate immunity.
Objectives. This longitudinal study investigated survival, risk factors and causes of death in the multicentre ItinérAIR-Sclérodermie cohort of patients with SSc without severe pulmonary fibrosis or ...severe left heart disease at baseline. Methods. At 3-year follow-up, vital status was obtained from investigators or French national death records. Causes of death were classified as SSc-related or otherwise. Data were censored at 37 months, time of death or loss to follow-up, whichever was earlier. Survival was estimated using the Kaplan–Meier method. Multivariate survival analyses were conducted using the Cox model. Results. In total, 546 patients were followed for a median duration of 37 months, representing 1547 patient-years. At baseline, the majority of patients were female, with lcSSc, mean age 54.9 ± 13.0 years and mean duration of SSc of 8.8 ± 8.1 years. In total, 47 patients died, giving a 3-year survival of 91.1% and cumulative mortality of 3.04 deaths per 100 patient-years; 17 deaths (32.2%) resulted from pulmonary arterial hypertension (PAH) and eight (17.1%) from cancer. Of the 47 patients with PAH at baseline, 20 died during follow-up, giving a 3-year survival of 56.3%. In a multivariate analysis, PAH hazard ratio (HR) 7.246, age at first symptom (HR 1.052), duration of SSc (HR 1.047 per year) and Rodnan skin score (per one point) (HR 1.045) were associated with increased mortality. Conclusion. This 3-year study observed survival and mortality estimates that were comparable with previous reports. PAH increased the HR for mortality in patients with SSc, justifying yearly echocardiographic screening.
Some authors consider that morphoea and systemic sclerosis (SSc) could be part of the same disease spectrum. The aim of this study was to analyse the prevalence of signs indicative of SSc in a cohort ...of patients with morphoea.
This is a prospective multi-centre study performed in four French academic dermatology departments: 76 patients with morphoea and 101 age- and sex-matched controls, who underwent complete clinical examination, were enrolled. A systemic search for signs indicative of SSc (e.g. Raynaud's phenomenon, reflux) was performed with the help of a standardised questionnaire.
There were 58 women and 18 men (ration=3/1) with a median age of 59 years. Mean age at diagnosis was 54 years (extremes, 13-87). 49 subjects had plaque morphoea, 9 had generalised morphoea and 18 had linear morphoea. Mean duration of morphoea was 7.9 years. Signs possibly indicative of SSc were noted in four patients of the control group and in 8 patients with morphoea. This difference was not statistically significant (p=0.129). Further investigations ruled out SSc in all patients.
Signs indicative of SSc are statistically not more frequently present in patients with morphoea than in controls and this study does not support the view that those 2 entities are part of a common disease spectrum.
Context:Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. Objective:To evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis. ...Design, Setting and Participants:Randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicentre trial lasting 3 months, and an open-label study from month 3 to month 6. Adults with clinical and histological diagnosis of cutaneous sarcoidosis were included in nine hospital centres in France. Intervention:Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for three months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide 100 mg to 200 mg daily. Main outcome measures:The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement of 3 target lesions scored for area and infiltration, were compared across randomisation groups. Results:The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients (20%) in the thalidomide group vs 4 out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% (95% CI -26% to +24%) for thalidomide vs placebo; p=1.0). Eight patients with side effects were recorded in the thalidomide group vs 3 in the placebo group. We observed a large number of adverse event-related discontinuations in patients under thalidomide in the first 3 months (4 patients with thalidomide, 0 with placebo), and in the 3 following months (5 patients). Conclusion:At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. Trial registration:NCT0030552 (ClinicalTrial.gov). Context: Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. Objective: To evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis. Design, Setting and Participants: Randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicentre trial lasting 3 months, and an open-label study from month 3 to month 6. Adults with clinical and histological diagnosis of cutaneous sarcoidosis were included in nine hospital centres in France. Intervention: Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for three months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide 100 mg to 200 mg daily. Main outcome measures: The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement of 3 target lesions scored for area and infiltration, were compared across randomisation groups. Results: The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients (20%) in the thalidomide group vs 4 out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% (95% CI -26% to +24%) for thalidomide vs placebo; p=1.0). Eight patients with side effects were recorded in the thalidomide group vs 3 in the placebo group. We observed a large number of adverse event-related discontinuations in patients under thalidomide in the first 3 months (4 patients with thalidomide, 0 with placebo), and in the 3 following months (5 patients). Conclusion: At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. Trial registration: NCT0030552 (ClinicalTrial.gov).
Objective
Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic ...factors. With regard to the latter, there has been a recent shift from the “common variant” to the “rare variant” paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc.
Methods
TREX1 single‐nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls).
Results
No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low‐frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 95% confidence interval 2.28–5.41, P = 8.58 × 10−9) in the combined populations. Genotype–messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression.
Conclusion
The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low‐frequency functional variants and the critical role of A20 in autoimmunity.
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