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New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease associated with several anti-nuclear antibodies (ANA), including those in the classification criteria (anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA Pol III). However, the presence of less common antibodies such as anti-fibrillarin (U3-RNP) that generate a clumpy nucleolar pattern by HEp-2 indirect immunofluorescence assay (IFA, ICAP AC-9) are considered disease specific and are with clinical subsets of SSc, therefore playing a role in diagnosis and prognosis. A specific and sensitive anti-fibrillarin assay would be an important addition to serological diagnosis and evaluation of SSc. The goal of this study was to evaluate a new particle-based multi-analyte technology (PMAT) for the measurement of anti-fibrillarin antibodies. A total of 149 patient samples were collected including 47 samples from France (Lyon and Paris, n = 32) and Italy (Careggi Hospital, Florence, n = 15) selected based on AC-9 HEp-2 IFA staining (> 1:640, clumpy nucleolar pattern) and 102 non-SSc controls (inflammatory bowel disease (IBD) n = 20, Sjögren’s syndrome (SjS) n = 20, infectious disease (ID) n = 7, systemic lupus erythematosus (SLE) n = 17, rheumatoid arthritis (RA) n = 17, and healthy individuals (HI) n = 21). All samples were tested on the anti-fibrillarin PMAT assay (research use only, Inova Diagnostics, USA). Additionally, the 47 anti-fibrillarin positive samples were also tested on PMAT assays for detecting other autoantibodies in ANA-associated rheumatic diseases (AARD). Anti-fibrillarin antibody data performed by fluorescence enzyme immunoassay (FEIA, Thermo Fisher, Germany) was available for 34 samples. The anti-fibrillarin PMAT assay was positive in 31/32 (96.9%, France) and 12/15 (80.0%, Italy) of samples preselected based on the AC-9 IIF pattern (difference p = 0.09). Collectively, the PMAT assay showed 91.5% (95% confidence interval (CI): 80.1–96.6%) sensitivity with 100.0% (95% CI: 96.4–100.0%) specificity in non-SSc controls. Strong agreement was found between PMAT and FEIA with 100.0% positive qualitative agreement (34/34) and quantitative agreement (Spearman’s rho = 0.89, 95% CI: 0.77.9–0.95%, p

A prompt diagnosis and treatment of patients with autoimmune cerebellar ataxia (CA) with antibodies against glutamic acid decarboxylase (GAD-Abs) may lead to a better prognosis. Herein, we report prodromal transient neurological symptoms that should raise clinical suspicion of CA with GAD-Abs. We initially identified a 70-year-old man who presented a first acute episode of vertigo, diplopia, and ataxia lasting 2 weeks. Two months later, he experienced a similar episode along with new-onset gaze-evoked nystagmus. After 4 months, downbeat nystagmus, left limb dysmetria, and gait ataxia progressively appeared, and an autoimmune CA was diagnosed based on the positivity of GAD-Abs in serum and cerebrospinal fluid (CSF). We searched retrospectively for similar presentations in a cohort of 31 patients diagnosed with CA and GAD-Abs. We found 11 (35.4%) patients (all women, median age 62 years; 8/11 [72.7%] with autoimmune comorbidities) with transient neurological symptoms antedating CA onset by a median of 3 months, including vertigo in 9 (81.8%; described as paroxysmal in 8) and fluctuating diplopia in 3 (27.3%) patients. The identification of transient neurological symptoms of unknown etiology, such as paroxysmal vertigo and fluctuating diplopia, should lead to GAD-Abs testing in serum and CSF, especially in patients with autoimmune comorbidities.

ObjectivesImpairment of type I interferon (IFN-I) immunity has been reported in critically-ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically-ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease.MethodsThe concentration of anti-IFN-α2 Abs was determined in the serum of 84 critically-ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France using a commercially available kit (Thermo-Fisher, Catalog #BMS217).ResultsA total of 21/84 (25%) critically-ill COVID-19 patients had circulating anti-IFN-α2 Abs above cut-off (>34 ng.mL-1). Among them, 15/21 had Abs with neutralizing activity against IFN-α2, i.e. 15/84 (18%) of critically-ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralizing anti-IFN-α2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralizing anti-IFN-α2 auto-Abs. We detected anti-IFN-α2 auto-Abs in COVID-19 patients’ sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-ω.ConclusionsWe reported that 18% of critically-ill COVID-19 patients were positive for IFN-I auto-Abs, confirming that the presence of these antibodies is associated with higher risk of developing a criticall COVID-19 form.

Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Background and Aims Glomerulonephritis is common in ANCA associated vasculitis (GN-AAV). There is extensive published data on the renal prognosis of these conditions. However, few authors have described predictive factors for end-stage renal disease (ESRD) in patients with GN-AAV. Many authors suggest that renal biopsy should be abandoned in patients whose diagnosis would be established by antibody positivity alone. The aim of the study was to establish a prognostic score for renal damage during ANCA vasculitis and demonstrate need for prognostic renal biopsy. Method One Hundred and eighteen patients referred to 2 french nephrology departments in Lyon between January 2003 and January 2019 were retrospectively analysed. Patients were randomly divided in 2 cohorts at a ratio of 70/30: training and validation cohorts. ESRD was defined as glomerular filtration rate (eGFR) ≤ 15mL/min/1.73m2,need of chronic dialysis or renal transplantation. Results Of the 118 patients, 38 (32.20%) developed ESRD. We identified 3 criteria associated with development of ESRD in patients with GN-AAV. One point was assigned to each criterion according to a threshold value: eGFR at the time of renal biopsy ≤ 15 mL/min; percentage of sclerotic glomeruli ≥ 11% and percentage of normal glomeruli < 20%. A new prognostic renal score was established in patients with GN-AAV. It classifies patients into 3 categories at risk of developing ESRD: low (≤ 1 point), moderate (2 points) and high (3 points). Conclusion Two of the three criteria of our score are histological. Biopsy remains, when possible, an essential tool for diagnosis and especially to predict renal prognosis of ANCA vasculitis with renal impairment.

ObjectiveTo investigate the diagnostic yield of commercial immunodots to detect onconeural antibodies associated with paraneoplastic neurologic syndromes (PNSs), we analyzed the proportion of confirmed positive results using alternative techniques.MethodsSera (n = 5,300) of patients with suspected PNS were tested by PNS+2 blot (Ravo Diagnostika; January 2016–May 2017) or EUROLINE PNS 12 Ag (Euroimmun; July 2017–November 2018). Positive samples were further explored by in-house indirect immunofluorescence and a third in-house technique (Western blot or cell-based assay) using recombinant protein. Those found negative by these 2 techniques were considered as nonconfirmed. We analyzed the relationship between band intensity and final confirmation. Clinical data were collected for all confirmed results and nonconfirmed EUROLINE immunodots.ResultsPNS+2 blot was positive in 128/1,658 (7.7%) sera and confirmed in 47/128 (36.7%). EUROLINE was positive in 186/3,626 (5.1%) and confirmed in 56/186 (30.1%). Confirmation was highly variable among the antibodies tested, from 7.2% (PNS+2 blot) and 5.8% (EUROLINE) for anti-Yo to 88.2% (PNS+2 blot) and 65.0% (EUROLINE) for anti-Hu. None of the 27 weak positive sera by EUROLINE was confirmed. Band intensity in confirmed cases was variable among the antibodies from strong positive for all anti-Yo (n = 3) and anti-Hu (n = 11) to positive (n = 19) or strong positive (n = 9) for anti-SOX1. Among patients with a nonconfirmed EUROLINE result and available clinical information, all had an alternative diagnosis, and only 6.7% had cancer.ConclusionsImmunodots may be useful for PNS screening, but a threshold should be established for each antibody, and clinical information and confirmation by other techniques are essential.Classification of evidenceThe study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.

