Publications by authors named "Nicole Fabien"

78 Publications

Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study.

J Neurol 2021 Feb 5. Epub 2021 Feb 5.

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France.

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 (λ) 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.
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http://dx.doi.org/10.1007/s00415-021-10424-wDOI Listing
February 2021

Evaluation of high-throughput SARS-CoV-2 serological assays in a longitudinal cohort of patients with mild COVID-19: clinical sensitivity, specificity and association with virus neutralization test.

Clin Chem 2021 Jan 5. Epub 2021 Jan 5.

CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.

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 nine 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 commercial assays have sufficient performance to detect a neutralizing titer of 80 (AUC<0.76).

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.
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http://dx.doi.org/10.1093/clinchem/hvaa336DOI Listing
January 2021

[Autoimmunity accreditation: training, accreditation and maintenance of skills in indirect immunofluorescence].

Ann Biol Clin (Paris) 2020 Dec;78(6):671-685

Service d'immunologie, UF auto-immunité, Hospices civils de Lyon, CHLS, Pierre-Bénite, France.

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.
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http://dx.doi.org/10.1684/abc.2020.1601DOI Listing
December 2020

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Nat Commun 2020 10 21;11(1):5341. Epub 2020 Oct 21.

Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 24 boulevard du Montparnasse, 75015, Paris, France.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.
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http://dx.doi.org/10.1038/s41467-020-18925-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578789PMC
October 2020

Anti-ZnT8 autoantibodies: A new marker to be screened in patients with anti-adrenal antibodies.

Clin Chim Acta 2020 Dec 16;511:1-6. Epub 2020 Sep 16.

Immunology Laboratory, Hospices Civils of Lyon, 69495 Pierre-Bénite, France. Electronic address:

Patients with autoimmune Addison's disease (AAD) can develop other autoimmune diseases. They often display autoantibodies other than anti-adrenal cortex autoantibodies (ACA) which could be of interest in predicting the development of other diseases such as type 1 diabetes (T1D). Among the well-established autoantibodies associated with T1D, anti-ZnT8 autoantibodies (ZnT8A) could be found in absence of anti-GADA and anti-IA2A. Thus, the aim of our study was to evaluate the prevalence of ZnT8A in a cohort of AAD patients. The presence of ZnT8A was studied in 36 patients (19 children and 17 adults) displaying ACA. ZnT8A were detected in both children and adults with an overall prevalence of 19%. The results also indicated that ZnT8A were associated with coexisting T1D in more than 70% of this population regardless of age. Even if the titer of ZnT8A for the one third of patients without T1D was low, they have to be followed due to the potential risk of developing T1D. ZnT8A in those cases could also be a marker of autoimmunity associated to the adrenal gland destruction in AAD. As ZnT8A screening has been included in the diagnostic investigation of T1D, it should also be incorporated in the autoantibodies screening panel of the AAD population.
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http://dx.doi.org/10.1016/j.cca.2020.09.019DOI Listing
December 2020

Transient Neurological Symptoms Preceding Cerebellar Ataxia with Glutamic Acid Decarboxylase Antibodies.

Cerebellum 2020 Oct;19(5):715-721

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France.

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.
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http://dx.doi.org/10.1007/s12311-020-01159-xDOI Listing
October 2020

DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity.

J Allergy Clin Immunol 2021 Feb 17;147(2):740-743.e9. Epub 2020 Jun 17.

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale (Inserm) UMR 1163, F-75015, Paris, France; Université de Paris, Imagine Institute, F-75015, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.05.052DOI Listing
February 2021

Precision of autoantibody assays in clinical diagnostic laboratories: What is the reality?

Clin Biochem 2020 Sep 4;83:57-64. Epub 2020 Jun 4.

Laboratoire d'Immunologie, Hôpital Européen Georges Pompidou, APHP, Paris, France; Université de Paris, Paris, France. Electronic address:

Background: ISO 15189 accreditation remains a challenge for specialized laboratories. In the field of autoimmunity, beside the crucial problem of absence of standardization, laboratories have to manage the analytical performances of the large panel of assays in terms of sensitivity and specificity, but also on their measurement precision for which no reference values are available on biorepositories.

Methods: As an initiative of the French EASI (European Autoimmunity Standardization Initiative) group, French clinical diagnostic laboratories were requested to participate in a survey aiming to analyze the coefficients of variation (CVs) of intra-run and inter-run variability obtained with assays quantifying 14 different autoantibodies. Two performance goals corresponding to the 90th percentile and the 50th percentile (lowest CV values reached by 90% and 50% of laboratories respectively) defined for three levels of concentration were calculated. The impact on the assay performances of the number of measurements, of the nature of the internal quality control (IQC) and the type of immunoassay, was also analyzed.

Results: 414 and 616 values of intra-run and inter-run CVs were collected, respectively. The 50th percentile performance goals were comprised between 1.0% and 8.9% for the intra-run CVs, and between 1.8% and 14.6% for the inter-run CVs. At 90th percentile, the performance goals were comprised between 3.2% and 13.5% for the intra-run CVs, and between 7.3% and 30.8% for the inter-run CVs. CVs calculated from 10 values were similar to those obtained from more values. Higher imprecision was observed when the antibody levels of the IQC was lower than 2 fold the positive threshold. Commercial IQCs gave lower CVs than IQCs derived from patient samples.

Conclusion: Our results allow proposing some acceptability limits for the precision performances of the autoantibody assays, compatible with the reality of life in diagnostic laboratories and clinical care.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.05.019DOI Listing
September 2020

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

Neurology 2020 07 2;95(1):e70-e78. Epub 2020 Jun 2.

From the Departments of Clinical Immunology and Internal Medicine (Y.A., S.T., G.L., B.H., N.C., K.M., O.B.), Immunobiology (M.M.), and Biostatistics, Public Health, and Medical Information (B.G.), Pitié-Salpêtrière Hospital, APHP, Sorbonne Universities; Myology Research Centre (Y.A., O.B.), INSERM, UMRS 974, Paris; Department of Pneumology (Y.U., H.N.), APHP, Avicenne Hospital, INSERM U1272, Université Sorbonne Paris Nord, Bobigny; Department of Internal Medicine (L.G., A. Marquet), Lyon Sud Hospital, Lyon Sud University, Paris; Reference Centre for Rare Autoimmune Diseases (A. Meyer) and Medical Intensive Care Unit, Hautepierre Hospital (V. Castelain), Hôpitaux Universitaires de Strasbourg, Strasbourg University; Division of Pneumology (R.B.), Bichat Hospital, AP-HP, Paris-Diderot University, Paris; Department of Pneumology (F.G., P.P.), Centre Hospitalier Universitaire, Angers University; Department of Internal Medicine Infectieuses (C.D.), CHU de Martinique, Fort de France; Departments of Internal Medicine and Clinical Immunology (S.A.) and Internal Medicine and Systemic Diseases (H.D.), François-Mitterrand University Hospital, University of Bourgogne-Franche-Comté, Dijon; Internal Medicine Department (B.T., A.B.), Cochin Hospital, AP-HP, René Descartes University, Paris; Department of Internal Medicine (C.G., N.L.), Henri Mondor Hospital, Paris Est Créteil University, Créteil, France; Department of Neurology (N.V.), Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Internal Medicine (E.D.), Hôpital Bretonneau Tours, Tours University; Internal Medicine Department (A.S.), Hôpital Robert-Debré, Reims University; Departments of Rheumatology (T.M.) and Internal Medicine (L.D.S.M.), Bretagne Occidentale University, Centre Hospitalo-Universitaire de Brest; Department of Internal Medicine (S.H.), CHU de Besançon; Department of Internal Medicine (C.B.-D.), Centre Hospitalier Général de Niort; Department of Internal Medicine (N.T.), Nice University, CHU Nice; Department of Internal Medicine (P.C.), Institut Mutualiste Montsouris, Paris; Department of Internal Medicine (M.G.), Jean Verdier Hospital, Paris Seine-Saint-Denis University, Bondy; Department of Internal Medicine (A. Mekinian), Saint Antoine Hospital, APHP, Sorbonne Universities, Paris; Department of Pneumology CHU (J.C.M.), Poitiers University; Department of Pneumology (A.T.), Hôpital Saint-Louis, APHP, Sorbonne Paris Cité, University Paris-Diderot, Paris; Department of Respiratory Medicine (V. Cottin), National Reference Center for Rare Pulmonary Diseases, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Lyon University; Department of Pneumology (D.I.-B.), European George Pompidou Hospital, APHP, Paris V University; Department of Pneumology (S.P.-H.), Sainte-Camille Hospital, Bry-sur-Marne; Department of Pneumology (C.B.), Foch Hospital, Saint Quentin en Yveline University, Suresnes; and Department of Immunology (N.F.), Lyon-Sud Hospital, Hospices Civils-de-Lyon, Pierre-Bénite, France.

Objectives: The 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.

Methods: To 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.

Results: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; < 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%; < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; < 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.

Conclusion: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.
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http://dx.doi.org/10.1212/WNL.0000000000009727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371381PMC
July 2020

Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3 T cells in a patient with IPEX syndrome.

Joint Bone Spine 2020 Oct 11;87(5):483-486. Epub 2020 May 11.

University Claude-Bernard Lyon 1, 69007 Lyon, France; Department of rheumatology, Lyon Sud hospital, hospices civils de Lyon, Pierre-Bénite, France; Inserm UMR1033, Lyon, France. Electronic address:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.
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http://dx.doi.org/10.1016/j.jbspin.2020.04.013DOI Listing
October 2020

Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes.

Neurol Neuroimmunol Neuroinflamm 2020 05 13;7(3). Epub 2020 Mar 13.

From the French Reference Center on Paraneoplastic Neurological Syndromes (B.D., S.M.-C., B.J., A.V., G.P., V.R., A.-L.P., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (B.D., S.M.-C., B.J., A.V., G.P., V.R., A.-L.P., V.D., J.H.), Institute NeuroMyoGène, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1; and Department of Immunology (B.D., C.L., N.F.), Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.

Objective: To 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.

Methods: Sera (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.

Results: PNS+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.

Conclusions: Immunodots 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 Evidence: The study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.
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http://dx.doi.org/10.1212/NXI.0000000000000701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136063PMC
May 2020

Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies.

J Neurol 2020 Jul 9;267(7):1906-1911. Epub 2020 Mar 9.

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France.

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.
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http://dx.doi.org/10.1007/s00415-020-09782-8DOI Listing
July 2020

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

Rheumatology (Oxford) 2020 08;59(8):1927-1937

Paediatric Hematology-Immunology and Rheumatology Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Necker-Enfants Malades, AP-HP, Paris.

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.
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http://dx.doi.org/10.1093/rheumatology/kez525DOI Listing
August 2020

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.

Cancer Cell 2019 09 22;36(3):268-287.e10. Epub 2019 Aug 22.

Université Côte d'Azur, INSERM, C3M, 06204 Nice, France; CIRI, Université de Lyon, INSERM U1111, ENS de Lyon, Université Lyon 1, CNRS, UMR 5308, 69007 Lyon, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ccell.2019.07.008DOI Listing
September 2019

The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Acta Diabetol 2019 Dec 19;56(12):1239-1245. Epub 2019 Aug 19.

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France.

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.
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http://dx.doi.org/10.1007/s00592-019-01402-wDOI Listing
December 2019

The IgG2 Isotype of Anti-Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis.

Arthritis Rheumatol 2019 08 8;71(8):1360-1370. Epub 2019 Jul 8.

Normandy University, University of Rouen, INSERM U1234, Rouen University Hospital, Rouen, France.

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.
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http://dx.doi.org/10.1002/art.40895DOI Listing
August 2019

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration.

Cerebellum 2019 Apr;18(2):245-254

French Reference Center for Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Hôpital Neurologique, F-69677, Bron, France.

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.
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http://dx.doi.org/10.1007/s12311-018-0987-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445697PMC
April 2019

Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype.

Acta Diabetol 2019 Apr 4;56(4):441-448. Epub 2018 Oct 4.

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, 165 chemin du Grand Revoyet, Pierre-Bénite, 69310, France.

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.
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http://dx.doi.org/10.1007/s00592-018-1234-8DOI Listing
April 2019

Research and identification of antinuclear antibodies: analysis of a questionnaire from the European EASI group and confrontation of French practices to international recommendations.

Ann Biol Clin (Paris) 2018 Apr;76(2):185-195

Laboratoire d'immunologie, Hôpital Européen Georges Pompidou, AP-HP, Université Paris Descartes, Paris, France.

Antinuclear antibodies (ANA) are prescribed as first-line autoantibodies in suspicion of mainly systemic autoimmune diseases. They include antibodies recognizing antigenic structures localized in the nucleus of cells, but also in the cytoplasm, at the membranes or transitional structures related to the cell cycle. Their research is based on screening and identification tests. For these tests, there is little or no standardization and harmonization of professional practices is necessary. From a questionnaire sent to healthcare professionals involved in the realization and interpretation of tests of autoimmunity, an overwiew of routine practices for the research of the ANA and their identification, was directed by the EASI Group International. Here, we present the results of the survey carried out in France. The analysis of these results faced with that of other countries as well as international recommendations allowed us to propose a synthesis of the main recommendations adapted to the regulatory texts of the NABM in France. These recommendations are addressed to those who prescribe, to those who perform biological analysis and to clinicians and biologists who interpret the results. They allow better understanding and admitting the methodological differences and their evolutions, to encourage the choice of the best technique based on the clinical context, to inform the clinician of the characteristics of the tests used.
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http://dx.doi.org/10.1684/abc.2018.1328DOI Listing
April 2018

Nivolumab-induced myositis: A case report and a literature review.

J Neurol Sci 2018 04 3;387:51-53. Epub 2018 Feb 3.

Service de Neuropathologie, Hospices Civils de Lyon, Université Claude Bernard Lyon1, Institut Neuromyogène CNRS UMR 5310 - Inserm U1217, France. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.01.030DOI Listing
April 2018

Anti-Programmed Death 1 (PD-1) Antibodies and the Pancreas: A Diabetic Storm Ahead?

Diabetes Care 2018 Mar;41(3):638-639

Department of Endocrinology and Diabetes, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France.

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http://dx.doi.org/10.2337/dc17-2243DOI Listing
March 2018

Multiplex family with GAD65-Abs neurologic syndromes.

Neurol Neuroimmunol Neuroinflamm 2018 Jan 5;5(1):e416. Epub 2017 Dec 5.

French Reference Center on Paraneoplastic Neurological Syndrome (A.B., B.J., V.R., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310 (A.B., B.J., V.R., J.H.), Université de Lyon-Université Claude Bernard Lyon 1, France; Stanford Blood Center (G.M.-M., M.F.-V., E.M.), Histocompatibility, Immunogenetics & Disease Profiling Laboratory, Palo Alto, CA; Immunology, Hospices Civils de Lyon (N.F.), Hôpital Lyon-Sud, France; and Stanford University Center for Sleep Sciences and Medicine (E.M), Palo Alto, CA.

Objective: Neurologic autoimmune syndromes associated with anti-glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic.

Methods: We describe a niece and her aunt with GAD65-Abs neurologic syndromes. High-resolution HLA typing of Class I and Class II alleles was performed using next-generation sequencing.

Results: The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects.

Conclusions: This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs.
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http://dx.doi.org/10.1212/NXI.0000000000000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778747PMC
January 2018

Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort.

Clin Chim Acta 2018 Mar 28;478:162-165. Epub 2017 Dec 28.

Immunology Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France. Electronic address:

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 ≥1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with ≥1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10years. 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.
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http://dx.doi.org/10.1016/j.cca.2017.12.043DOI Listing
March 2018

Clinical, histological, immunological presentations and outcomes of bullous systemic lupus erythematosus: 10 New cases and a literature review of 118 cases.

Semin Arthritis Rheum 2018 08 4;48(1):83-89. Epub 2017 Nov 4.

AP-HP, Service de Médecine Interne 2, Centre National de Référence des Maladies Systémiques Rares, Lupus et Syndrome des Anticorps antiphospholipides, Institut e3m, Groupe Hospitalier Pitié-Salpêtrière, Paris 75013, France; Université Paris VI Pierre et Marie Curie, Sorbonnes Universités, Paris 75013, France.

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 and literature review 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 subepidermal 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 rather an autoimmune neutrophilic blistering disease associated with SLE than a cutaneous manifestation and may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.
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http://dx.doi.org/10.1016/j.semarthrit.2017.11.003DOI Listing
August 2018

Nivolumab-Induced Acute Diabetes Mellitus and Hypophysitis in a Patient with Advanced Pulmonary Pleomorphic Carcinoma with a Prolonged Tumor Response.

J Thorac Oncol 2017 11;12(11):e182-e184

Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France.

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http://dx.doi.org/10.1016/j.jtho.2017.07.021DOI Listing
November 2017

Testing anti-neutrophil cytoplasmic antibodies (ANCA): analysis of the European EASI survey on the daily practice of the French laboratories.

Ann Biol Clin (Paris) 2017 Oct;75(5):531-541

Laboratoire d'immunologie, CHU de Dijon, France.

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.
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http://dx.doi.org/10.1684/abc.2017.1273DOI Listing
October 2017

Comment on Jackson et al. Insulitis in Autoantibody-Positive Pancreatic Donor With History of Gestational Diabetes Mellitus. Diabetes Care 2017;40:723-725.

Diabetes Care 2017 10;40(10):e155

Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France.

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http://dx.doi.org/10.2337/dc17-1044DOI Listing
October 2017

Isolated positive anti-SS-B autoantibodies are not related to clinical features of systemic autoimmune diseases: Results from a routine population survey.

PLoS One 2017 20;12(9):e0185104. Epub 2017 Sep 20.

Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Claude Bernard University Lyon 1, University of Lyon, Lyon, France.

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 Sjögren'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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607193PMC
October 2017

Chilblain lupus erythematosus treated successfully with mycophenolate mofetil.

Int J Dermatol 2017 08 27;56(8):e158-e159. Epub 2017 Mar 27.

Dermatology Department, Centre Hospitalier Lyon Sud, Pierre-Bénite, Lyon 1 University, France.

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http://dx.doi.org/10.1111/ijd.13614DOI Listing
August 2017