Search

The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1mutations. Up to 72% of patients may show lung involvement.

The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown.

The antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by thrombotic events that can require ICU admission because of organ dysfunction related to macrovascular and/or microvascular thrombosis. Critically ill patients with thrombosis and APS were studied to gain insight into their prognoses and in-hospital mortality-associated factors.

ObjectiveTo 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.MethodsRetrospective nationwide multicenter study of patients diagnosed with both AAV and bronchiectasis.ResultsSixty-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.ConclusionThe 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.

Le syndrome VEXAS (vacuoles, E1 ubiquitin conjugating enzyme, lié au chromosome X, auto-inflammatoire, somatique) est une maladie auto-inflammatoire acquise résultant d’une mutation somatique de l’enzyme activateur d’ubiquitine UBA1 caractérisée par un très haut risque thrombotique. Une revue de la littérature des cas de syndrome VEXAS révèle une incidence notable de thrombo-embolie veineuse à environ 40 % et de thrombose artérielle à environ 2 %, avec une prédominance de la thrombose veineuse profonde par rapport à l’embolie pulmonaire. Les mutations somatiques dans le gène UBA1 altèrent l’ubiquitination, activent le système immunitaire inné et libèrent des cytokines pro-inflammatoires telles que le TNF-a, l’IL-8, l’IL-6, l’IFN-gamma, entraînant une inflammation systémique sévère. Les patients atteints du syndrome VEXAS présentent diverses manifestations cliniques, notamment de la fièvre, des chondrites, une dermatose neutrophilique, des polyarthralgies ou une polyarthrite, des infiltrats pulmonaires et une vascularite systémique. Le pronostic évolutif du VEXAS est sévère avec souvent la nécessité d’administrer de très fortes doses de corticoïde pour atténuer les symptômes du patient. Bien que l’inflammation chronique, la vascularite, la dysfonction endothéliale et les perturbations des mécanismes anticoagulants soient proposées comme mécanismes, la pathogenèse exacte de la thrombose reste à élucider. Les mutations UBA1 affectent principalement les cellules de la lignée myéloïde dans la moelle osseuse et le sang périphérique, activant de multiples voies de cytokines inflammatoires et favorisant la formation spontanée de la nétose. La veinulite pourrait être une caractéristique distinctive du syndrome VEXAS et un mécanisme sous-jacent de la thrombose. Des recherches supplémentaires sont en cours pour découvrir les mécanismes précis de la thrombose et le rôle de la mutation du gène UBA1 dans ce contexte. Cibler la dysfonction endothéliale et réduire l’inflammation systémique et locale grâce à l’utilisation des glucocorticoïdes, immunosuppresseurs et une anticoagulation est actuellement la stratégie utilisée pour prévenir les événements thrombotiques récurrents.

Relapsing polychondritis (RP) is a very rare autoimmune disease characterised by a relapsing inflammation of the cartilaginous tissues (joints, ears, nose, intervertebral discs, larynx, trachea and cartilaginous bronchi), which may progress to long-lasting atrophy and/or deformity of the cartilages. Non-cartilaginous tissues may also be affected, such as the eyes, heart, aorta, inner ear and skin. RP has a long and unpredictable course. Because no randomised therapeutic trials are available, the treatment of RP remains mainly empirical. Minor forms of the disease can be treated with non-steroidal anti-inflammatory drugs, whereas more severe forms are treated with systemic corticosteroids. Life-threatening diseases and corticosteroid-dependent or resistant diseases are an indication for immunosuppressant therapy such as methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide. Biologics could be given as second-line treatment in patients with an active disease despite the use of steroids and immunosuppressive drugs. Although the biologics represent new potential treatment for RP, very scarce information is available to draw any firm conclusion on their use in RP.

Background

Dans un contexte clinique évocateur, le diagnostic de maladie d’Erdheim-Chester (MEC) repose sur l’analyse des histiocytes tissulaires : ils sont volontiers spumeux, CD68+ CD1a–, alors que dans l’histiocytose langerhansienne (HL), l’immunomarquage est CD68+ CD1a+. Les formes de chevauchement sont fréquentes. La fixation intense des os longs sur la scintigraphie osseuse au 99Tc est très évocatrice de MEC ; l’aspect de « reins chevelus » est retrouvé dans plus de la moitié des cas sur le scanner abdominal. L’atteinte du système nerveux central dans la MEC est un facteur pronostique indépendant prédictif de mortalité. Le traitement de première intention de la MEC est l’interféron α (et/ou l’interféron α pégylé), dont l’administration prolongée augmente significativement la survie ; sa tolérance est cependant médiocre. L’anakinra, l’infliximab et le sirolimus ont une efficacité possible, et sont principalement efficaces pour des formes modérées de la maladie. La MEC est associée à une réaction systémique inflammatoire, intéressant principalement les voies de l’IFNα, IL-1/IL1-RA, IL-6, IL-12, et MCP-1, en rapport avec une réponse immunitaire de type Th1. Cinquante-sept à 75 % des patients avec une MEC sont porteurs de la mutation BRAFV600E, une mutation activatrice du proto-oncogène BRAF. Une cinquantaine de patients ayant une atteinte réfractaire et multisystémique de MEC (parfois associée à une HL), mutés BRAFV600E, ont été traité avec succès par le vemurafenib, un inhibiteur de BRAF. D’autres mutations fréquentes de la voie des MAP kinases (NRAS, MAP2K1) et de PIK3CAont été identifiées chez des patients ayant une MEC. Des mutations récurrentes de la voie des MAP kinases étant fréquemment retrouvées dans la MEC et l’HL, nous pensons que ces deux pathologies pourraient être « reclassifiées » comme des néoplasies myéloïdes inflammatoires.