ObjectivesThe predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.MethodsTo characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5−; n = 190/201) based on selected variables, collected retrospectively, without any missing data.ResultsWithin anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5− patients with myositis.ConclusionAnti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

International audience; Objective: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM.Methods: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model.Results: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality.Conclusion: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

Background Juvenile dermatomyositis (JDM) is a rare heterogeneous autoimmune disease. The identification of myositis specific antibodies (MSAs) has allowed the characterization of subgroups of JDM patients who each have specific phenotypes. Antibody (Ab) against transcriptional intermediary factor-1-γ (TIF-1-γ or p155/140) is the most common MSA in JDM 1. In the American and English JDM cohorts, anti-TIF-1-γ associated JDM is classically associated with a larger proportion of caucasians, mild or moderate severity with typical cutaneous manifestations (Gottron’s papules, and/or heliotrope rash, photosensitivity), and a chronic disease course with a low mortality. The frequency of skin ulcerations and lipodystrophy differs between the two cohorts Objectives To report the clinical and muscle histology associations of anti-TIF-1-γ Ab in a series of patients with JDM followed in the French referral center for rare pediatric systemic autoimmune diseases. Methods Retrospective study of patients with JDM (according to the EULAR/ACR criteria) associated with anti-TIF-1-γ autoantibodies and included in our CEMARA database approved by the French National Committee on Informatics and Liberty. Results Thirteen patients were included (males: 5, females: 8; Caucasians: 6, Black Africans: 2, North Africans: 5). Age at diagnosis ranged from 1.5 to 11 years. Serum creatine kinase was elevated in 12 patients (range: 180-43 000 IU/L). Three different phenotypes were identified according to the severity and course. In group 1 (n=4), 3 patients had a moderate JDM: classical cutaneous manifestations and moderate muscle involvement; relapsing course, which remitted under methotrexate/corticosteroids; an additional 2-year-old girl had an amyopathic JDM. In group 2 (n=7), patients had a severe JDM : ulcerating skin lesions, severe muscle involvement, dysphagia, gastrointestinal vasculitis and/or requirement to an intensive care unit, and required more than two lines of treatment. In this group, 2/7 patients died from refractory JDM, comparing to a mortality rate of 2% in the remaining JDM patients tested for MSA and negative for anti-TIF-1-γ. Only 2/5 patients achieved a complete remission under treatment. Group 3 comprised two patients with severe muscle atrophy, calcinosis and lipodystrophy and a chronic course; one of them had a very-early-onset JDM at 1.5 year-old and the other an inherited neurological involvement, potentially suggestive of a genetic predisposing condition to JDM. None of the patients developed lung involvement or malignancy. Six patients underwent a muscle biopsy which was scored using the JDM severity score tool. The histo-pathologists’ overall severity score (VAS) varied from to 1 to 9/10; the highest scores were observed in the two patients who died. Conclusion In the present series of patients with JDM, TIF-1-γ Ab-associated-clinical phenotypes and ethnicities are more heterogeneous than previously reported. TIF-1-γ Ab is associated with a high mortality rate in a subset of patients. References [1] Rider LG, Nistala K. The juvenile idiopathic inflammatory myopathies: pathogenesis, clinical and autoantibody phenotypes, and outcomes. J Intern Med. 2016;280(1):24-38 Disclosure of Interests Brigitte Bader-Meunier: None declared, cyril gitiaux: None declared, jean-luc charuel: None declared, Nicole Fabien: None declared, isabelle melki: None declared, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, alexandre belot: None declared, Nathalie Streichenberger: None declared, christine bodemer: None declared, audrey aussy: None declared, olivier boyer: None declared

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Introduction Les myopathies idiopathiques inflammatoires (MIIs) sont un groupe heterogene de pathologies caracterise par une atteinte musculaire inflammatoire et des atteintes extra-musculaires variables. Plusieurs sous-groupes de MIIs sont definis a partir d’elements anatomopathologiques, immunologiques et cliniques : la dermatomyosite, la myosite a inclusions, la myosite necrosante auto-immune, le syndrome des anti-synthetases et les myosites de chevauchement. D’autres entites ont ete identifiees et apparaissent tres rares, notamment les myosites induites par les immunotherapies. Le type (myalgies, faiblesse musculaire) et la topographie (proximale ou distale) de l’atteinte musculaire est cruciale dans la demarche diagnostique, avec des tableaux variables en fonction du sous type de MIIs. L’atteinte de la musculature axiale est rare mais engendre des consequences fonctionnelles majeures. En termes semiologiques, le syndrome de tete tombante qui affecte les muscles extenseurs de la nuque se distingue de la camptocormie qui touche les muscles para-vertebraux thoraco-lombaires. Dans la litterature internationale, une trentaine de cas de syndrome de tete tombante et de camptocormie associes a des MIIs ont ete decrits, de maniere isolee ou sous la forme de petites series de cas, sans claire definition des caracteristiques cliniques, histologiques ou evolutives. L’objectif de ce travail est d’approfondir la definition du phenotype clinique et du cadre nosologique des MIIs en presence d’une atteinte musculaire axiale inaugurale en analysant de maniere exhaustive une serie de MIIs associees a une atteinte axiale inaugurale. Patients et methodes L’ensemble des cas de MIIs presentant une atteinte axiale inaugurale suivi dans un centre hospitalo-universitaire entre 2000 et 2019 ont ete inclus pour analyse. Les criteres d’inclusions correspondaient a un diagnostic de MIIs, une atteinte axiale inaugurale (tete tombante et/ou camptocormie), et l’exhaustivite des donnees clinico-bio-morpho-histologiques. Une etude descriptive ainsi que des analyses en cluster et de survie sont realisees sur cette cohorte. Resultats Dix-huit patients ont ete inclus dans l’etude. Les diagnostics de MIIs retenus etaient : scleromyosites (n = 9), dermatomyosites (n = 2), myosites a inclusions (n = 5) et myosites induites par les immunotherapies (n = 2). Certains patients presentaient a la fois un syndrome de la tete tombante et une camptocormie (n = 8), d’autres avaient seulement une atteinte des extenseurs de la nuque (n = 9) et un seul patient avait une atteinte isolee des muscles para-vertebraux thoraco-lombaires (n = 1). Le suivi moyen etait de 7 ans et demi. L’atteinte de la musculature axiale etait inaugurale ou survenait dans la premiere annee d’evolution de la MII pour les 18 patients, survenant dans 50 % des cas de maniere aigue ou rapidement progressive (i.e. Conclusion Dans ce travail descriptif, analysant la plus grande serie de cas de MIIs avec atteinte axiale inaugurale, cette symptomatologie rare semble retrouvee de facon predominante au cours des scleromyosites et des myosites a inclusions. Selon la pathologie sous-jacente, la presentation clinique est variable. L’installation est plus insidieuse dans les myosites a inclusion, la reponse au traitement est moindre alors que la morbidite induite est importante. L’evolution peut etre consideree comme superposable aux pathologies neurodegeneratives. A l’inverse, en cas d’installation aigue, la presence d’une telle atteinte semble tirer benefice d’un traitement maximal.

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since vendredi 13 avril 2018

International audience; Aim of the study: Evaluate the added value of screening anti-ZnT8 antibodies (ZnT8A) in addition to the classical anti-GAD (GADA) and anti-IA-2 (IA-2A) antibodies for the diagnosis of type-1 diabetes (T1D) within a large cohort of both children and adults. Materials and methods: Retrospective 2-year study including 516 patients (215 children, 301 adults) who had blood tests at diabetes onset and/or for diabetes classification. ZnT8A, GADA, and IA-2A were analyzed in all samples. Results: Among those individuals included, 142 (28%) were ZnT8A-positive. A total of 228/516 suffered from T1D, of whom 110 (48%) were ZnT8A-positive and 166 (73%) GADA and/or IA-2A positive. When adding ZnT8A to GADA/IA-2A, 184 (81%) patients were positive for \textgreater= 1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with \textgreater= 1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10 years. Fourteen of the 124 patients positive for ZnT8A with a known clinical diagnosis suffered from a disease other than T1D. Conclusions: ZnT8A should be included in routine evaluation at diabetes onset and is a valuable biological marker to classify newly-diagnosed diabetics. The predictive value in our high-risk subjects has to be confirmed.

Background.The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed.Methods.Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array.Results.The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies.Conclusion.Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.

Objective To assess in clinical practice the frequency and diagnosis associated with the SS-B-positive/SS-A negative autoantibody profile. Methods We analyzed a one-year consecutive population of 624 patients referred by clinicians to the immunology laboratory to investigate anti-SS-A and/or anti-SS-B autoantibodies, who were detected using luminex technology. Data were analyzed for patients with isolated anti-SS-B autoantibodies. The clinical characteristics and diagnosis of connective tissue diseases (CTD) were retrieved according to the international criteria. Results Among 1173 sera positive for anti-SS-A and/or anti-SS-B autoantibodies from 624 patients, we identified 84 patients (13.5%) that had isolated anti-SS-B. Among the 75 patients positive for anti-SS-B with known clinical data, 15 were diagnosed with a CTD (20%) including 4 systemic lupus erythematosus (5%), 4 rheumatoid arthritis (5%), 2 idiopathic inflammatory myositis (3%), 1 primary Sjogren’s syndrome pSS (1%), 1 systemic sclerosis (1%), 2 undefined CTD (3%), and 1 mixed CTD (1%). Among the 60 other patients, 18 had non-CTD autoimmune diseases and 42 had non-autoimmune diseases. Within the CTD population, the presence of isolated anti-SS-B was not significantly associated to characteristic indicating a specific syndrome. There was no association between diagnosis of CTD and level of anti-SS-B autoantibodies (p = 0.70). Arthralgia was the more frequent sign and encountered in 10 patients (67%), of whom 3 had arthritis. Conclusion The presence of anti-SS-B, without anti-SS-A autoantibodies using luminex technology, was not associated with CTD, especially pSS, in daily clinical practice. Our data suggests that the SS-B serological profile is not contributive for the classification criteria of pSS.

Objective Celiac disease is a complex autoimmune disease affecting patients of any age, who may present a wide variety of clinical manifestations. Different guidelines for the diagnosis and management of celiac disease have been recently published. The aim of this study was to determine whether the recommendations issued in these guidelines have been adopted by physicians in France when celiac disease was suspected. Methods A total of 5521 physicians were asked to fill in a detailed questionnaire on diagnosing celiac disease to evaluate their medical practice, as to the type of symptoms leading to the suspicion of celiac disease, the prescription of duodenal biopsy or serological tests, the type of serological tests (anti-tissue transglutaminase, anti-endomysium, anti-gliadin and anti-reticulin antibodies, total immunoglobulin A measurement) prescribed to diagnose celiac disease. Results The analysis of the responses of 256 general practitioners (GPs), 221 gastroenterologists and 227 pediatricians showed that the protean clinical presentations of celiac disease might be better recognized by gastroenterologists and pediatricians than by GPs. Gastroenterologists asked for duodenal biopsy much more often than GPs and pediatricians when celiac disease was suspected. Serological testing and knowledge of critical markers, prescribed to diagnose celiac disease, differed among GPs, gastroenterologists and pediatricians. Conclusion Analysis of medical prescriptions showed that the recommendations for celiac disease diagnosis are not necessarily followed by physicians, emphasizing the fact that the impact of national or international guidelines on medical behavior should be evaluated.

Introduction La glomerulonephrite est frequente au cours des vascularites a ANCA (GN-VAA). De nombreuses donnees ont ete publiees sur le pronostic renal de ces affections. Cependant, peu d’auteurs ont decrit les facteurs predictifs d’insuffisance renale chronique terminale (IRCT) chez les patients atteints de VAA. De nombreux auteurs suggerent l’abandon de la biopsie renale chez les patients atteints de vascularites dont le diagnostic serait etabli par la seule positivite des anticorps. L’objectif de notre travail etait d’etablir un score pronostique des atteintes renales au cours des vascularites et ainsi demontrer la necessite de la biopsie renale a visee pronostique. Patients et methodes Cent dix-huit patients suivis dans 2 services de nephrologie a Lyon entre janvier 2003 et janvier 2019 ont ete etudies retrospectivement. Les patients ont ete repartis apres randomisation dans deux cohortes selon un ratio 70/30 : une cohorte d’entrainement une de validation. L’IRCT etait definie par un debit de filtration glomerulaire (eDFG) ≤ 15 mL/min/1,73 m2, la dialyse chronique ou la transplantation renale. Resultats Sur les 118 patients, 38 (32,20 %) ont developpe une IRCT. Nous avons identifie 3 criteres associes au developpement de l’IRCT chez les patients atteints de GN-VAAV. Pour chaque critere, nous avons determine 1 point selon une valeur seuil : eDFG au moment de la biopsie renale ≤ 15 mL/min ; pourcentage de glomerules sclerotiques ≥ 11 % et pourcentage de glomerules normaux Conclusion Notre score comprend 1 critere biologique et 2 criteres histologiques. La biopsie reste, dans la mesure du possible, un examen essentiel dans le diagnostic et surtout le pronostic renal de la vascularite ANCA avec atteinte renale. Elle reste donc un outil indispensable pour adapter le traitement et eviter ainsi de surtraiter certains patients.

Objectives Systemic sclerosis (SSc) is a heterogeneous autoimmune disease associated with several antinuclear autoantibodies useful to diagnosis and prognosis. The aim of the present multicentric study was to determine the clinical relevance of anti-fibrillarin autoantibodies (AFA) in patients with SSc. Methods The clinical features of 37 SSc patients positive for AFA (AFA+) and 139 SSc patients without AFA (AFA-) were collected retrospectively from medical records to enable a comparison between AFA- and AFA+ patients. Anti-fibrillarin autoantibodies were screened by an indirect immunofluorescence technique using HEp2 cells and identified by an in-house Western blot technique and/or an EliA test. Results Comparing AFA+ and AFA– patients, AFA+ patients were significantly younger at disease onset (36.9 vs. 42.9; p=0.02), more frequently male (p=0.02) and of Afro-Caribbean descent (65% vs. 7.7%; p

Objective Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE. Methods GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov # NCT01992666 ). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE ( n = 10) and familial SLE ( n = 12) – both presumed to have a strong genetic component – and other forms of early-onset SLE ( n = 42). Results The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE ( P Conclusions In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability.

Childhood-onset systemic lupus erythematosus (cSLE) is rare, and considered more severe than its adult-onset counterpart. Lupus nephritis (LN) occurs more frequently in children, accounting for higher long-term morbidity and mortality compared with adults. Thus, reliable biological markers are needed to predict disease course. This study aimed to investigate the capacity of anti-C1q autoantibodies (Abs) to predict renal flare and global disease activity in cSLE patients, and association with disease activity and kidney involvement. Twenty-eight patients with cSLE including 19 patients (68%) with a history of LN were included retrospectively. Anti-C1q Abs were analysed by ELISA at renal flare-up or in the quiescent phase of disease and compared with Farr dsDNA assay. Thirty-one flares occurred during follow-up: anti-C1q Abs were positive in 26 (84%), strongly associated with active disease status (p

Nivolumab, a human IgG4 programmed death 1 (PD-1) immune checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and restores antitumor immunity (1). Many recent studies have emphasized the importance of anti–PD-1 antibodies to improve survival outcomes among patients with advanced melanoma or lung cancer. Several endocrinological side effects have been reported and a few patients developed insulin-requiring diabetes (2). Some …

Resume Propos Plusieurs cas de thrombose ont ete decrits dans la maladie cœliaque. Dans ce travail, nous avons analyse les caracteristiques cliniques et les facteurs de thrombophilie de sept patients adultes ayant presente une thrombose associee a une maladie cœliaque. Methodes Il s’agit d’une serie retrospective de sept observations de thrombose parmi une cohorte de 87 patients ayant une maladie cœliaque revelee a l’âge adulte. Les facteurs de thrombophilie ont ete repertories et une recherche d’anticorps antiphospholipides a ete faite de maniere retrospective sur le serum des sept patients. Resultats La prevalence globale des thromboses etait de 8 %, celle des thromboses spontanees de 5,7 %, avec des thromboses veineuses (n = 5) ou arterielles (n = 1) ou l’association des deux (n = 2). Il s’agissait de six femmes et d’un homme d’âge moyen 44,8 ans au moment de la thrombose. Les manifestations thrombotiques precedaient le diagnostic de maladie cœliaque dans quatre cas. Dans trois cas, la thrombose etait de siege inhabituel : veine porte (n = 2), veine splenique (n = 1). Des facteurs de risque de thrombose etaient identifies dans six cas et pouvaient tous etre relies a la maladie cœliaque : hyperhomocysteinemie (n = 1), deficit en proteine C et S (n = 3) lies a une carence en vitamine K et anticorps antiphospholipides (n = 2). Conclusion Des facteurs de risque de thrombose peuvent etre acquis au cours de la maladie cœliaque par carence vitaminique ou anticorps antiphospholipides. Il faut rechercher ces facteurs, les corriger, voire mettre en place une prophylaxie thromboembolique.

SUMMARY Esophageal involvement occurs in about 80% of patients with systemic sclerosis, with a marked diminution of peristaltic pressures in the distal two-thirds of the esophagus. Our aims were to more fully characterize esophageal motility disorders in systemic sclerosis using high-resolution manometry (HRM) and to determine predictive factors of esophageal involvement. Fifty-one patients (46 females) with systemic sclerosis were included in this retrospective study. Esophageal motility was characterized with HRM. The demographic data, esophageal symptoms, presence of other organ involvement, and autoantibody profile (anti-Scl70 antibodies [Scl70], anticentromere antibodies [ACA]) were recorded for all patients. Esophageal body dysmotility was present in 33 patients (67.3%) and was associated with hypotensive esophagogastric junction in 27 patients (55.1%). The velocity of proximal contractions was higher in patients with esophageal body dysmotility compared to patients with normal peristalsis (median 10.8 cm/s vs. 5.5, P = 0.04). The amplitude of middle esophageal contraction but not of distal esophageal contraction was reduced in patients with hypoperistalsis. Diffuse esophageal skin involvement, presence of Scl70 and absence of ACA were associated with esophageal involvement. Esophageal symptoms encountered in 87.5% of patients were not predictive of esophageal dysmotility. This HRM series confirms the high prevalence of esophageal body dysmotility in systemic sclerosis. Diffuse skin involvement, positive Scl70 and negative ACA, but not esophageal symptoms, may predict esophageal body dysmotility.

Introduction La sclerodermie systemique (ScS) est une maladie systemique auto-immune rare et heterogene associant une fibrose diffuse et une vasculopathie. La presence d’autoanticorps permet d’identifier et de stratifier les malades. Les anticorps anti-Th/To sont des anticorps anti-nucleolaires decrits pour la premiere fois en 1982. Leur prevalence et leur phenotype clinique ne sont pas bien caracterises et varient grandement en fonction des series de patients. L’objectif de cette etude est d’estimer la prevalence de cet autoanticorps et le spectre clinique associe. Patients et methodes Nous avons effectue une revue systematique via PubMed jusqu’en decembre 2017. Les etudes incluses comprenaient au moins 30 patients presentant une ScS selon les criteres internationaux et âges de 16 ans ou plus. La prevalence a ete estimee apres une transformation arsine. Les odds ratio (OR) explorant l’association des manifestations des patients en fonction des autoanticorps ont ete ponderes par l’inverse de la variance. Un modele d’effet aleatoire a ete utilise en cas d’heterogeneite significative (I2 > 50 %). L’heterogeneite a ete exploree par une meta-regression (variable continue) et une analyse en sous-groupe (variable discrete). Resultats Nous avons inclus 23 etudes comprenant un total de 7829 patients dont 244 positifs pour les anticorps anti-Th/To. L’âge moyen variait de 39 a 62 ans et les femmes representaient 70 a 93 % des patients. La prevalence des anticorps anti-Th/To etait estimee a 2,7 % (IC95 % : 1,8–3,7 %) avec une grande heterogeneite en fonction des etudes (I2 = 84 %). La prevalence etait moins importante en cas d’utilisation d’immunoblot (1,6 %, IC95 % : 0,7–2,8) comparivement a la technique d’immunoprecipitation (3,4 %, IC95 % : 2,0–5,1) ( p = 0,006 entre les deux techniques). La distribution en fonction des pays n’etaient pas en faveur d’une difference genetique quant a la prevalence ( p = 0,10). Les anticorps anti-Th/To etaient principalement trouves chez les patients ayant une ScS cutanee limitee ; seulement 18 % (IC95 % : 6–33) des patients positifs pour ces autoanticorps avaient une ScS cutanee diffuse. Les ulceres digitaux etaient presents chez 47 % (IC95 % : 28–68) des patients ayant des anticorps anti-Th/To, le reflux gastro-œsophagien (RGO) chez 40 % (IC95 % : 32–49), les arthralgies chez 16 % (IC95 % : 2–40) et les atteintes musculaires chez 5 % (IC95 % : 2–10) de ces patients. Concernant les atteintes severes, 37 % (IC95 % : 29–45) des patients presentaient une pneumopathie interstitielle diffuse (PID), 12 % (IC95 % : 3–25) une hypertension arterielle pulmonaire (HTAP), 6 % (IC95 % : 0–18) une atteinte cardiaque et 3 % (IC95 % : 0–10) une atteinte renale. Les patients avec anti-Th/To avaient plus de chance de presenter une HTAP (OR : 4,70, IC95 % : 3,00–7,37) et une PID (OR : 3,02, IC95 % : 1,60–5,71). Comparativement aux autres autoanticorps, les patients ayant des anticorps anti-Th/To avaient moins de ScS cutanee diffuse en particulier compare aux patients ayant des anticorps anti-Scl70 (OR : 0,12, IC95 % : 0,04–0,37), anti-ARN polymerase III (OR : 0,06, IC95 % : 0,02–0,22), anti-PM/Scl (OR : 0,34, IC95 % : 0,15–0,79) et anti-fibrillarine (OR : 0,05, IC95 % : 0,02–0,11). Comparativement aux patients porteurs anticorps anti-centromeres, ces patients avaient plus souvent une atteinte musculaire (OR : 3,69, IC95 % : 1,25–10,89), de PID (OR : 4,95, IC95 % : 3,12–7,88), et d’atteinte renale (OR : 7,09, IC95 % : 1,87–26,94) mais moins souvent de RGO (OR : 0,40, IC95 % : 0,27–0,61). Comparativement aux porteurs d’anticorps anti-Scl70, ils avaient moins souvent de PID (OR : 0,4,2, IC95 % : 0,23–0,75). Compare aux porteurs d’anticorps anti-ARN polymerase III, ils presentaient moins souvent une atteinte articulaire (OR : 0,1,9, IC95 % : 0,10–0,38) et plus souvent une HTAP (OR : 5,11, IC95 % : 2,3–11,30). Comparativement aux porteurs d’anti-PM/Scl, ils avaient moins souvent d’atteinte cardiaque (OR : 0,34, IC95 % : 0,16–0,72). Comparativement aux porteurs d’anticorps anti-fibrillarine, ils presentaient plus souvent une atteinte articulaire (OR : 0,19, IC95 % : 0,07–0,47) et moins souvent une atteinte musculaire (OR : 0,32, IC95 % : 0,11–0,95). Conclusion Les anticorps anti-Th/To sont des anticorps rares avec une prevalence globale de 3 % au cours de la sclerodermie systemique. Leur frequence semble etre influencee par la technique de dosage, suggerant une difference de sensibilite entre l’immunoblot et l’immunoprecipitation, cette derniere etant la technique de reference. Ils delimitent un phenotype particulier et sont associes aux formes systemiques cutanees limitees avec une frequence plus frequente des atteintes viscerales comparativement a celle des formes associees aux anti-centromeres.

We examined a 27-year-old woman who developed rapidly progressive quadriplegia and acute respiratory failure that required mechanical ventilation in the intensive care unit. It was unclear whether this was a presentation of Guillain-Barre syndrome (GBS) or acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). Remarkable features included multiple cranial nerve involvement, respiratory failure, dysautonomia, and skin manifestations. Several autoantibodies were elevated, including antinuclear (ANA), anticardiolipin (aCL), thyroid, and calcium-sensing receptor (CaSR) autoantibodies. The patient was initially diagnosed with GBS and treated with intravenous immunoglobulin (IVIg). After almost complete recovery, relapse with quadriplegia and respiratory failure was observed 12 weeks after motor symptom onset. She then received IVIg and steroid pulse therapy followed by maintenance oral methylprednisolone and plasma exchange. She recovered completely 4 months after the relapse. The further clinical and serological course was consistent with systemic lupus erythematosus (SLE)-associated CIDP. Herein we evaluate the association between A-CIDP and some biological markers of autoimmunity.

McKusick type metaphyseal chondrodysplasia, or cartilage hair hypoplasia (CHH), is a rare autosomal recessive osteochondrodysplasia secondary to a mutation in the RMRP gene. In addition to the metaphyseal chondrodysplasia and the short-limb dwarfism, patients may present with a multisystemic disease, associating immune deficiency with recurrent infantile or childhood infections, hematological abnormalities, and gastrointestinal dysfunction. The probability of malignancy is increased in these patients, as are disimmune manifestations. We report on a 12-year-old girl with a new mutation of the RMRP gene and a severe multisystemic CHH (hematological and pulmonary lesions, severe immune deficiency, arthritis, pancreatic insufficiency, malabsorption, chronic diarrhea) receiving parenteral nutrition who presented with acute symptomatic hypocalcemia and hypercalciuria associated with the presence of autoantibodies directed against the calcium-sensor receptor. At the same time, there was an important escalation of diarrhea. Corticosteroids led to a progressive improvement of biological signs (hypocalcemia, hypoparathyroidism). By contrast, gastrointestinal symptoms and malabsorption did not improve. To our knowledge, this is the first report of autoimmune hypoparathyroidism in CHH.

The aim of this study was to investigate the influence of age at disease onset in the outcome of paediatric SLE (pSLE).Fifty-six patients with pSLE, divided into three groups (pre-pubertal, peripubertal and post-pubertal onset), were studied. The SDI (SLICC/ACR Damage Index for SLE), patients' characteristics, disease manifestations and treatments were compared using Fisher's exact test and Kruskal-Wallis test. Kaplan-Meier curves were constructed to compare the risk of damage occurrence.The risk of damage (SDIor=1) significantly decreased when age at disease onset increased (89% in pre-pubertal pSLE, 57% in peripubertal pSLE and 38% in post-pubertal pSLE). This excess of risk was found in all disease duration intervals studied (1-3, 3-5, 5-8, 8-10,10 years) and at the end of follow-up. Kaplan-Meier curves indicated a higher and earlier risk of damage in younger patients. Young children showed higher frequency of autoimmune family history. The frequency of neuropsychiatric disorders and damages decreased with age at disease onset (P0.05). Cumulative duration of high-dose prednisone (0.5 mg/kg/day) and number of immunosuppressive drugs used that seem to contribute to damage significantly increased when age at disease onset decreased.The risk of damage is inversely correlated with age at disease onset in pSLE. The poorer outcome observed in younger children may be explained by a more severe disease expression, may be a higher infectious susceptibility, and a more aggressive therapy, particularly within the first 6 months of disease course.

Our objective was to evaluate the prevalence of autoantibodies to cyclic citrullinated peptides (anti-CCP aAbs) in a cohort of patients with a variety of inflammatory or non-inflammatory rheumatic diseases other than rheumatoid arthritis (RA). Six hundred and nine serum samples were tested for anti-CCP aAbs and for rheumatoid factor (RF) using enzyme-linked immunosorbent assays and immunonephelometry. The prevalence of anti-CCP aAbs and RF reached 10% and 25%, respectively, using the positive cutoff value suggested by the manufacturers. Using a higher cutoff value (50 U/ml) for both aAbs, the prevalence was lower with 6% and 16%, respectively. The specificity of both markers for RA thus reached 94% and 84%, respectively. Anti-CCP aAbs were found to be elevated in inflammatory and also in non-inflammatory rheumatic diseases in the same proportion. Clinical data obtained for 36 positive patients showed that 17% developed RA within 5 years. In conclusion, anti-CCP aAbs are clearly more specific than RF for RA. Follow-up of anti-CCP aAbs-positive patients with inflammatory or non-inflammatory rheumatic diseases other than RA could be important considering the predictive value of these aAbs for the development of RA.

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Objective: Diabetes is clinically classified into two types: type 1 (T1D) and type 2 diabetes (T2D). Nevertheless, intermediate forms of diabetes are frequent and difficult to recognize and manage appropriately. In this study, we investigated whether patients with intermediate form of diabetes, here called unclassified diabetes (UD), have β-cell autoimmune markers. Research design and methods: β-cell autoimmune markers (β-cell autoantibodies (aAb), peripheral blood mononuclear cells (PBMC) responsive to five islet proteins, cytokine secretion, and human leukocyte antigen (HLA)-DQB1 genotypes) were analyzed in 50 UD patients, 23 age- and HLA-matched normal control subjects, and 23 classic T2D patients. Results: We observed that 16 out of 50 (32%) UD patients demonstrated responsive PBMCs, as opposed to 1 out of 23 (5%) age- and HLA-matched normal control subjects, and 0 out of 23 classic T2D patients. Overall, 29 (58%) UD patients had at least one marker of β-cell autoimmunity (β-cell aAb and/or PBMC autoreactivity), in association with high-risk HLA genotypes DQB1*0201 and/or DQB1*0302. Moreover, the 13 (26%) UD patients who had β-cell aAb were not the same as those with PBMC autoreactivity, except for one patient. Patients with PBMC autoreactivity were older at the onset of the disease and had a better residual β-cell function than those with β-cell aAb. Conclusions: Our data confirm that T-cell autoimmunity can be detected in latent autoimmune diabetes in adults patients. We show an inverse correlation between humoral and cellular β-cell autoimmunities. Possible protective cellular responses in the patients with β-cell PBMC autoreactivity could have potential therapeutic implications.

An association between autoimmunity and hematological malignancies has been reported including the detection of antinuclear autoantibodies (ANAs) in patients suffering from non-Hodgkin's lymphoma (NHL), with a high prevalence of ANAs directed to components of the mitotic apparatus or the mitosis-associated proteins. Previous studies have demonstrated that one of the targets of such ANAs could be the CENP-F protein, especially in some carcinomas. The prevalence and specificity of anti-CENP-F autoantibodies (aAbs) thus were analyzed in 347 patients with different histological subgroups of NHL before any treatment of NHL, along with 150 controls. The detection of these aAbs was performed using two techniques: a radioimmunological assay (RIA) and an indirect immunofluorescence technique (IIF). Twenty-five (7.2%) NHL patients and 2 (1.3%) control patients displayed anti-CENP-F aAbs using RIA. This difference between the two groups was found to be significant (P < 0.01), with a higher prevalence of aAbs in the follicular (13%) and in the marginal zone B and MALT (10.2%) lymphoma subgroups. By IIF, 10 (2.9%) patients with NHL displayed aAbs with a CENP-F or CENP-F-like pattern, whereas none of the control group did. In conclusion, these data demonstrate that a significant incidence of anti-CENP-F aAbs is observed, before any treatment, in some histological subgroups of NHL patients. In addition to the usefulness of anti-CENP-F aAbs as a marker for some NHL subgroups, prospective studies may be important to evaluate the predictive value of anti-CENP-F aAbs for the development of carcinomas.

We investigated the presence of autoantibodies (aAbs) directed against the parathyroid gland in 17 patients with spontaneous isolated acquired hypoparathyroidism. Fourteen patients with acquired hypoparathyroidism (AH) associated with type I or II autoimmune polyendocrinopathy syndrome were also tested in comparison with a control group of 68 subjects without AH, including patients with other autoimmune diseases and healthy blood donors. aAbs against parathyroid tissue were screened using an indirect immunofluorescence technique on primate parathyroid tissue and human parathyroid adenoma. aAbs against the calcium-sensing receptor (CaSR) were analyzed using an immunoblotting assay with the recombinant extracellular domain of the human CaSR as antigen. Seven of the 31 patients with AH were positive for CaSR aAbs. Five of the positive sera were obtained from the group with isolated AH. The two other positive sera were from patients with autoimmune polyendocrinopathy syndrome. The sensitivity of the immunoblotting technique was higher than that of both the radioimmunological test using the extracellular domain of the CaSR and the indirect immunofluorescence technique. There were no positive sera in the control group. In conclusion, using an immunoblotting assay, we demonstrate the presence of CaSR aAbs in about one third of the patients with isolated AH, pointing out the value of detecting such aAbs to assess the autoimmune origin of the disease.

Introduction Les auto-anticorps anti-Glutamic acid decarboxylase 65 (GAD65-Ac) sont observes chez les patients presentant un diabete auto-immun et a taux tres eleves dans 3 grands syndromes neurologiques (SN) rares que sont le Stiff-Person syndrome (SPS), un sous type d’ataxies cerebelleuses (AC) et certains patients presentant des encephalites limbiques (EL). Les EL auto-immunes sont rares et se definissent par l’apparition subaigue d’un deficit de la memoire a court terme, de crises d’epilepsie ou de troubles comportementaux associes a une inflammation mesiotemporale constatee a l’IRM et sur la ponction lombaire. Neanmoins, cette definition large peut donner lieu a de nombreuses variations en fonction des auto-anticorps associes et la semiologie est mal decrite pour les patients presentant des GAD65-Ac. Dans un but de clarification, nous avons revu systematiquement tous les troubles cognitifs associes a des taux eleves de GAD65-Ac. Resultats De janvier 1993 a janvier 2016, nous avons identifie 85 patients avec un syndrome neurologique associe a un titre eleve de GAD65-Ac dans le serum ou le liquide cephalorachidien (LCR). Sur ces 85 patients, 11 ont ete exclus du fait d’un manque d’information clinique. Sur les 74 restants, 40 presentaient des troubles pour lesquels une EL avait ete discutee. Sur ces 40 patients, 16 presentaient des troubles definissant une EL associant un debut subaigu, une confusion, des troubles du comportement, des crises d’epilepsie et une amnesie anterograde. Il est a noter que 4 d’entre eux avaient une symptomatologie initiale particuliere avec de courts episodes d’amnesie isolee repetes et intercales de periode de recuperation complete. Ces 16 EL typiques etaient generalement isolees sauf chez un patient presentant egalement un Stiff-person syndrome. L’âge median etait de 30 ans (extremes : 6–63) et le suivi median de 4,75 ans (extremes : 0,4–18). L’evolution de ces EL a ete favorable dans un premier temps dans la majorite des cas, mais 12/16 patients gardaient des sequelles cognitives dont 6 ont installe progressivement une aggravation des troubles de memoire. Tous presentaient une epilepsie sequellaire. A cote de ces 16 patients, 21 n’ont presente que des crises d’epilepsie pendant plusieurs mois ou annees. Cette epilepsie etait d’origine temporale dans la majorite des cas (20 patients) et debutait avec une mediane de 30 ans (extremes : 10–72). Elle se manifestait le plus souvent par des crises partielles complexes avec des generalisations secondaires frequentes. Malgre l’instauration d’un traitement antiepileptique adapte, cette epilepsie restait pharmacoresistante pour 15 patients et la frequence moyenne des crises restait elevee avec au moins une crise par mois. Il est interessant de noter que parmi les 6 patients qui presentaient une epilepsie benigne non pharmacoresistante, 5/6 avait un autre trouble neurologique associe (4 AC et 1 SPS) alors qu’il n’y en avait que 4/15 dans le groupe pharmacoresistant. L’evolution de ces 21 patients epileptiques a ete marquee chez un tiers des patients (7 cas) par l’installation de troubles de memoire progressifs survenant avec une mediane de 5 ans apres le debut des crises (0,6 a 23). Ces 7 patients presentaient une inflammation mesiotemporale sur l’IRM initiale alors qu’elle n’etait observee que chez 2/14 patients epileptiques sans troubles de memoire. Par contre, l’inflammation du LCR (pleiocytose et bandes oligoclonales), la frequence des crises ou la pharmacoresistance n’etaient pas plus frequentes chez ces 7 patients par rapport aux 14 autres. A cote de ces 2 groupes, 3 patients, deux femmes et un homme, de plus de 55 ans ont presente une demence progressive. Tous etaient connus pour une ataxie cerebelleuse associee a des GAD65-Ac. Fait interessant, ces troubles mnesiques etaient associes a une inflammation temporale a l’IRM chez deux patients et a une inflammation du LCR chez l’ensemble de ces patients (bandes oligoclonales). Conclusion Notre travail permet de conclure qu’il existe plusieurs modes d’apparition de troubles cognitifs associes a la presence de GAD65-Ac et que les tableaux cliniques ne se limitent pas a une EL classique. Des troubles plus progressifs sont possibles et les hypersignaux FLAIR mesiotemporaux pourraient etre un facteur de risque majeur necessitant la mise ne place d’un traitement immunomodulateur plus agressif.

Introduction La detection des auto-anticorps specifiques ou associes a la sclerodermie systemique (SSc) est une aide importante au diagnostic et au pronostic. Les auto-anticorps anti-fibrillarine (AFA) sont decrits comme etant rares, avec des prevalences variables selon les series. Du fait de leur rarete (5 a 10 % des patients), le spectre clinique associe est mal connu. Le but de cette etude est de decrire la frequence et les manifestations cliniques des AFA dans la SSc. Materiels et methodes Nous avons conduit une revue systematique sur Pubmed (1990–juillet 2017). Une meta-analyse de la prevalence des AFA et des atteintes d’organes a ete realisee. Les frequences des manifestations associees aux AFA ont ete comparees a celles des autres auto-anticorps (anti-Scl70, anti-centromere, anti-PM/Scl, anti-RNA pol III, anti-Ku, anti-Th/To). En cas d’heterogeneite significative (I2 > 50), un modele a effet aleatoire a ete utilise. Les intervalles de confiance (IC) sont estimes a 95 %. Resultats Au total, 21 etudes totalisant 10 146 patients ont ete incluses. La prevalence des AFA etait de 3,9 % (IC 2,3–6,4, I2 = 99 %), avec des variations importantes en fonction des pays (Australie 0,4 %, IC 0,0–5,8 ; Etats-Unis 9,3 %, IC 3,6–21,9). Les patients AFA positifs presentaient majoritairement une SSc cutanee diffuse (53 %, IC 33–45, I2 = 30 %). Les manifestations les plus frequentes associees aux AFA etaient l’atteinte articulaire (56 %, IC 24–84, I2 = 89 %), la pneumopathie interstitielle diffuse (37 %, IC 19–59, I2 = 89), l’atteinte musculaire (31 %, IC 25–36, I2 = 71), l’hypertension arterielle pulmonaire (22 %, IC 17–27, I2 = 12) et l’atteinte cardiaque (17 %, IC 24–84, I2 = 89). Les patients avec AFA avaient plus souvent une atteinte cutanee (OR 2,24, IC 1,38–3,64), excepte pour les patients anti-Scl70. L’atteinte articulaire chez les patients avec AFA etait plus frequente que chez ceux sans AFA (OR 2,05, IC 1,01–4,17), surtout chez les patients positifs pour les anti-centromere (OR 4,63, IC 2,09) ou les anti-Th/To (OR 5,32, IC 2,31–13,28). L’atteinte musculaire etait plus prevalente chez les patients avec AFA comparativement a ceux avec des anti-Scl70 (OR 2,53–1,30–4,94) et anti-Th/To (OR 3,33, IC 1,07–10,31). Conclusion La prevalence des AFA est faible, de l’ordre de 4 %, avec des variations importantes selon les series. Les patients avec AFA sont plus frequemment atteints d’une SSc cutanee diffuse. Les manifestations arthromusculaires et pulmonaires sont au premier plan chez ces patients.

To assess the specificity of autoantibodies (aAbs) directed against the ribosomal P-proteins (RPPaAbs) in patients with systemic lupus erythematosus (SLE) and to investigate aAbs directed to other ribosomal proteins, 100 SLE, 100 rheumatoid arthritis (RA), 25 thyroiditis and 20 blood-donors were analyzed in a comparative study using an immunoblotting technique. Forty-eight percent of SLB sera contained aAbs directed against the ribosomal proteins of the 60 S subunit compared to 9% for RA, 5% for blood donors and 0% for thyroiditis. RPPaAbs were only found in SLE (25%) and aAbs directed to a 31 kDa and/or a 28 kDa protein of the 60 S subunit were found with a statistically higher frequency for SLE compared to RA (p < 0.0001). aAbs directed to proteins of the 40 S subunit were present in 63% of the SLE sera compared to 42% for RA, 4% for thyroiditis and 5% for blood donors. The number of positive sera was not statistically different between SLE and RA but a much more intense reactivity was observed for SLE sera. These data shows that the aAbs against the ribosomal proteins, especially the P-proteins along with the 28 and 31 kDa proteins of the 60 S subunit proteins, can be considered as useful biological markers for t he diagnosis of SLE inclinical practice.To assess the specificity of autoantibodies (aAbs) directed against the ribosomal P-proteins (RPPaAbs) in patients with systemic lupus erythematosus (SLE) and to investigate aAbs directed to other ribosomal proteins, 100 SLE, 100 rheumatoid arthritis (RA), 25 thyroiditis and 20 blood-donors were analyzed in a comparative study using an immunoblotting technique. Forty-eight percent of SLB sera contained aAbs directed against the ribosomal proteins of the 60 S subunit compared to 9% for RA, 5% for blood donors and 0% for thyroiditis. RPPaAbs were only found in SLE (25%) and aAbs directed to a 31 kDa and/or a 28 kDa protein of the 60 S subunit were found with a statistically higher frequency for SLE compared to RA (p < 0.0001). aAbs directed to proteins of the 40 S subunit were present in 63% of the SLE sera compared to 42% for RA, 4% for thyroiditis and 5% for blood donors. The number of positive sera was not statistically different between SLE and RA but a much more intense reactivity was observed for SLE sera. These data shows that the aAbs against the ribosomal proteins, especially the P-proteins along with the 28 and 31 kDa proteins of the 60 S subunit proteins, can be considered as useful biological markers for t he diagnosis of SLE inclinical practice.

We read with interest the article by Jackson et al. (1) illustrating mild insulitis in the pancreas of a 28-year-old lean Hispanic female with recent gestational diabetes mellitus (GDM) who died of anoxic encephalopathy of unknown etiology 32 days after cesarean delivery. She was positive for GAD antibody (GADA) and islet cell antibody, while autoantibodies against insulin, IA-2, and zinc transporter 8 (ZnT8A) were negative. This observation, as well as earlier studies (2), raises a possible role of …

The association of positive cytoplasmic antineutrophil antibody (ANCA) necrotizing crescentic glomerulonephritis with endocarditis raises diagnostic issues. Indeed, it is often difficult to determine if the kidney injury is either secondary to an infectious disease or caused by an ANCA-associated small vessel vasculitis. We report a 59-year-old man admitted in nephrology for acute glomerular syndrome in whom the renal biopsy showed a crescentic necrotizing glomerulonephritis. A diagnosis of vasculitis was initially considered in the presence of high titer of ANCA (anti-proteinase 3). Because of associated Staphyloccocus aureus endocarditis the patient received both corticosteroids and antibiotics that allowed remission of both kidney injury and endocarditis. The renal presentation and the disappearance of ANCA support the infectious etiology of this glomerulonephritis rather than an ANCA-associated small vessel vasculitis. It is important to be cautious in the presence of ANCA positive extracapillary glomerulonephritis and endocarditis should be ruled out before initiation of corticosteroids that may be nevertheless necessary in severe acute glomerulonephritis.

Oral administration of antigens has been proposed in the prevention and treatment of autoimmune diseases. We reported that oral administration of 0.8 mg of recombinant human insulin to 6-week-old NOD mice every other day for a month generated regulatory T-cells that were able to reduce the severity of insulitis and the percentage of clinical diabetes in naive irradiated recipients when co-injected with diabetogenic T-cells. In the present study, immunohistochemical analysis of the pancreatic glands revealed that injection of T-cells from insulin-fed mice upregulated the number of interleukin (IL)-4-secreting cells within the islets. Using two strains of NOD mice congenic at the Theta, or Thyl, locus, we observed a higher proportion of T-cells from insulin-fed mice in both the spleen (7.73 ± 0.3 vs. 5.57 ± 0.2%; P < 0.001) and the pancreatic lymph nodes (10.1 ± 0.8 vs. 7.2 ± 0.7%; P < 0.05) of cotransferred mice. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, mice reconstituted with T-cells from insulin-fed animals had detectable amounts of IL- 4 mRNA, specifically in the pancreatic lymph nodes (8 of 9 experimental mice vs. 1 of 9 control mice) and the pancreas (3 of 3 experimental mice vs. 0 of 3 control mice). γ-Interferon mRNA was detectable in all cotransferred animals, but IL-10 mRNA and transforming growth factor β mRNA were undetectable. These results suggested a shift from a T-helper 1 (Thl) to a Th2 pattern of cytokine expression and underlined the role of pancreatic lymph nodes in the protection. Repeated injections of 500 ug s.c. of anti-IL-4 monoclonal antibody led to an accentuation of the severity of islet infiltration and to the development of clinical diabetes. We concluded that oral administration of insulin can induce the presence of regulatory T-cells in the pancreas and the corresponding draining lymph nodes, initiate the secretion of IL-4 in this microenvironment sufficiently to suppress the activity of Thl autoreactive T-cell clones, and ultimately provide protection against autoimmune diabetes.

International audience; Objective: To describe the clinical spectrum associated with aminoacyl-transfer RNA synthetase (ARS) autoantibodies in patients with idiopathic inflammatory myositis defined according to Peter and Bohan's criteria. Methods: Cohort studies were selected from MEDLINE and Embase up to August 2013. Two investigators independently extracted data on study design, patient characteristics, and clinical features (interstitial lung disease [ILD], fever, mechanic's hands [MH], Raynaud's phenomenon [RPh], arthralgia, sclerodactyly, cancer and dermatomyositis-specific rash) according to the presence of myositis-specific (anti-aminoacyl-transfer RNA synthetase [ARS], anti-signal recognition particle [anti-SRP] and anti-Mi2) and myositis-associated (anti-PM/Scl, anti-U1-RNP and anti-Ku) autoantibodies. Results: 27 studies (3487 patients) were included in the meta-analysis. Arthralgia (75%, CI 67-81) and IW (69%, CI 63-74) were the most prevalent clinical signs associated with anti-ARS autoantibodies. Anti-Mi2 and anti-SRP autoantibodies were associated with few extramuscular signs. ARS autoantibodies were identified in 13% of patients with cancer-associated myositis (5-25). Patients with non-anti-Jo1 ARS had greater odds of presenting fever (RR 0.63, CI 0.52-0.90) and ILD (RR 0.87, CI 0.81-0.93) compared to those with anti-Jol autoantibodies. The frequencies of myositis (RR 1.60, CI 1.38-1.85), arthralgia (RR 1.52, CI 1.32-1.76) and MH (RR 1.47, CI 1.11-1.94) were almost 50% higher in patients with anti-Jo1 compared to non-anti-Jo1 ARS autoantibodies. Patients with anti-PM/Scl differed from those with anti-ARS autoantibodies by a greater prevalence of RPh (RR 0.70, CI 0.53-0.94) and sclerodactyly (RR 0.47, Cl 025-0.89). IID was less frequent in patients with anti-Ul-RNP autoantibodies (RR 3.35, CI 1.07-10.43). No difference was observed between anti-ARS and myositis-associated autoantibodies for other outcomes. Conclusions: The presence of anti-ARS autoantibodies delimits a heterogeneous subset of patients with a high prevalence of myositis, MH, arthralgia in anti-Jo1 patients, and RPh and fever in non-anti-Jo1 patients. The clinical signs of populations positive for anti-PM/Scl and anti-ARS autoantibodies largely overlap, especially with regard to ILD, challenging the clinical delimitation of the antisynthetase syndrome.

Objectives The aims of our study were to compare in a cohort of 705 patients the diagnostic performance of two tests to detect autoantibodies to cyclic citrullinated peptides (CCP) and to determine whether a bead-based assay within a multiplex flow immunoassay (MFA) can be used instead of an enzyme linked immunosorbent assay (ELISA) technique in routine practice. Design and methods Six hundred and thirty patients with rheumatic symptoms and 75 patients with systemic lupus erythematosus (SLE) were tested for anti-CCP autoantibodies using two techniques: ELISA (Inova) and MFA (BioPlex®, Bio-Rad). Results Using kappa coefficient, there was an excellent agreement between ELISA and MFA when comparing 630 patients with rheumatic symptoms (κ coefficient, 0.82). In this cohort 174 patients were identified as suffering from RA, while 456 patients suffered from other diseases. Sensitivity and specificity values of anti-CCP autoantibodies for RA were 70.7% and 92.3% for ELISA and 64.4% and 92.8% for MFA. The positive and negative predictive values were 77.4% and 89.2% for ELISA and 77.2% and 87.2% for MFA, respectively. There were no differences in the diagnostic performances between the two assays (Z = 0.67). The specificity values of anti-CCP autoantibodies analysing patients with SLE were 97.3% with MFA and 96% with ELISA with an excellent agreement between the methods (98.7%; κ coefficient, 0.79). Conclusion Concordance between ELISA and MFA is high in routine practice. Overall, MFA is a powerful tool for rapid assessment of anti-CCP autoantibodies and can replace the ELISA technique, which could be used as a second-line test in some cases.

We have previously demonstrated that feeding six-week-old female mice with 20 units of human insulin every 2 - 3 days for 15 or 30 days induced an active mechanism of suppression through the generation of regulatory T cells that reduced the number of successful diabetic transfers in irradiated NOD recipients. In the present study, we analyzed the effects of antigen dosage and the critical period of cell injection to obtain protection. The effects of the dose of insulin feeding were therefore compared during cotransfer experiments of 5 x 10(6) T cells from diabetic mice and 5 x 10(6) T cells from the spleen of mice receiving 10 units, 20 units, or 40 units of insulin or saline every 2 - 3 days for 15 days. Only T lymphocytes from mice fed with 20 units conferred active cellular protection during adoptive transfer with a significant delay in diabetes onset (p = 0.002). No significant difference was noticed during histological analysis of pancreatic glands, indicating tha insulitis was not prevented. However, mice receiving T lymphocytes from the 20 units of insulin-fed animals had a milder form of inflammation, with a significantly lower percentage of severely infiltrated islets. Injecting regulatory T cells 7 days and 14 days after iv injection of diabetogenic T cells did not modify the incidence curves of diabetes in the recipients, suggesting that cellular interactions and delay in cell trafficking were determinants. These results may have important clinical implications in humans. In conclusion, this study indicates the importance but also the limits of antigen therapy in type I diabetes. Antigen dosage is a critical element for active suppression. Such analysis is important to perform in humans before the initiation of a large-scale prevention trial in prediabetic individuals.

Objective.To compare anti-PM/Scl autoantibody-associated interstitial lung disease (ILD) with anti-aminoacyl-tRNA synthetases (anti-ARS) autoantibody-associated ILD.Methods.We retrospectively studied 21 patients with ILD from a department of respiratory medicine, including 9 with anti-PM/Scl autoantibodies (6 women, median age 55 yrs, followup 5.5 yrs) and 12 with anti-ARS autoantibodies (6 women, median age 59 yrs, followup 2.3 yrs).Results.Pulmonary manifestations in patients with anti-PM/Scl autoantibody-associated ILD usually followed the extrapulmonary manifestations of the connective tissue disease (CTD) (7/9 cases). The predominant imaging features on initial high resolution computed tomography were ground-glass attenuation and reticular opacities, and mainly suggested nonspecific interstitial pneumonia in both groups. CTD was classified as dermatomyositis (DM; 2), undifferentiated CTD (2), cutaneous limited systemic sclerosis (2), rheumatoid arthritis (RA; 1), and overlap syndrome (1) in the anti-PM/Scl group; and polymyositis (4), undifferentiated CTD (5), DM (1), amyopathic DM (1), and RA (1) in the anti-ARS group. Frequencies of arthralgia, Raynaud phenomenon, cutaneous rash, and mechanic’s hands were comparable in both groups. Myalgia or muscle weakness was present in 0/9 PM/Scl and 5/12 ARS patients (p < 0.05). More than 1 autoantibody was present in 11 patients. ILD worsened despite treatment in 4 patients with anti-PM/Scl autoantibodies and 2 with anti-ARS autoantibodies, and included 1 death.Conclusion.Anti-PM/Scl and anti-ARS antibodies are associated with similar clinical manifestations, with the exception only of more overt myositis in the latter, therefore challenging the clinical specificity of the antisynthetase syndrome.

Background Mutations in the extracellular calcium-sensing receptor ( CaSR ) gene are known to be implicated in some cases of primary hyperparathyroidism. However, not all patients display such mutations and so the mechanisms of primary hyperparathyroidism are still largely unknown. An autoimmune origin has been suggested, as autoantibodies against the CaSR have been detected in some patients. The aim of our study was to investigate the presence of CaSR autoantibodies in a large cohort of patients with primary hyperparathyroidism. Methods Seventy-five patients were tested for the presence of anti-parathyroid antibodies using an immunoblotting assay with the recombinant extracellular domain of the human CaSR and an immunofluorescence technique with parathyroid adenoma. Results Five of 75 (6.7%) patients had CaSR autoantibodies. There was no statistically significant difference in the decrease of parathyroid hormone (PTH) level after surgery between patients with or without autoantibodies. Histological examination of parathyroid tissue did not show greater lymphocytic infiltration in patients with autoantibodies than in those without. Conclusions This study confirmed that some patients with primary hyperparathyroidism displayed CaSR autoantibodies. The pathophysiological role of these autoantibodies in hyperparathyroidism needs to be further elucidated.

Autoimmune hypercalcemia has been reported in only a few cases, and never in the context of autoimmune polyglandular syndrome. A patient with type 1, insulin-dependent diabetes mellitus, Graves' disease, and antiparietal cell antibodies presented with persistent hypercalcemia with inappropriate PTH secretion. Other causes of hypercalcemia were excluded. In this context of two associated organ-specific autoimmune diseases we searched for autoantibodies directed to parathyroid tissue and to calcium-sensing receptor. Anti-parathyroid autoantibodies were detected by indirect immunofluorescence on parathyroid adenomas, and autoantibody against a peptide of the extracellular domain of the calcium-sensing receptor were detected by immunoblotting. Autoimmune hypercalcemia may be another organ-specific feature of autoimmune polyglandular syndrome.

International audience

Introduction Parmi les auto-anticorps (AA) antinucleaires (ANA), les AA anti-SS-A 60 kDa et anti-SS-B sont associes aux connectivites, et notamment au syndrome de Gougerot-Sjogren (SGS), au lupus systemique (LS), et aux myosites inflammatoires idiopathiques (MII). La presence des AA anti-SS-B est fortement associee aux anti-SS-A, les patients porteurs d’anti-SS-B etant toujours positifs pour les deux AA. Les AA anti-SS-A sont parfois isoles dans 20 % des SGS. Cependant, la valeur clinique des AA anti-SS-B sans anti-SS-A, n’a jamais ete decrite. L’objectif de l’etude est d’etudier la frequence et le spectre clinique des patients AA anti-SS-B isoles. Patients et methodes Les patients presentant un des deux AA anti-SS-A et/ou SS-B detectes par technologie Luminex (Bioplex 2200, Biorad) ont ete inclus retrospectivement a partir de la base de donnees du laboratoire d’immunologie des Hospices Civils de Lyon entre janvier 2013 et 2014. Une extraction des donnees cliniques et biologiques a ete faite a partir des dossiers. Le diagnostic des connectivites etait pose selon les criteres internationaux. Les patients ont ete classes en deux groupes selon la presence d’une connectivite. La detection des anticorps antinucleaires a ete realisee par immunofluorescence indirecte sur cellules HEp 2. Les AA ont ete doses par fluorimetrie de flux ou immunonephelemetrie. Les comparaisons de moyenne ont ete faites par les tests de Student ou de Mann-Whitney, les comparaisons de proportion avec le test exact de Fisher. Resultats Mille cent soixante-treize patients avec AA anti-SS-A et/ou d’AA anti-SS-B positifs ont ete retrouves entre 2013 et 2014. 84 (7,2 %) etaient des AA anti-SS-B isoles (âge moyen 59 ans, 79 % de femmes). Un dosage anterieur ou posterieur avec des AA anti-SS-A positifs a ete retrouve chez 4 patients. Un second dosage des AA anti-SS-B etait negatif pour 2 patients. Pour 3 patients, aucune donnee clinique n’etait disponible. Un total de 75 patients a ete retenu pour l’analyse clinico-biologique. Dix-huit patients etaient porteurs de connectivite (5 LS, 5 PR, 3 SS, 2 MII, 2 SGS, 1 syndrome de Sharp). Les principaux symptomes retrouves etaient des arthralgies ou synovites (28 % des patients), et un syndrome de Raynaud (14,5 % des patients). Aucun patient n’avait une atteinte viscerale severe de LS, 4 patients avec SS (5 %) presentaient une pneumopathie interstitielle diffuse ou une hypertension arterielle pulmonaire. Aucun deces n’etait survenu pendant le suivi. 14 patients avaient une autre MAI (dont 2 vascularites a ANCA, 2 scleroses en plaque, 1 rhumatisme psoriasique, 1 sclerodermie localisee, 1 syndrome de Vogt-Koyanagi-Harada, 1 hepatite auto-immune, 4 non etiquetes), 4 patients avaient un cancer (3 lymphomes et 1 cancer pulmonaire), 20 patients n’avaient pas de diagnostic organique retenu, et 15 patients avaient une autre affection (glomerulonephrite aigue post-infectieuse, insuffisance renale aigue immunoallergique, maladie de Vaquez, sclerose laterale amyotrophique…). Parmi les 75 patients, 30 (40 %) avaient des ANA positifs a un titre superieur a 1/160 dont la fluorescence etait homogene pour 13 patients (17 %), mouchete pour 15 patients (20 %), centromere pour 2 patients (2,6 %). Etaient significativement correles a la presence d’une connectivite le titre des ANA (titre median 480 versus 0, p Conclusion Chez les patients porteurs d’anti-SS-A ou d’anti-SS-B, la prevalence des AA anti-SS-B isolee n’est pas rare et est estimee de 8 % dans notre serie. Seuls 24 % d’entre eux souffrent d’une connectivite, ce chiffre pouvant varier en fonction des habitudes de prescription locale. Les patients positifs avec AA anti-SS-B isoles souffrant de connectivite representent un groupe heterogene. Les diagnostics les plus frequents sont le LS et la PR. Aucun spectre clinique associe aux AA anti-SS-B isoles ne se degage de l’analyse de notre serie. La seule presence d’AA anti-SS-B et son titre n’apportent pas d’argument pour poser le diagnostic d’une connectivite. En revanche, le titre des ANA et la presence d’autres AA sont un facteur predictif de la presence sous-jacente d’une connectivite.

According to international criteria, autoimmune hepatitis (AIH) type 1 is characterized by the presence of antinuclear or anti-smooth muscle antibodies (SMA) with F-actin specificity. SMA have been found in 85% of AIH patients, but are not specific to this disease, and anti-F-actin specificity is not always verified when SMA are detected. The objective of this study was to determine the diagnostic value of anti-F-actin antibodies in a large population. A multicenter study involving 12 clinical centers was performed. Patients were selected on the basis of the presence of F-actin SMA detected by indirect immunofluorescence (IIF) on rat liver-kidney-stomach sections and was confirmed by IIF on Hep2 cells treated with colchicine, or F-actin dot-blot. The clinical status of patients was determined from their medical records. One hundred sixty-eight patients were included: 76% women, 24% men; mean age of 45 years (range, 2-88 years), with a bimodal age distribution. Sixty percent had AIH type 1, and 40% had another disease. In the group of women younger than 25 years, 90% had AIH type 1. Other pathologies associated with antiactin were other liver diseases (19%), including viral hepatitis C (7%), and non-liver diseases (21%), including connective tissue diseases (12%). Antibody titers were higher in AIH than in other diseases. Antiactin antibodies are of major diagnostic value in AIH, especially in young women; they may be found in other disease settings, but mostly at low levels.