Sjögren’s Syndrome (SjS) has historically been associated with classical anti-Ro60/SSA, Ro52/SSA and La/SSB, however they are lacking in one third of the patients, which induces delays in diagnosis, and their disease-contributing role is debated. Here we have applied a SjS-tailored Systems Serology approach to a cohort of 58 SjS and 16 non-SjS sicca syndrome patients, and 40 healthy individuals, involving a multiplex assay measuring antibody isotype, subclass, Fc Receptor and complement engagement to 14 SjS-related autoantigens, an antibody-glycosylation profiling assay and a phagocytosis cell-based assay. Via a machine learning approach, we have identified unique autoantibody signatures, including classical and non-classical autoantigens-related features especially involving autoantigen-specific Fc Receptor binding, with apparent functional consequences. These findings provide interesting insights into the autoantibody responses in SjS, possibly paving the way for improved diagnostics, especially in difficult-to-diagnose patients (e.g., seronegative SjS and non-SjS sicca syndrome patients), and novel therapeutic options targeting autoantibody-specific Fc/Fc Receptor-related effector functions. This study reports that a Systems Serology approach, dedicated to the evaluation multiple Sjögren’s syndrome autoantibodies’ Fab and Fc related features, could possibly improve its diagnosis, and reveal novel pathogenic mechanisms. This study reports that a Systems Serology approach, dedicated to the evaluation multiple Sjögren’s syndrome autoantibodies’ Fab and Fc related features, could possibly improve its diagnosis, and reveal novel pathogenic mechanisms.

OBJECTIVE:Systemic sclerosis (SSc) is an autoimmune disease characterized by autoantibody production, fibrosis, and vasculopathy. The coexistence of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) in SSc is rare and poorly characterized, with limited data on the impact of treatments, particularly high-dose glucocorticoids (GCs), on both conditions. This study aimed to describe the clinical phenotype, management, and outcomes of patients with overlapping SSc and AAV. METHODS:We conducted a multicenter retrospective study in 18 French centers, including patients who met the 2013 American College of Rheumatology (ACR)/EULAR criteria for SSc and the 2022 ACR/EULAR criteria for AAV. Clinical, biologic, and radiologic data were collected. RESULTS:We included 30 patients (median age 51.5 years, 83% female). SSc preceded AAV in all cases; 27% had diffuse cutaneous SSc, whereas 73% had limited cutaneous SSc. Anti-Scl70 antibodies were detected in 50%, and interstitial lung disease (ILD) was present in 80%, predominantly with a fibrosing nonspecific interstitial pneumonia pattern (54%). AAV was microscopic polyangiitis in 90%, with myeloperoxidase (MPO)-ANCA positivity in 93%. Renal involvement was common (76%), with a median serum creatinine level of 170 μmol/L (interquartile range [IQR] 120-361 μmol/L) and proteinuria (urine protein to creatinine ratio of 2 g/g creatinine [IQR 0.9-2.3 g/g creatinine]). All patients received GCs in combination with cyclophosphamide (50%) or rituximab (47%). No cases of scleroderma renal crisis were observed. SSc manifestations, including ILD and skin involvement, remained stable during follow-up. CONCLUSION:AAV, predominantly microscopic polyangiitis with MPO-ANCA, can occur in SSc, particularly in patients with fibrosing ILD and anti-Scl70. Standard vasculitis treatments appear to be effective and do not worsen outcomes in SSc.

Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs+ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.

OBJECTIVES:We aimed to assess the incidence of cancer-associated myositis among patients with anti-synthetase syndrome, identify factors associated with cancer-associated myositis, and assess its impact on prognosis. METHODS:We conducted a retrospective multicenter study, including adult patients with anti-synthetase syndrome. Factors associated with cancer were assessed using a multivariable logistic regression model. Unsupervised analysis was used to identify a cluster of patients associated with cancer. Cox proportional hazard ratio model was used to assess impact of cancer-associated myositis on mortality. RESULTS:Among the 122 patients included, 14 (11.4%) met cancer-associated myositis criteria. Standardized incidence ratio was 5.4 (5.14 to 5.65, P < .0001). Patients with cancer-associated myositis were older, more often had a history of cancer, and had lower creatine kinase level and less muscular weakness. They had a significantly worse overall survival compared with those without (log-rank test χ2 = 16.2, P < .0001). Age and history of cancer were independently associated with cancer-associated myositis. Patients with cancer-associated myositis segregated within a cluster characterized by an older age, a milder muscular involvement, and less Jo-1 antibodies. Finally, cancer-associated myositis was an independent predictor of death. CONCLUSION:Cancer-associated myositis is not rare in anti-synthetase syndrome, with higher incidence compared with the general population. Due to its higher mortality, cancer should be carefully screened, especially in older patients with history of cancer.

