Characterisation of airway disease associated with Sjögren disease.

OBJECTIVE: Although airway disease associated with Sjögren's disease (Sjo-AD) is common, it is poorly studied compared with interstitial lung disease (ILD). In this study, we aimed to assess factors associated with Sjo-AD, the characteristics and prognosis of this manifestation. METHODS: We performed a retrospective multicentric study involving nine centres. We included Sjo-AD patients confirmed by at least one clinician and one CT scan report. Clinical and biological data, pulmonary function test (PFT), and CT scans were collected. A single radiologist specialist in thoracic diseases reviewed CT scans. Sjo-AD patients were compared with Sjo controls without pulmonary involvement, randomly selected after matching for age and disease duration. RESULTS: We included 31 Sjo-AD and 62 Sjo controls without pulmonary history. Sjo-AD had a higher disease activity (ESSDAI) compared with controls, even when excluding the pulmonary domain of the score (7 vs 3.8, p<0.05), mainly due to the biological activity. Sjo-AD was multilobar (72%) and associated with signs of both bronchiectasis and bronchiolitis (60%). Obstructive lung disease occurred in 32% at the time of Sjo-AD diagnosis. Overall, PFT was stable after 8.7±7 years follow-up but repeated CT scans showed extended lesions in 41% of cases within 6±3.2 years. No patient developed Sjo-ILD. Sjo-AD progression was independent of the global disease activity. CONCLUSIONS: Sjo-AD preferentially affects Sjo patients with higher biological activity. It is often characterised as a diffuse disease, affecting both proximal and distal airways, with a slow evolution over time and no progression to Sjo-ILD.

PICAFlow: a complete R workflow dedicated to flow/mass cytometry data, from pre-processing to deep and comprehensive analysis.

Summary: PICAFlow is a R-written integrative workflow dedicated to flow/mass cytometry data handling, from pre-processing to deep and comprehensive analysis. It is designed as a powerful all-in-one tool which contains all the necessary functions and packages presented in a user-friendly and ease-to-use fashion. PICAFlow also includes important features that are very frequently lacking in other close software, such as interactive R Shiny applications for real-time data transformation and compensation as well as normalization methods aiming to remove batch effects and unwanted inter- and intra-group heterogeneity. It also allows to perform dimensionality reduction, cell clustering (using different available approaches), as well as complementary statistical analyses and export different support for data interpretation and visualization. Availability: PICAFlow is available as a R-written package hosted at the following GitHub repository: https://github.com/PaulRegnier/PICAFlow and is complemented by a fully detailed tutorial available at the following URL: https://paul-regnier.fr/tutoriel-picaflow/.

Occurrence of focal myositis during Behçet's disease: The identification of a specific vasculitis-associated focal myopathy.

AIMS: This study aimed to report the association of focal myositis (FM) and Behçet's disease (BD) and to analyse the main characteristics of such an association. METHODS: This is a retrospective multicentre study of patients with BD and FM (BD + FM+ group) and those without FM (BD - FM+ group). Clinical, laboratory, radiological, pathological, treatment and outcome data were analysed. RESULTS: The BD + FM+ group included 10 patients; the median [interquartile range] age at BD diagnosis was 25 [16-35] years, and at FM diagnosis, it was 30 [26-42] years. The diagnosis of BD preceded FM in the majority of cases (n = 8/10). FM occurrence was associated with BD flare-ups in three cases. The creatine kinase levels remained normal or slightly increased. Histological analyses identified relatively preserved muscle tissue, associated with vasculitis (n = 5/6). All patients required treatment; most patients relapsed (n = 9/10). The BD - FM+ group included 35 patients. A comparison of the groups identified a trend towards a younger median age at diagnosis of FM among those with BD (p = 0.063) and more frequent focal muscle swelling in the BD + FM+ group (p = 0.029). The pathological analysis identified significantly less frequent muscle alterations in the BD + FM+ group (muscle fibre size heterogeneity, p = 0.021; necrosis, p = 0.007; and fibrosis, p = 0.027). BD + FM+ patients had a higher frequency of relapse (p = 0.003) and systematic treatment (p = 0.042). CONCLUSIONS: FM occurring during BD appears to be part of the systemic vasculitis process and presents as a vasculitis-associated focal myopathy with a specific clinico-histological pattern. Patients with this association require long-term follow-up and adapted management. This case series also highlights the need for research on BD diagnostic criteria in cases of FM.

[Pericarditis]. / Péricardites.

"Pericarditis Acute pericarditis is a common disease, most often idiopathic or viral. This is usually a mild condition but recurrences are frequent. The predominant pathophysiological hypothesis is that of underlying dysimmune disorders, involving an inflammatory response of the innate immune system typical of "autoinflammatory diseases", mainly mediated by interleukin-1 [IL-1] with activation of inflammasome; and an adaptive immune system response, typical of «autoimmune diseases¼, primarily mediated by autoantibodies and autoreactive T cells. The clinical picture associates fever, chest pain, changes in the electrocardiogram and possible pericardial effusion. Treatment is based on the combination of aspirin/nonsteroidal anti-inflammatory drugs and colchicine for several weeks. In refractory pericarditis, low dose corticosteroid therapy and / or immunosuppressive agents have been proposed with limited efficacy. Growing evidency suggest a place for IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many studies have shown the effectiveness of anakinra with a good safety profile. Other IL-1 receptor antagonists have shown promising results (canakinumab, rilonacept). Further evaluation in larger prospective clinical trials is needed to confirm the long-term efficacy and safety of anti-IL1."

