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Objective The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. Methods We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. Results A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th–75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0–4)], significant fatigue (55.5%, P Conclusion LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

ObjectivesTo analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA).MethodsPatients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA.ResultsA total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models.ConclusionFatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

ObjectiveAmong the most significant challenges in SLE are the excessive diagnosis delay and the lack of coordinated care. The aim of the study was to investigate patient pathways in SLE in order to improve clinical and organisational challenges in the management of those with suspected and confirmed SLE.MethodsWe conducted a cross-sectional study of patients with SLE, healthcare providers and other representative stakeholders. Focus groups were conducted, and based on the collected data the most impactful disruption points in SLE patient pathways were identified. A novel framework to improve individual patient pathways in SLE was developed, discussed and validated during a consensus meeting with representative stakeholders.ResultsSix thematic clusters regarding disruption in optimal patient pathways in SLE were identified: appropriate and timely referral strategy for SLE diagnosis; the need for a dedicated consultation during which the diagnosis of SLE would be announced, and following which clarifications and psychological support offered; individualised patient pathways with coordinated care based on organ involvement, disease severity and patient preference; improved therapeutic patient education; prevention of complications such as infections, osteoporosis and cancer; and additional patient support. During the consensus meeting, the broader panel of stakeholders achieved consensus on these attributes and a framework for optimising SLE patient pathways was developed.ConclusionsWe have identified significant disruption points and developed a novel conceptual framework to improve individual patient pathways in SLE. These data may be of valuable interest to patients with SLE, their physicians, health organisations as well as policy makers.

International audience; Background: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. Objective: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. Methods: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy–associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. Results: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W– group). Cumulative probabilities of 10-year survival in W+ versus W– groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W– groups were 72% versus 58% (P = 0.3) and 2.5 (0.3–4) versus 1 (0–2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. Conclusions: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.

Objective To explore, at an item-level, the effect of disease activity (DA) on specific health-related quality of life (HRQoL) in SLE patients using an item response theory longitudinal model. Methods This prospective longitudinal multicentre French cohort EQUAL followed SLE patients over 2 years. Specific HRQoL according to LupusQoL and SLEQOL was collected every 3 months. DA according to SELENA-SLEDAI flare index (SFI) and revised SELENA-SLEDAI flare index (SFI-R) was evaluated every 6 months. Regarding DA according to SFI and each SFI-R type of flare, specific HRQoL of remitting patients was compared with non-flaring patients fitting a linear logistic model with relaxed assumptions for each domain of the questionnaires. Results Between December 2011 and July 2015, 336 patients were included (89.9% female). LupusQoL and SLEQOL items related to physical HRQoL (physical health, physical functioning, pain) were most affected by musculoskeletal and cutaneous flares. Cutaneous flares had significant influence on self-image. Neurological or psychiatric flares had a more severe impact on specific HRQoL. Patient HRQoL was impacted up to 18 months after a flare. Conclusion Item response theory analysis is able to pinpoint items that are influenced by a given patient group in terms of a latent trait change. Item-level analysis provides a new way of interpreting HRQoL variation in SLE patients, permitting a better understanding of DA impact on HRQoL. This kind of analysis could be easily implemented for the comparison of groups in a clinical trial. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904812.

Older patients are underrepresented in studies of rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Little is known about outcomes and adverse events associated with the use of rituximab therapy among patients 75 years and older with ANCA-associated vasculitis.To examine outcomes and adverse events associated with the use of rituximab therapy in patients 75 years and older with ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).This multicenter cohort study involved 93 patients 75 years and older with ANCA-associated vasculitis from 36 university and nonuniversity hospitals in France. Data were obtained from the French Vasculitis Study Group database between January 1, 2000, and July 1, 2018, and a call for observation sent to French Vasculitis Study Group members on June 6, 2019. Data analysis was performed from November 15 to December 31, 2021. Inclusion criteria included a diagnosis of GPA or MPA according to European Medicines Agency classification criteria and receipt of treatment with rituximab after age 75 years. Patients were excluded if they were missing relevant clinical or biological data. Data on race and ethnicity were not reported because inclusion of this information was not authorized by the ethics committee.At least 1 infusion of rituximab as induction or maintenance therapy.Occurrence of remission, relapse, drug discontinuation, death, and serious infections (including types of serious infections).Of 238 patients screened, 93 were included (median [IQR] age, 79.4 [76.7-83.1] years; 51 women [54.8%]); 52 patients (55.9%) had a diagnosis of GPA, and 41 (44.1%) had a diagnosis of MPA. Thirty patients (32.3%) received rituximab as induction therapy in combination with high-dose glucocorticoid regimens, 27 (29.0%) received rituximab as maintenance therapy, and 36 (38.7%) received rituximab as both induction and maintenance therapy. The median (IQR) follow-up was 2.3 (1.1-4.0) years. Among 66 patients who received rituximab as induction therapy, 57 (86.4%) achieved remission, and 2 (3.0%) experienced relapses. The incidence of serious infection was significantly higher when rituximab was used as induction therapy vs maintenance therapy (46.6 [95% CI, 24.8-79.7] per 100 patient-years vs 8.4 [95% CI, 3.8-15.9] per 100 patient-years; P = .004). Most infections (12 of 22 [54.5%]) were gram-negative bacterial infections. The incidence of death was 19.7 (95% CI, 7.2-42.9) per 100 patient-years among those who received rituximab as induction therapy and 5.3 (95% CI, 1.9-11.6) per 100 patient-years among those who received rituximab as maintenance therapy.In this cohort study, rituximab therapy was associated with achievement and maintenance of remission in most patients 75 years and older with ANCA-associated vasculitis. The incidence of serious infections and death was high when rituximab was used as induction therapy in combination with high-dose glucocorticoid regimens but not when rituximab was used as maintenance therapy. Efforts might focus on reducing serious infections during the first months of therapy.