OBJECTIVES:Anti-MDA5 dermatomyositis (anti-MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)- and calcineurin-inhibitor combination (JAK-CNI) in anti-MDA5 DM patients. METHODS:A nested case-control study was conducted within a retrospective cohort of 234 anti-MDA5 DM patients. Patients receiving JAK-CNI were matched 1:2 with comparators. All-cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed. RESULTS:Twenty-seven patients receiving JAK-CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty-nine (49%) died or were transplanted during follow-up. No significant improvement in survival or transplant-free survival was observed with JAK-CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48-2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK-CNI combination was observed in non-ICU patients. Infectious complications were frequent (n = 49, 62%), with no excess risk in patients receiving JAK-CNI. CONCLUSION:JAK-CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK-CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non-ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK-CNI therapy in anti-MDA5 DM.

We report the case of a patient with ulcerative colitis (UC) who, 4 years after diagnosis, developed large vessel vasculitis (LVV), revealed by high fever, joint pain and headache. Laboratory tests showed C-reactive protein at 326mg/L, leukocytosis at 18.9 G/L, with 14.2G/L of neutrophils and elevated serum IL6 (12pg/mL [N 0.76-6.38]). Thoraco-abdominal CT scan was normal, apart from evidence of involvement of the rectum and colon consistent with UC. The diagnosis of LVV was established by a positron emission tomography (PET-CT) scan that revealed thoracic and abdominal aortitis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by autoantibody production, fibrosis, and vasculopathy. The coexistence of ANCA‐associated vasculitides (AAV) in SSc is rare and poorly characterized, with limited data on the impact of treatments, particularly high‐dose glucocorticoids (GCs), on both conditions. This study aimed to describe the clinical phenotype, management, and outcomes of patients with overlapping SSc and AAV. We conducted a multicenter retrospective study in 18 French centers, including patients who met the 2013 ACR/EULAR criteria for SSc and the 2022 ACR/EULAR criteria for AAV. Clinical, biologic, and radiologic data were collected. We included 30 patients (median age 51.5 years, 83% female). SSc preceded AAV in all cases; 27% had diffuse cutaneous SSc, while 73% had limited cutaneous SSc. Anti‐Scl70 antibodies were detected in 50%, and interstitial lung disease (ILD) was present in 80%, predominantly with a fibrosing non‐specific interstitial pneumonia pattern (54%). AAV was microscopic polyangiitis in 90%, with MPO‐ANCA positivity in 93%. Renal involvement was common (76%), with a median serum creatinine of 170 μmol/l (IQR 120‐361) and proteinuria of 2 g/g (IQR 0.9‐2.3). All patients received GCs in combination with cyclophosphamide (50%) or rituximab (47%). No cases of scleroderma renal crisis were observed. SSc manifestations, including ILD and skin involvement, remained stable during follow‐up. AAV, predominantly microscopic polyangiitis with MPO‐ANCA, can occur in SSc, particularly in patients with fibrosing ILD and anti‐Scl70. Standard vasculitis treatments appear to be effective and do not worsen outcomes in SSc.