"Péricardites La péricardite aiguë est une maladie fréquente, le plus souvent idiopathique ou virale. Il s'agit en règle générale d'une affection bénigne mais fréquemment récidivante. L'hypothèse physiopathologique prédominante est celle de troubles dysimmunitaires sous-jacents, mettant en jeu une réponse inflammatoire du système immunitaire inné typique des « maladies auto-inflammatoires ¼, principalement médiée par l'interleukine-1 (IL-1) avec activation de l'inflammasome ; et une réponse du système immunitaire adaptatif, typique des « maladies auto-immunes ¼, principalement médiée par des auto-anticorps et des lymphocytes T autoréactifs. Le tableau clinique associe des signes généraux, une douleur thoracique, des modifications de l'électrocardiogramme et un possible épanchement péricardique à l'échographie. Le traitement repose sur l'association d'aspirine/anti-inflammatoires non stéroïdiens et de colchicine pendant plusieurs semaines. Dans les péricardites réfractaires, une corticothérapie à faible dose et/ou des agents immunosuppresseurs ont été proposés, avec une efficacité limitée. De plus en plus de preuves suggèrent une place des antagonistes des récepteurs IL-1 dans le traitement de la péricardite récurrente. De nombreuses études ont montré l'efficacité de l'anakinra avec un bon profil de sécurité. D'autres antagonistes des récepteurs IL-1 ont montré des résultats prometteurs (canakinumab, rilonacept). Une évaluation plus approfondie dans des essais cliniques prospectifs plus larges est nécessaire pour confirmer l'efficacité à long terme et l'innocuité des anti-IL-1."

Acute recurrent pericarditis: from pathophysiology towards new treatment strategy.

Acute idiopathic or so-called viral pericarditis is a frequent and usually benign disease, although recurrences are frequent. Data strongly suggest the presence of underlying autoinflammatory and/or autoimmune disorders. It has been reported that there is an inflammatory response of the innate immune system typical of 'autoinflammatory diseases', predominantly mediated by interleukin-1 (IL-1). This may result from the activation of the inflammasome by a cardiotropic virus or a non-specific agent. The inflammatory response of the adaptive immune system, typical of 'autoimmune diseases'-mainly mediated by autoantibodies or autoreactive T lymphocytes-seems also involved as anti-heart or anti-intercalated disk autoantibodies were associated with a higher number of recurrences and hospitalisations. Current guidelines recommend that aspirin/non-steroidal anti-inflammatory drugs for a few weeks should be associated to colchicine for 6 months in recurrent pericarditis. In refractory cases, low-dose corticosteroids or immunosuppressive drugs have been proposed with limited efficacy. Growing evidences suggest a place of IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many retrospective studies, one recent randomised placebo-controlled study and data of a real-life large international registry showed the good efficacy of anakinra with a good safety profile. Other IL-1 receptor antagonists showed promising results (canakinumab, rilonacept). However, IL-1 receptor antagonists' position in the treatment algorithm of recurrent pericarditis needs further evaluation in larger prospective clinical trials to replicate initial findings as well as to assess safety, cost-effectiveness and long-term efficacy.

Prognostic Factors in Anti-glomerular Basement Membrane Disease: A Multicenter Study of 119 Patients.

We report the overall and renal outcome in a French nationwide multicenter cohort of 119 patients with anti-glomerular basement membrane (anti-GBM) disease. Sixty-four patients (54%) had an exclusive renal involvement, 7 (6%) an isolated alveolar hemorrhage and 48 (40%) a combined renal and pulmonary involvement. Initial renal replacement therapy (RRT) was required in 78% of patients; 82% received plasmapheresis, 82% cyclophosphamide, and 9% rituximab. ANCA positive (28%) patients were older (70 vs. 47 years, p < 0.0001), less frequently smokers (26 vs. 54%, p = 0.03), and had less pulmonary involvement than ANCA- patients. The 5 years overall survival was 92%. Risk factors of death (n = 11, 9.2%) were age at onset [HR 4.10 per decade (1.89-8.88) p = 0.003], hypertension [HR 19.9 (2.52-157 0.2) p = 0.005], dyslipidemia [HR 11.1 (2.72-45) p = 0.0008], and need for mechanical ventilation [HR 5.20 (1.02-26.4) p = 0.047]. The use of plasmapheresis was associated with better survival [HR 0.29 (0.08-0.98) p = 0.046]. At 3 months, 55 (46%) patients had end-stage renal disease (ESRD) vs. 37 (31%) ESRD-free and 27 (23%) unevaluable with follow-up < 3 months. ESRD patients were older, more frequently female and had a higher serum creatinine level at presentation than those without ESRD. ESRD-free survival was evaluated in patients alive without ESRD at 3 months (n = 37) using a landmark approach. In conclusion, this large French nationwide study identifies prognosis factors of renal and overall survival in anti-GBM patients.

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/- atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity. METHODS: The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronicallyHCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. RESULTS: The Tbet+CD11c+CD27+CD21- AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127-/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region. CONCLUSION: Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses. LAY SUMMARY: B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells.