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To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs.Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence).Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0-90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive "antigenic-specific test + immunofluorescence" and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p 0.001).SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses.

The link between paraneoplastic neurological syndromes (PNS) and renal cell and bladder cancer (RCC/BC) is rare and uncertain. Our aim was to clinically evaluate, in light of the updated PNS criteria, these uncommon associations.Retrospective nationwide cohort chart review study and systematic review of the literature.After excluding 5 patients due to the diagnosis of another co-occurrent malignancy, 10/18 patients with RCC and 8/18 patients with BC were identified. A total of 31 cases were previously published, yielding an overall series of 27/49 RCC and 22/49 BC patients. There was a predominance of cerebellar syndromes in both cancers (10/27, 37% for RCC; 9/22, 41% for BC), followed by encephalitis in 9/27 (33%) patients with RCC and encephalomyelitis/sensory neuronopathy in 5/22 (23%) patients with BC. The detection of high-risk Abs was more frequent among BC patients (16/19, 84% vs. 3/13, 23% in RCC, p = 0.0009), Ri antibodies being the most frequent thereof. After applying the updated PNS criteria, patients with BC met highest degrees (possible, probable, and definite) of certainty for PNS diagnosis (20/22, 91% vs. 16/27, 59% in RCC, p = 0.021).A second neoplasm should always be ruled out before establishing the diagnosis of PNS in patients with RCC or BC. However, while this association remains dubious for most patients with RCC, a casual role is more probable in patients with BC and high-risk antibodies presenting with cerebellar ataxia, brainstem encephalitis or encephalomyelitis/sensory neuronopathy.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease’s activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA.

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 (

Introduction Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p n = 23 paired samples). Conclusion CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Background The association between SARS-CoV-2 commercial serological assays and virus neutralization test (VNT) has been poorly explored in mild patients with COVID-19. Methods 439 serum specimens were longitudinally collected from 76 healthcare workers with RT-PCR-confirmed COVID-19. The clinical sensitivity (determined weekly) of 9 commercial serological assays were evaluated. Clinical specificity was assessed using 69 pre-pandemic sera. Correlation, agreement, and concordance with the VNT were also assessed on a subset of 170 samples. Area under the ROC curve (AUC) was estimated at 2 neutralizing antibody titers. Results The Wantai Total Ab assay targeting the receptor binding domain (RBD) within the S protein presented the best sensitivity at different times during the course of disease. The clinical specificity was greater than 95% for all tests except for the Euroimmun IgA assay. The overall agreement with the presence of neutralizing antibodies ranged from 62.2% (95%CI; 56.0–68.1) for bioMérieux IgM to 91.2% (87.0–94.2) for Siemens. The lowest negative percent agreement (NPA) was found with the Wantai Total Ab assay (NPA 33% (21.1–48.3)). The NPA for other total Ab or IgG assays targeting the S or the RBD was 80.7% (66.7–89.7), 90.3% (78.1–96.1), and 96.8% (86.8–99.3) for Siemens, bioMérieux IgG, and DiaSorin, respectively. None of the commercial assays have sufficient performance to detect a neutralizing titer of 80 (AUC Conclusions Although some assays show a better agreement with VNT than others, the present findings emphasize that commercialized serological tests, including those targeting the RBD, cannot substitute a VNT for the assessment of functional antibody response.

The ISO 15189 accreditation of biological analysis needs the validation of the analytical methods allowing the evaluation of their performance including all the factors that could influence the quality of their results. The field of autoimmunity includes many analyses and methods such as the indirect immunofluorescence technique (IIF) and the performance of this technique largely depends on the competency of staff members. For each staff member, the required levels of competency have to be precisely defined and evaluated after a period of formation before the final habilitation for the IIF technique. The French group of the international group called EASI (European autoimmunity standardisation initiative) proposes two habilitation forms to be filled with criteria, evidence and maintenance of target skills for the IIF preparation of slides and reading. These forms could be used as a model for the IIF formation and habilitation and have to be adapted to the routine practice of the laboratories.

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.

ObjectivesTo discover new and detect known antisynthetase autoantibodies (ASAs) through protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS).MethodsIP-MS was performed using sera of individuals showing features of antisynthetase syndrome (ASyS) without (n=5) and with (n=12) previously detected ASAs, and healthy controls (n=4). New candidate aminoacyl-tRNA-synthetase (ARS) autoantigens identified through unbiased IP-MS were confirmed by IP-western blot. A targeted IP-MS assay for various ASA specificities was developed and validated with sera of patients with known ASAs (n=16), disease controls (n=20) and healthy controls (n=25). The targeted IP-MS assay was applied in an additional cohort of patients with multiple ASyS features or isolated myositis without previously detected ASAs (n=26).ResultsAutoantibodies to cytoplasmic cysteinyl-tRNA-synthetase (CARS1) were identified by IP-MS and confirmed by western blot as a new ASA specificity, named anti-Ly, in the serum of a patient with ASyS features. Rare ASAs, such as anti-OJ, anti-Zo and anti-KS, and common ASAs could also be identified by IP-MS. A targeted IP-MS approach for ASA detection was developed and validated. Application of this method in an additional cohort identified an additional patient with anti-OJ autoantibodies that were missed by line and dot immunoassays.DiscussionCARS1 is the dominant cognate ARS autoantigen of the newly discovered anti-Ly ASA specificity. Rare and common ASA specificities could be detected by both unbiased and targeted IP-MS. Unbiased and targeted IP-MS are promising methods for discovery and detection of autoantibodies, especially autoantibodies that target complex autoantigens.

Objective: Dermatomyositis associated with anti-MDA5 autoantibodies (DM-MDA5+) is a rare autoimmune disease usually characterized by skin involvement, often-severe lung involvement, and general features. Several reports of infections have been described, sometimes early after the introduction of immunosuppressive therapy. We studied the infection risk in a DM-MDA5+ population. Methods: A retrospective cohort study comparing the number and type of infections during the follow-up of 19 patients with DM-MDA5+ and 37 patients with another type of inflammatory myopathy was analyzed. Patients in both groups were matched on initial immunosuppressive therapy. We described and compared significant infectious complications (SIC) in each group. Results: Patients DM-MDA5+ had more SIC: 27 events in the DM-MDA5+ group versus 6 in the controls (HR 7.08, 95% CI 2.50–20.04, p < 0.0001). The number of SIC per patient was higher in DM-MDA5+ (1.4 ± 1.57 vs. 0.16 ± 0.44, p < 0.001). These were mainly lung (n = 13, 48%) and skin infections (n = 6, 22%), more often infections of an undetermined infectious agent (n = 11, 41%) or of bacterial origin (n = 9, 33%). A few cases of opportunistic infections were reported. The median duration of follow-up without SIC event in the DM-MDA5+ cohort was 3.5 months. Conclusion: Patients with DM-MDA5+ have an increased infection risk compared to others inflammatory myopathies irrespective of immunosuppressive therapy exposure. These results highlight the importance of monitoring for infection during patient follow-up.

With the availability of vaccines, commercial assays detecting anti-SARS-CoV-2 antibodies (Ab) evolved towards quantitative assays directed to the spike glycoprotein or its receptor binding domain (RBD). The main objective of the present study was to compare the Ab titers obtained with quantitative commercial binding Ab assays, after 1 dose (convalescent individuals) or 2 doses (naïve individuals) of vaccine, in healthcare workers (HCW).Antibody titers were measured in 255 sera (from 150 HCW) with 5 quantitative immunoassays (Abbott RBD IgG II quant, bioMérieux RBD IgG, DiaSorin Trimeric spike IgG, Siemens Healthineers RBD IgG, Wantai RBD IgG). One qualitative total antibody anti RBD detection assay (Wantai) was used to detect previous infection before vaccination. The results are presented in binding Ab units (BAU)/mL after application, when possible, of a conversion factor provided by the manufacturers and established from a World Health Organization (WHO) internal standard.There was a 100% seroconversion with all assays evaluated after two doses of vaccine. With assays allowing BAU/ml correction, Ab titers were correlated (Pearson correlation coefficient, ρ, range: 0.85-0.94). The titer differences varied by a mean of 10.6% between Siemens and bioMérieux assays to 60.9% between Abbott and DiaSorin assays. These results underline the importance of BAU conversion for the comparison of Ab titer obtained with the different quantitative assays. However, significant differences persist, notably, between kits detecting Ab against the different antigens.A true standardization of the assays would be to include the International Standard in the calibration of each assays to express the results in IU/mL.

Anti-MDA5 dermatomyositis is a rare systemic autoimmune disease, historically described in Japanese patients with clinically amyopathic dermatomyositis and life-threatening rapidly progressive interstitial lung disease. Subsequently, the complete clinical spectrum of the disease was enriched by skin, articular and vascular manifestations. Depending on the predominance of these symptoms, three distinct clinical phenotypes with different prognosis are now defined. To date, the only known molecular component shared by the three entities are specific antibodies targeting MDA5, a cytosolic protein essential for antiviral host immune responses. Several biological tools have emerged to detect these antibodies, with drawbacks and limitations for each of them. However, the identification of this highly specific serological marker of the disease raises the question of its role in the pathogenesis. Although current knowledge on the pathogenic mechanisms that take place in the disease are still in their enfancy, several lines of evidence support a central role of interferon-mediated vasculopathy in the development of skin and lung lesions, as well as a possible pathogenic involvement of anti-MDA5 antibodies. Here, we review the clinical and biological evidences in favor of these hypothesis, and we discuss the contribution of emerging therapies that shed some light on the pathogenesis of the disease.

Background and ObjectivesTo clinically characterize post–immune checkpoint inhibitor (ICI) Hu antibody (Ab) neurologic disorders, we analyzed Hu-Ab–positive patients with neurologic immune-related adverse events (n-irAEs) and compared them with patients with other n-irAEs, ICI-naive patients with Hu-Ab paraneoplastic neurologic syndromes (PNSs) identified in the same study center, and those with Hu-Ab n-irAEs reported elsewhere.MethodsPatients whose samples were sent to the French reference center for a suspicion of n-irAE (2015–2021) were identified; those with a final diagnosis of n-irAE and Hu-Ab were included. Control groups included patients with a final diagnosis of n-irAE occurring during the same period as the patients included (2018–2021) but without Hu-Ab, and ICI-naive patients with Hu-Ab PNS diagnosed during the same period; a systematic review was performed to identify previous reports.ResultsEleven patients with Hu-Ab and n-irAEs were included (median age, 66 years, range 44–76 years; 73% men). Ten patients had small cell lung cancer, and 1 had lung adenocarcinoma. The median follow-up from onset was 3 months (range 0.5–18 months). Compared with those with other n-irAEs (n = 63), Hu-Ab–positive patients had more frequently co-occurring involvement of both central and peripheral nervous systems (36% vs 8%,p= 0.02) and limbic (54% vs 14%,p< 0.01), brainstem (27% vs 5%,p= 0.02), and dorsal root ganglia (45% vs 5%,p< 0.01) involvement. The proportion of patients with severe disability (modified Rankin Scale score >3) at diagnosis was higher among Hu-Ab n-irAEs (91% vs 52%,p= 0.02). Patients with Hu-Ab had also poorer outcome (100% vs 28%,p< 0.01) and higher mortality (91% vs 46%,p< 0.01). There was no significant difference in terms of clinical features between Hu-Ab n-irAEs and ICI-naive Hu-Ab PNS (n = 92), but there was a poorer outcome (56/78, 71%,p< 0.01) and higher mortality (26%,p< 0.01) among the former. No significant difference was found between the patients reported herein and those in the literature.DiscussionThe presence of Hu-Ab identifies a subgroup of n-irAEs that consistently reproduce the phenotypes of Hu-Ab-related PNS, supporting the hypothesis of ICI triggering or unmasking PNS. As these patients show high disability and mortality, further studies are required to investigate the underlying immunopathogenic mechanisms and to improve the outcome of Hu-Ab n-irAEs.

Background: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. Objectives: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. Methods: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. Results: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. Conclusions: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).

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.

The common co-occurrence of autoimmune systemic diseases in patients with neurological disorders and antibodies against glutamic acid decarboxylase 65 (GAD65) suggests a shared genetic predisposition to these disorders. However, the nature and frequency of familial aggregation of autoimmune diseases, which might also support this hypothesis, have been poorly investigated. Herein, an exploratory, interview-based study was conducted with the aim of describing the autoimmune diseases displayed by the relatives of GAD65 neurological patients, their frequency, kinship, and potential patterns of inheritance. Patients were enrolled only if they had GAD65 antibodies in the cerebrospinal fluid and typical clinical phenotypes associated with such antibodies (stiff-person syndrome, cerebellar ataxia, limbic encephalitis, or temporal lobe epilepsy). A total of 65 patients were included in the study, and 44/65 (67.7%) reported family history of autoimmunity, including first-degree relatives in 36/65 (55.4%); the sibling recurrence risk (λS) was 5.5, reinforcing the hypothesis of an underlying strong genetic predisposition. Most pedigrees with familial autoimmunity (38/44, 86.4%) showed multiple autoimmune diseases, all but 2 of them with diabetes mellitus or autoimmune thyroid disease, therefore resembling autoimmune polyendocrine syndromes. Inheritance patterns were diverse, possibly autosomal dominant in 17/44 (38.6%) pedigrees or autosomal recessive in 5/44 (11.4%), and un-defined or complex in 24/44 (54.5%). However, a total of 21/65 (32.3%) patients had no identified family history of autoimmunity. In conclusion, these results suggest a variable and heterogeneous genetic predisposition to GAD65 neurological disorders, possibly involving multiple loci and modes of inheritance with different contribution in each family.

ObjectivesWe evaluated widely-used SARS-CoV-2 serological tests and their potential association with virus neutralization test (VNT) in a cohort of mild COVID-19 patients.MethodsA total of 439 specimens were longitudinally collected from 76 healthcare workers with RT-PCR-confirmed mild COVID-19. Nine serological assays developed by leading global companies (Abbott, DiaSorin, Siemens, Bio-Rad, Wantai, bioMérieux, Euroimmun) were assessed. For each test the sensitivity to detect SARS-CoV-2 antibodies was determined weekly after symptom onset. Correlation and concordance were assessed using the Spearman and Cohen’s Kappa coefficients, respectively. Positive percent agreement and negative percent agreement (NPA) with the VNT were also determined.ResultsThe Wantai Total Ab assay targeting the receptor binding domain (RBD) within the S protein presented the best sensitivity at different times during the course of disease. The best correlation between antibody level and neutralizing antibody titer was found with the Euroimmun S1-based IgA assay (Spearman coefficient [95%CI]: 0.71 [0.61-0.79]). A moderate concordance (Kappa [95%CI]: 0.43[0.23-0.63]) as well as the lowest NPA (33%) was found between the Wantai Total Ab assay and the VNT. Compared to the Wantai Total Ab assay, other total Ab or IgG assays targeting the S or the RBD (bioMérieux, DiaSorin, Siemens,) were more concordant with the VNT (Kappa>0.7 for the three tests) and had a higher NPA (range: 90% to 97%).ConclusionsAlthough some assays presented a better concordance with VNT than others, the present findings emphasize that commercialized serological tests including those targeting the RBD cannot substitute VNT for the assessment of functional antibody response.

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.

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

Background Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition associated with systemic lupus erythematosus (SLE). Patients and Methods We conducted a multi-center retrospective study in order to describe the clinical, immunological, and histological presentations and outcomes of BSLE. The skin biopsies were centrally reviewed, and sera obtained during a flare of BSLE were analyzed for identification of circulating anti-basement membrane zone antibodies. Results Ten patients (all women, median age at SLE diagnosis of 22 years) were included, as well as 118 cases from a systematic review of the literature. Lupus nephritis was associated in 50% of the cases. BSLE presented as tensed bullae on normal or erythematous skin, predominantly localized on the trunk, arms, head and neck. Urticarial lesions were associated in 31% of the cases, and mucous membrane involvement was seen in 51%. Histological analyses displayed sub-epidermal detachment, dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclasis. The direct immunofluorescence was polymorphic, showing linear and/or granular deposits of IgG, IgA, IgM and/or C3. Anti-type VII collagen antibodies were detected in 69% of cases. Dapsone was efficacious in 90% of cases. Conclusion BSLE is an autoimmune neutrophilic blistering disease associated with SLE; it is not a cutaneous manifestation of lupus but may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.

Anti-neutrophil cytoplasmic antibodies (ANCA) are mainly searched for the diagnosis of autoimmune vasculitis. They may be found also in other conditions with chronic inflammation. Testing ANCA is based on two main technics: indirect immunofluorescence (IFI) and immunochemical technics to identify the antigenic specificity of the autoantibodies. There is heterogeneity among the laboratories' daily practice. An international group called EASI (European autoimmunity standardisation initiative), composed of 15 countries, comprising France, works to harmonize the practices of the biological diagnosis of the autoimmune diseases. It elaborated a survey consisting of 54 questions related to the analytic parameters of the technics, the algorithms for their use and their biological interpretation; and submitted it to European laboratories. We propose an analysis of the answers obtained from 36 French laboratories specialized in autoimmunity. We compare them to the ones obtained from the other countries and discussed them according to the international recommendations. The analysis reveals a predominant use of IFI as a first step with variable strategies for the identification of the antigenic specificity of the autoantibodies. Overall, the practices are chiefly conformed to the recommendations for the diagnosis of vasculitis, but they are less consensual when the ANCA are performed in other clinical situations.

Resume Objectif L’etude des formes pediatriques de lupus erythemateux systemique (LES) a permis recemment l’identification de formes monogeniques de LES. L’objectif principal de cette etude est de decrire les premiers patients inclus dans l’etude GENIAL/LUMUGENE et les comparer aux donnees de la litterature. L’objectif secondaire est d’identifier les patients a plus forte composante genetique sur une base clinico-biologique. Methodes L’etude GENIAL/LUMUGENE est une etude nationale clinique, immunologique et genetique des lupus a debut pediatrique ( clinical trial : NCT01992666 ). Les 64 premiers patients âges de moins de 18 ans inclus dans ce premier volet de l’etude ont fait l’objet d’un recueil retrospectif des donnees clinico-biologiques. Les sous-groupes ont ete determines a priori et definissent : (1) les lupus syndromiques ( n = 10), (2) les lupus familiaux ( n = 12) et (3) les autres formes de lupus precoces ( n = 42). Resultats La constitution de groupes de patients, a priori, sur la base des connaissances des signes cliniques ou epidemiologiques des lupus monogeniques identifie d’une part un âge au debut plus precoce dans les formes syndromiques ( p Conclusions Cette etude ne permet pas, sur la base des donnees cliniques et epidemiologiques seules, de determiner un sous-groupe de patient partageant une presentation ou une evolution commune. Cette observation peut etre liee au faible effectif ou temoigner de la grande heterogeneite des lupus juveniles. L’analyse de ces patients par les nouvelles techniques de sequencage pourrait identifier des elements de l’heredite responsable de cette variabilite importante.

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.

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01–DQB1*02:01–DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54–10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40–8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02–0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

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.

International audience; We report here the case of a 50-years-old man treated for mixed ă connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein ă (U1RNP) antibodies who secondarily developed a granulomatosis with ă polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil ă cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of ă the association between anti-U1RNP and anti-PR3-ANCA antibodies by a ă systematic retrospective study in ten European hospitals. Overall, out ă of 11,921 samples analyzed for both auto-antibodies, 18 cases of ă anti-U1RNP and anti-PR3-ANCA double positivity were found and only one ă patient presented with both MCTD and GPA symptoms. Our retrospective ă analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double ă positivity is infrequent and very rarely associated with both MTCD and ă GPA. Our observation describes for the first time the coexistence of ă MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP ă and ANCA antibodies was rarely reported in the literature. Eleven cases ă of MCTD and ANCA vasculitis have been reported to date, with only two ă cases with anti-PR3-ANCA association, and only one vasculitis. The seven ă other cases reported in the literature presented with an association of ă MCTD and microscopic polyangiitis which appears to be a more frequent ă presentation than MTCD associated with GPA.

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

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

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.

Background: Detection of anti-neutrophil cytoplasmic antibodies (ANCA) is important for the diagnosis of the ANCA-associated vasculitides (AAV). For AAV, especially ANCA directed against myeloperoxidase (MPO) and proteinase 3 (PR3) are most relevant. ANCA with less well-defined specificities may, however, also be detected in other inflammatory and non-inflammatory conditions. Methods: A questionnaire, initiated by the European Autoimmunity Standardisation Initiative (EASI), was used to gather information on methods and testing algorithms used for ANCA in clinical laboratories of 12 European countries (EASI survey). Results: Four hundred and twenty-nine responses were included in the EASI survey analysis which revealed differences within countries and between countries. Laboratories overall were poor in adherence to international consensus on ANCA testing. Substantial variation was observed with respect to the use of ANCA indirect immunofluorescence (IIF) in the algorithm, application of distinct methods for MPO- and PR3-ANCA, the daily availability of new ANCA results, and interpretation of test results. Conclusions: Awareness of these differences may stimulate further harmonization and standardization of ANCA testing. This may be promoted by an update of the international ANCA consensus and the introduction of international standards.

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.

Anti-NXP2 antibodies should be tested in patients with dermatomyositis, ILD and idiopathic inflammatory myopathies http://ow.ly/KiEMe

Objective: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease, assumed to occur due to a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. Here, our objective was to identify the cause of an autosomal recessive form of SLE. Methods: We investigated three siblings from one consanguineous kindred with juvenile-onset SLE and used next generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunological and functional assays to assess the impact of the identified mutations on B cell biology. Results: We identified a homozygous missense mutation in PRKCD, encoding protein kinase delta (PKC?) in all three affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKC?, involved in the deletion of autoreactive B cells, leading to a resistance to BCR- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKC?, which exhibit an SLE phenotype and B cell expansion, we observed an increase of immature B cells in affected patients, and a developmental shift toward an immature phenotype of na�ve B cells. Conclusion: Our findings indicate that PKC? is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKC? deficiency represents a novel genetic defect of apoptosis leading to SLE. � 2013 American College of Rheumatology.

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

Access to good quality biological samples is a prerequisite for highlevel translational research. The BIG-RENAPE Biobank has been established by the French hyperthermic intraperitoneal chemotherapy centers involved in the management of peritoneal surface malignancies. The Biobank is a core facility aiming to support researchers who conduct studies with sample collections, both within and outside the Big- RENAPE Network. The Biobank is certified according to NFS 96-900 and has been launched in February 2016 as a service of processing, storage and transfer of high quality biological (plasma, serum, buffy coat) and tissue (formalin-fixed-paraffin-embedded) samples from patients with digestive peritoneal carcinomatosis. Biospecimens are collected at each stage of diagnostic and therapeutic care. The patient and his derivates are anonymized and registered in a web database reporting disease status, treatments, surgical procedures, pathological diagnosis, quality of life’s assessment and long term follow-up. All participants have given their informed consent before any sample. The Biobank was approved by the local Ethical Committee, based on the assessed compliance to French regulatory rules. The Biobank is located in the Centre Hospitalier Lyon (SudBioTech), which is known to be an expert center in the management of the peritoneal carcinomatosis. Research projects that require material stored in the Biobank are submitted by specific form and evaluated by the BIG-RENAPE Scientific Committee. A material transfer agreement is agreed with the recipient before samples are allowed to be sent from the Biobank.