IMPORTANCE Hydroxychloroquine-induced pigmentation is not a rare adverse effect. Our data support the hypothesis that hydroxychloroquine-induced pigmentation is secondary to ecchymosis or bruising. OBJECTIVE To describe the clinical features and outcome of hydroxychloroquine (HCQ)-induced pigmentation in patients with systemic lupus erythematosus (SLE). DESIGN, SETTING, AND PARTICIPANTS In a case-control study conducted at a French referral center for SLE and antiphospholipid syndrome, 24 patients with SLE, with a diagnosis of HCQ-induced pigmentation, were compared with 517 SLE controls treated with HCQ. MAIN OUTCOMES AND MEASURES The primary outcome was the clinical features of HCQ-induced pigmentation. Skin biopsies were performed on 5 patients, both in healthy skin and in the pigmented lesions. The statistical associations of HCQ-induced pigmentation with several variables were calculated using univariate and multivariate analyses. RESULTS Among the 24 patients, skin pigmentation appeared after a median HCQ treatment duration of 6.1 years (range, 3 months–22 years). Twenty-two patients (92%) reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas, which gave way to a localized blue-gray or brown pigmentation that persisted. Twenty-three patients (96%) had at least 1 condition predisposing them to easy bruising. Results from skin biopsies performed on 5 patients showed that the median concentration of iron was significantly higher in biopsy specimens of pigmented lesions compared with normal skin (4115 vs 413 nmol/g; P < .001). Using multivariate logistic regression, we found that HCQ-induced pigmentation was independently associated with previous treatment with oral anticoagulants and/or antiplatelet agents and with higher blood HCQ concentration. CONCLUSIONS AND RELEVANCE Hydroxychloroquine-induced pigmentation is not a rare adverse effect of HCQ. Our data support the hypothesis that HCQ-induced pigmentation is secondary to ecchymosis or bruising.

The lupus anticoagulant-hypoprothrombinemia syndrome (LAHS)—the association of acquired factor II deficiency and lupus anticoagulant—is a rare disease drastically different from antiphospholipid syndrome in that it may cause predisposition not only to thrombosis but also to severe bleeding. We performed a retrospective study of 8 patients with LAHS referred to 6 French tertiary care centers between January 2003 and February 2011, and a literature review retrieving all related articles published between 1960 and April 2011. Including our 8 new cases, LAHS has been reported in 74 cases. The disease mostly occurs in young adults, with a female to male sex ratio of 1.4. Associated conditions mostly include autoimmune diseases such as systemic lupus erythematosus and infectious diseases. Bleeding is a frequent feature (89 of cases), while arterial andor venous thrombosis is less common (13). Factor II level is severely decreased at diagnosis (median value, 11; range, 1–40). LAHS associated with autoimmune diseases is more persistent than LAHS associated with infection, and hemorrhagic complications are more common. Corticosteroids should be considered the first-line treatment, but the thrombotic risk strongly increases during treatment because of the improvement of factor II level. Despite the fact that 50 of patients develop severe bleeding, the mortality rate is <5, after a median follow-up of 13 months (range, 0.5–252 mo). LAHS associated with autoimmune diseases should be diagnosed and managed carefully because the disease is persistent and severe hemorrhagic complications are common.

Sarcoidosis is characterized by a disproportionate Th1 granulomatous immune response in involved organs. It is also associated with both peripheral and intratissular regulatory T cell (Treg) expansion. These cells exhibit powerful antiproliferative activity, yet do not completely inhibit the production of either tumor necrosis factor-α or interferon-γ. The origin of the observed Treg amplification and, more importantly, its impact on the evolution of sarcoidosis remain unresolved issues. Here, we show that CD4+CD45RA−FoxP3brightTregs proliferate and accumulate within granulomas. However, circulating and tissue Treg numbers are neither correlated with the dissemination of the disease nor correlated locally with the extent of granulomatous inflammation. Rather, we found a positive correlation between the presence of Tregs in renal granulomas and the degree of interstitial fibrosis (r= 0.46, P= 0.03, n= 20). Furthermore, Treg depletion accelerates in vitrogranuloma growth in mononuclear cell cultures of healthy controls, but not in those from patients with active sarcoidosis. The results of this study show that although healthy Tregs suppress the initial steps of granuloma formation, they have no positive influence on sarcoidosis lesions. Our findings argue for a more preventive than curative effect of Tregs on inflammatory processes.

Background

Comont: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terrier: LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Georgin-Lavialle: Novartis: Membership on an entity's Board of Directors or advisory committees; Soby: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Fenaux: Syros Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

Early specific antibody responses against SARS-CoV-2 include IgG, IgM, and IgA, but IgA may neutralize virus and control infection to a larger extent.

IgA influences bacterial fitness in the intestinal lumen and is only partially compensated for by IgM in selective IgA-deficient patients.