OBJECTIVE:To compile a list of approved training sites for the Residency Training Program [Diplôme d'Études Spécialisées] in Internal Medicine and Clinical Immunology (DES-MIIC) in France. METHOD:All local coordinators of the DES-MIIC were contacted to establish the list of approved internship sites for the MIIC DES within their geographical subdivision. RESULTS:We listed 244 approved training sites, of which 87 (35.7%) were in university hospitals. Depending on the region/subdivision, the number of approved training sites varied significantly. Internship sites within and outside of university hospitals were approved for the core-phase in 85% (74/87) and 63.7% (100/157) of cases, for the "development phase" in 94.3% (82/87) and 84.1% (132/157) of cases and for the consolidation phase 80.5% (70/87) and 52.2% (82/157) of cases, respectively. The vacancy rate for selection was lower in university hospitals than in general hospitals with ratios of 1.5 (89.3% vs. 61%), 1.8 (88.8% vs. 48.9%) and 1.6 (88,5% vs. 55.4%) - for respectively the core, development and consolidation phases. CONCLUSION:Thirty-five percent of internship sites were located in University hospitals. Depending on the region/subdivision, the number of approved training sites for the DES-MIIC varies greatly. Half of internship positions are vacant outside of University hospitals, just as nearly half of training sites in these same hospitals lack approval for the "consolidation phase".

Introduction Cold agglutinin haemolytic anaemia, aplastic anaemia, immune thrombocytopaenia and hemophagocytosis are well-established complications of Mycoplasma pneumoniae infection. In contrast, severe neutropenia has rarely been described. Case report We report the case of a 71-year-old with systemic lupus erythematosus who presented with severe febrile neutropenia (0.2G/L) and mild thrombocytopenia (75 G/L) revealing M. pneumoniae pneumonia. Erythema multiforme appeared secondary. Granulocyte autoantibodies were negative. Neutropenia and thrombocytopenia resolved within three days after azithromycin initiation. Discussion Four other cases of M. pneumoniae pneumonia presenting with severe febrile neutropenia have been reported in the literature. They were associated with thrombocytopenia and/or anemia in all cases. Granulocyte autoantibodies were positive in 2 cases. This rare case highlights the importance of considering M. pneumoniae infection in the differential diagnosis of febrile neutropenia and illustrates that rapid resolution of neutropenia can be observed under antibiotic therapy alone.

Introduction Le syndrome des anti-synthétases (SAS) est une connectivite de chevauchement, associant de façon variable une myosite, une pneumopathie interstitielle diffuse (PID), une atteinte articulaire inflammatoire, un phénomène de Raynaud et une atteinte cutanée à type d’hyperkératose fissuraire des mains et doigts. La PID touche plus de 75 % des patients et constitue la première cause de mortalité au cours du SAS. L’évolution à long terme de la PID est variable selon les patients et difficilement prévisible. Un objectif majeur de la prise en charge est d’évaluer le risque de progression au cours du temps lors du diagnostic de PID chez un patient donné. L’objectif de l’étude était de déterminer des groupes homogènes de patients avec SAS selon le profil évolutif de la PID au cours du temps et de les caractériser. Patients et méthodes Étude rétrospective de cohorte multicentrique inter-régionale au sein du Grand Est (réseau Myosit’EST). Les critères d’inclusion étaient : (1) diagnostic de SAS défini selon les critères de Connors avec (2) PID définie sur les données du scanner thoracique et (3) CVF au diagnostic de la PID et à au moins une reprise au cours du suivi. Afin de décrire les trajectoires évolutives de la PID, plusieurs modèles linéaires mixtes de 1 à 6 classes latentes (ou latent-class mixed models) ont été évalué pour la variable CVF en fonction du temps. Le nombre optimal de classes a été déterminé selon des critères statistiques (AIC et BIC) et l’adéquation du modèle (probabilités à posteriori d’appartenance à une classe donnée). Le temps 0 correspondait à la valeur de CVF au diagnostic de la PID. Les trajectoires ont été censurées après la visite de suivi n°8 en raison du grand nombre de données manquantes au-delà. Résultats Au total, 92 patients ont été inclus, dont 56 patients avec anticorps anti-Jo1 (61 %), 14 patients avec anticorps anti-PL7 (15 %), 13 patients avec anticorps anti-PL12 (14 %) et 9 patients avec anticorps anti-EJ (10 %). Une PID sévère au diagnostic était observée chez 30 patients (33 %). Des atteintes musculaire, articulaire, microvasculaire et cutanée étaient présentes respectivement chez 50 patients (54 %), 55 patients (60 %), 36 patients (39 %) et 30 patients (33 %). Le modèle à 3 classes était le plus adapté avec une probabilité moyenne d’appartenance à une classe de 0,78. La classe 1 (n=17 patients) était caractérisée par une diminution progressive de la CVF au cours du temps et un pronostic péjoratif comparativement aux autres classes (hypertension pulmonaire, insuffisance respiratoire chronique et décès). La prévalence d’atteinte microvasculaire (47 %), cardiaque (12 %) et d’anticorps anti-Ro52 (73 %) était élevée. Un cancer associé était présent chez 4 patients (24 %). La classe 2 (n=44 patients) était caractérisée par une CVF conservée au diagnostic avec une trajectoire stable au cours du temps. Les patients étaient jeunes (âge médian 48 [43-59] ans), avec une prévalence élevée d’atteinte articulaire (66 %) et de mains de mécaniciens (39 %) et moins d’anticorps anti-Ro52 (42 %). La classe 3 (n=31 patients) était caractérisée par une CVF basse au diagnostic avec une trajectoire biphasique (amélioration significative au cours des 4 premières années de suivi puis diminution de la CVF). 14 patients (45 %) avaient une PID sévère au diagnostic. Les patterns de PINS et PO étaient observés chez 82 % et 29 % des patients respectivement. La prévalence de l’atteinte musculaire (48 %) et des anticorps anti-Jo1 (52 %) étaient faibles. Conclusion L’analyse de notre cohorte de patients SAS a permis de dégager 3 trajectoires évolutives de la PID distinctes au cours du temps, associées à la présentation clinico-biologique des patients (atteintes d’organe et profil d’anticorps notamment).

Purpose: To describe the molecular diagnosis and atypical ocular presentation of a patient who suffered for a Rendu-Osler-Weber syndrome associated with juvenile polyposis (JP) syndrome. Methods: This is a case report of a patient that underwent fundus examen, brain Magnetic Resonance Imaging (MRI) and arteriography. Genetic testing was performed by next-generation-sequencing (NGS). Results: A 35-year-old woman presented with right hemiplegia with right homonymous lateral hemianopia and homolateral complete sensory deficit. She also had Roth spots in her left fundus. Genetic testing revealed a pathogenic variation in the heterozygous state in the SMAD-4 gene (c.1245_1248del). Conclusion: Hereditary Hemorrhagic Telangiectasia (HTT) also known as Rendu-Osler-Weber syndrome is a rare autosomal dominant disease which reveals mostly with epistaxis and cutaneous telangiectasias. Our clinical case reports Roth spots in the context of HTT associated with juvenile polyposis syndrome. SMAD-4 mutation may explain the presence of a carotid-ophthalmic aneurysm which is not a lesion usually found in HTT.

Introduction Le syndrome des anti-synthétases (SAS) est une connectivité de chevauchement hétérogène. La pneumopathie interstitielle diffuse (PID) constitue le facteur pronostic majeur (principale cause de mortalité). Peu d’études ont été spécifiquement dédiées à l’évaluation de la sévérité de la PID selon le profil d’anticorps, avec des données contradictoires et des critères de jugement évaluant des paramètres différents (CVF au diagnostic, dyspnée au diagnostic, PID rapidement progressive, évolution de la CVF au cours du temps). L’objectif de l’étude était de comparer la sévérité de la PID au diagnostic et l’évolution de la PID au cours du temps selon le profil d’anticorps au cours du SAS. Patients et méthodes Étude rétrospective de cohorte multicentrique inter-régionale au sein du Grand Est (réseau Myosit’EST). Les critères d’inclusion étaient : diagnostic de SAS défini selon les critères de Connors et présence d’une PID définie sur les données du scanner thoracique. La PID sévère était définie par un critère composite : PID hypoxémiante au diagnostic (PaO2<60mmHg et/ou oxygénoréquérance) et/ou PID rapidement progressive (1) diminution≥10 % de la CVF, ou 2) diminution≥5 % de la CVF avec aggravation de la dyspnée et/ou extension des lésions au scanner, ou 3) diminution≥15 % de la DLCO dans les 3 mois suivant le diagnostic). Résultats Au total, 132 patients avec PID ont été inclus, dont 80 patients avec anticorps anti-Jo1 (61 %), 21 patients avec anticorps anti-PL7 (16 %), 21 patients avec anticorps anti-PL12 (16 %) et 10 patients avec anticorps anti-EJ (8 %). Une PID sévère au diagnostic était constatée chez 51 patients (39 %). Comparativement aux patients avec PID non sévère, les patients avec PID sévère au diagnostic étaient plus souvent de sexe masculin (43 vs 23 %, p=0,02), avec une pleurésie et une fièvre plus fréquentes (respectivement 38 vs 5 %, p<0,001 et 62 vs 16 %, p<0,001), mais un phénomène de Raynaud et une atteinte musculaire sévère plus rares (respectivement 16 vs 32 %, p=0,04 et 18 vs 33 %, p=0,05). Il n’y avait pas de différence significative selon le profil d’auto-anticorps. En analyse multivariée, les variables associées à la PID sévère au diagnostic étaient le sexe masculin (OR 2,98, IC95 % 1,01–9,18, p=0,05), la pleurésie (OR 5,02, IC95 % 1,06–28,8, p=0,05), la fièvre (OR 7,7, IC95 % 2,61–25,2, p<0,001) et le taux de CRP (OR 1,01, IC95 % 1,00–1,02, p=0,05) ; alors que le taux de CPK était un facteur protecteur (OR 0,29, IC95 % 0,13–0,60, p=0,002). La survie à 10ans était diminuée chez les patients avec PID sévère comparativement aux patients avec PID non sévère (p=0,07) et chez les patients avec anticorps anti-PL7 comparativement aux autres anticorps (p=0,03). L’analyse non supervisée par classification ascendante hiérarchique a identifié 4 clusters distincts. Le cluster no 1 (n=62) regroupait des patients avec atteinte systémique (musculaire, articulaire et vasculaire), PID non sévère au diagnostic, anticorps anti-Jo1 et peu d’insuffisance respiratoire chronique au cours du suivi (à l’inverse des 3 autres clusters). Le cluster no 2 (n=40) regroupait des patients âgés avec PID sévère au diagnostic, pleuropéricardite, cancer associé et anticorps anti-PL7 ou anti-Jo1. Les clusters 3 (n=20) et 4 (n=10) regroupaient tous les patients avec anticorps anti-PL12 et anti-EJ respectivement. Conclusion Si cette étude n’a pas mis en évidence d’association directe entre le profil d’auto-anticorps et la sévérité de la PID au diagnostic au cours du SAS, différents phénotypes de patients ont été identifiés avec un regroupement selon le type d’auto-anticorps, notamment des formes systémiques avec PID non sévères associées aux anticorps anti-Jo1 pour la moitié de la cohorte.

La fasciite à éosinophiles (FE), ou maladie de Shulman, est une pathologie rare du tissu conjonctif caractérisée par un œdème et une induration douloureuse des membres et du tronc, souvent associés à une hyperéosinophilie et une hypergammaglobulinémie. Elle provoque des arthralgies et une limitation des amplitudes articulaires induisant un important retentissement fonctionnel et une altération de la qualité de vie. Depuis sa description par Shulman en 1974, plus de 300 cas ont été rapportés. Nous présentons ici une revue des actualités diagnostiques, physiopathologiques, et thérapeutiques de cette maladie. L’imagerie par résonance magnétique est utile pour orienter le diagnostic et la biopsie. Le diagnostic repose sur la biopsie cutanée profonde comportant le fascia qui met en évidence un œdème, une scléro-fibrose du fascia musculaire et du tissu sous-cutané et un infiltrat inflammatoire parfois composé de polynucléaires éosinophiles. Des formes secondaires à l’utilisation des inhibiteurs de checkpoint ont été décrites et l’apparition d’une sclérose cutanée chez ces patients doit faire évoquer le diagnostic. La physiopathologie reste mal connue et la prise en charge mal codifiée, reposant sur des données issues de cohorte rétrospectives et cas cliniques. Le traitement de première intention consiste en corticothérapie orale, parfois associée à un immunosuppresseur, en premier lieu le méthotrexate. Une meilleure compréhension de la physiopathologie permet d’envisager de nouvelles perspectives thérapeutiques et de préciser la place de thérapies ciblées telles que les inhibiteurs de l’interleukine 5 (IL-5) et de l’IL-6.

IntroductionSystemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc.MethodsData for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality.ResultsWe included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection.ConclusionThis study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients’ classification based on only skin extension is not sufficient for defining prognosis and phenotype.