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

Objectives: To compare adult patients’ characteristics suffering from idiopathic retroperitoneal fibrosis between “relapse-free” and relapsing patients at the diagnosis and identify factors associated with relapse at initial presentation. Methods: We conducted a retrospective multicentric study in four hospitals in Eastern France, from 1993 to 2020, of adult patients suffering from idiopathic retroperitoneal fibrosis. We analyzed clinical, biological, and radiological features at diagnosis and during a forty-month follow-up. Results: Of 47 patients suffering from retroperitoneal fibrosis, 21 patients had idiopathic retroperitoneal fibrosis. Among them, 13 experienced one or more relapses during follow-up. At diagnosis, clinical characteristics, relevant comorbidities, biological and radiological features were similar between groups. Smoking cessation seems associated with decreased relapse risk (p: 0.0624). A total of 8 patients developed chronic renal failure during follow-up. Ureteral infiltration at diagnosis was associated with evolution to chronic renal failure (p: 0.0091). Conclusion: No clinical, biological, or radiological features could predict relapse at retroperitoneal fibrosis diagnosis, but smoking cessation may prevent relapse.

ObjectivesNo immunomodulatory drug has been approved for primary Sjögren’s syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren’s syndrome-related systemic complications.MethodsMulticentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren’s syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren’s Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician’s global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment.Results110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of −11.4% (95% credible interval −30.6 to 9.0) (Pr[Toc >Pla]=0.14).ConclusionAmong patients with primary Sjögren’s syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo.Trial registration numberNCT01782235.

OBJECTIVE Silica is an environmental substance strongly linked with autoimmunity. The aim of this study was to assess the prevalence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal limited vasculitis, in a northeastern region of France and to evaluate whether there was a geospatial association between the localization of quarries in the region and the prevalence of these AAVs. METHODS Potential AAV patients were identified using 3 sources: hospital records, immunology laboratories, and the French National Health Insurance System. Patients who resided in the Alsace region of France as of January 1, 2016 and who fulfilled the American College of Rheumatology criteria for GPA or the 2012 Chapel Hill Consensus Conference definitions for GPA or MPA were included. Incomplete case ascertainment was corrected using a capture-recapture analysis. The spatial association between the number of cases and the presence of quarries in each administrative entity was assessed using regression analyses weighted for geographic region. RESULTS Among 910 potential AAV patients, we identified 185 patients fulfilling inclusion criteria: 120 patients with GPA, 35 patients with MPA, and 30 patients with renal limited vasculitis. The number of cases missed by any source as estimated by capture-recapture analysis was 6.4 (95% confidence interval [95% CI] 3.6-11.5). Accordingly, the estimated prevalence in Alsace in 2016 was 65.5 GPA cases per million inhabitants (95% CI 47.3-93.0), 19.1 MPA cases per million inhabitants (95% CI 11.3-34.3), and 16.8 renal limited vasculitis cases per million inhabitants (95% CI 8.7-35.2). The risk of AAV was significantly increased in communities with quarries (odds ratio 2.51 [95% CI 1.66-3.80]), and geographic-weighted regression analyses revealed a significant spatial association between the proximity to quarries and the number of GPA cases (P = 0.039). In analyses stratifying the AAV patients by ANCA serotype, a significant association between the presence of quarries and positivity for both proteinase 3 ANCAs (P = 0.04) and myeloperoxidase ANCAs (P = 0.03) was observed. CONCLUSION In a region with a high density of quarries, the spatial association between the presence of and proximity to quarries and the prevalence of AAVs supports the idea that silica may have a role as a specific environmental factor in this disease.

IntroductionAnti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.ObjectiveThe main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or withoutproliferativerenal damage and compared to a healthy control group.MethodologyThis retrospective study was performed on SLE patients’ sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).ResultsThe cohort was composed of 100 SLE patients withproliferativeLN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found “ambivalent” (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.ConclusionAnti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.

La maladie thromboembolique veineuse etant relativement frequente et source d’une morbi-mortalite importante, la question du depistage des thrombophilies hereditaires se pose, d’autant que des moyens potentiels de prevention existent. Cette question reste controversee et debattue chez les apparentes asymptomatiques d’un cas-index porteur d’une thrombophilie hereditaire symptomatique. Les recommandations actuelles reposent sur de faibles niveaux de preuves. Theoriquement, ce depistage pourrait aboutir a une diminution du nombre d’evenements thromboemboliques veineux sous reserve de la mise en place d’une thromboprophylaxie. Toutefois, dans cette population, le benefice sur la mortalite de cette thromboprophylaxie n’est pas, a ce jour, clairement etabli, cette derniere exposant en outre a un risque hemorragique en cas d’utilisation d’antiagregants plaquettaires et/ou d’anticoagulants. Dans ce cadre, la mise a disposition des anticoagulants oraux directs va peut-etre bousculer ces certitudes et dans tous les cas donner lieu a de nouvelles etudes. Dans tous les cas, cela nous amene a reevaluer cette question au regard de la litterature factuelle (etudes prospectives).

Introduction Les cryoglobulines (CG) sont des immunoglobulines seriques ayant la faculte de precipiter a une temperature inferieure a 37 °C. Leur presence est associee a diverses pathologies: infectieuses, auto-immunes et hematologiques. Les CG peuvent etre symptomatiques. La recherche de CG necessite des mesures strictes de prelevement, de conditionnement, plusieurs etapes d’analyse et un resultat rendu tardivement. Le dosage de CG peut etre realise par plusieurs methodes avec une precision croissante. Dans notre etablissement, le seuil de rendu positif a ete fixe arbitrairement a 20 mg/l mais une augmentation de ce seuil est envisagee pour reduire le nombre d’immunofixations realisees pour les prelevements positifs. L’objectif de ce travail est d’evaluer les implications de la modification du seuil de positivite en decrivant une cohorte de patients avec CG positives, et de comparer les dosages de CG chez les patients consideres symptomatiques versus patients asymptomatiques. Patients et methodes Nous avons mene une etude retrospective unicentrique de l’ensemble des dossiers des patients avec CG positives dosees dans notre hopital entre mai 2015 et avril 2019. Un dosage de CG positif permettait l’inclusion dans notre etude. Nous avons recueilli les donnees cliniques, biologiques, radiologiques, anatomopathologiques et therapeutiques. Les services prescripteurs ont ete recueillis. Le caractere symptomatique de la CG etait determine par le praticien en charge du patient aumoment du dosage. Resultats Nous avons inclus 166 patients, avec un taux moyen de CG de 124 mg/l. 90 femmes (54 %) et 76 hommes (46 %), dont l’âge moyen au diagnostic est de 64 ans . Seize patients presentaient une CG type 1 (10 %), 77 une CG de type 2 (46 %), et 63 une CG de type 3 (38 %), 10 CG etaient non-typees (6 %). Pour 3 dosages de CG positifs, aucune donnee clinique n’etait disponible, ces prelevements etaient issus d’un autre etablissement, ces dossiers n’ont pas ete retenus pour les analyses. Les diagnostics etiologiques etaient pour 23 % auto-immuns (14 polyarthrites rhumatoides, 7 Gougerot-Sjogren, 4 lupus, 4 vascularites a IgA); 23 % infectieux (23 lies au VHC, 5 bacteriemies a Staphylocoque); 22 % hematologiques (24 lymphomes, 9 gammapathies monoclonales). Les principales manifestations cliniques etaient des manifestations cutanees (54 %) dont un purpura (18 %) et un syndrome de Raynaud (13 %), des arthralgies (16 %) et une asthenie (26 %). Trente et une biopsies cutanees et 7 biopsies renales etaient realisees. La majorite des dosages etaient prescrits par des internistes (53 %), des dermatologues (10 %), des gastrohepatologues (7 %) et des rhumatologues(7 %). Parmi les 163 patients, 30 avaient une CG consideree symptomatique (groupe 1) contre 133 non symptomatique (groupe 2). La repartition homme/femme, l’âge et la repartition des types de CG etaient equivalentes selon les groupes. Les patients du groupe 1 presentaient significativement plus d’atteintes cutanees (77 % vs 31 %), de purpura (46 % vs 11 %), de syndrome de Raynaud (26 % vs 10 %), de vascularites leucocytoclasiques a l’histologie (83 % vs 21 %) mais pas de difference significative sur l’asthenie (23 % vs 27 %), les arthrites (16 % vs 16 %), la fievre (3 % vs 12 %), ni de difference d’antecedents d’infection au VHC (13 % vs 13 %). Les principaux diagnostics retenus au sein du groupe 1 etaient: une infection au VHC (13 %), un Lymphome B non Hodgkiniens (13 %), une maladie de Waldenstrom (10 %) et dans le groupe 2: une infection au VHC (13 %), une polyarthrite rhumatoide (9 %), une gammapathie monoclonale (7 %). Le taux deCG essentielle etait equivalent dans les deux groupes (27 % vs 28 %). Le taux moyen de CG dans le groupe 1 etait de 319 mg/L et de 82 mg/L dans le groupe 2 (p = 0,106). Le seuil de rendu positif de CG a 20 mg/L actuellement utilise a dans notre effectif une specificite de 3 % et une sensibilite de 100 %. Un seuil de 50 mg/L aurait une sensibilite de 50 % et une specificite de 65,4 %. En cas de seuil a 50 mg/l, 14 patients (46,6 % des patients) ayant une CG symptomatique auraient eu un resultat rendu negatif. Discussion Saisir le texte. Conclusion Dans les limites de notre effectif et de notre methodologie, cette etude permet d’evaluer l’impact d’une modification du seuil de positivite du dosage des cryoglobulinemie. La determination d’un seuil de positivite reste difficile a etablir. Il parait preferable de maintenir le seuil bas afin de ne pas meconnaitre des patients symptomatiques avec un faible taux de CG.

Introduction Les anticorps anti-DPPX (dipeptidyl-peptidase-like protein-6) ont ete decrits en 2013 [1] , chez des patients presentant des troubles psychiatriques, digestifs et neurologiques. Cette description a fait suite a une decennie de decouverte de nouveaux anticorps (anti-NMDAR, AMPAR, GABA(B), LGI1, Caspr2, GlyR, et mGluR5) ayant differentes cibles au sein du systeme nerveux central et etant responsables d’encephalite dysimmunitaire associees a des signes cliniques polymorphes. Nous en rapportons une observation. Observation En 2008, une patiente de 53 ans est adressee pour un tableau complexe et polymorphe evoluant depuis plusieurs mois. Ces antecedents sont : un asthme allergique, une hypothyroidie substituee et un fibrome uterin. Depuis le mois de septembre 2007, la patiente rapporte une perte de poids de 18 kg associe a une diarrhee chronique sans vomissement ni anorexie avec endoscopie haute et basse normale, des sensations ebrieuses, sans vrai vertige et des difficultes a la lecture en lien avec des oscillopsies. L’examen clinique ne revele ni desorientation ni signe meninge, les reflexes osteotendineux sont percus de maniere bilaterale et symetrique, le reflexe cutaneo-plantaire est en flexion bilaterale, il existe un trouble de la marche avec elargissement du polygone de sustentation et une danse des tendons sans adiadococinesie ni dysmetrie. L’examen des paires crâniennes met en evidence un nystagmus inepuisable. Differents examens d’imageries sont realises : une TDM TAP met en evidence volumineuse masse de 13 cm pelvienne fibromateuse, la TEP TDM montre la masse ovarienne ou pelvienne sans hypermetabolisme, et une IRM cerebrale est sans anomalie. Des examens biologiques sont effectues : NFS, ionogramme sanguin, bilan hepatique, electrophorese des proteines plasmatique sont sans particularite, serologie de lyme negative, AAN positifs au 1/160 sans specificite, ANCA negatifs, anticorps anti-TPO, anti-transglutaminase et anti-GAD negatifs, anticorps anti-neurones positifs mais sans possibilites de typage, serologies VIH, VHB, et VHC negatives. L’analyse du LCR : 1 leucocyte, 2 hematies, proteinorachie a 0,26 et glycorachie normale. Un syndrome paraneoplasique est evoque mais la chirurgie gynecologique ne diagnostique aucune neoplasie. Un traitement par immunoglobuline polyvalente est efficace permettant a la patiente de lire a nouveau. La surveillance clinique de la patiente met en evidence une proteinurie. Une ponction biopsie renale revele une glomerulopathie avec depots d’IgG au niveau de la membrane basale glomerulaire. Les perfusions d’immunoglobulines sont interrompues et il est decide de realiser des seances de plasmapherese (4) puis un traitement par rituximab (octobre 2008). En decembre 2008 on note une nette amelioration du syndrome cerebelleux. De meme les troubles oculomoteurs sont en cours d’amelioration. Le diagnostic de syndrome cerebelleux auto immun associe une glomerulopathie est retenue ; un traitement d’entretien par CELLCEPT est poursuivi. En octobre 2009, devant l’aggravation des saccades oculaires et une majoration du syndrome cerebelleux, le traitement par rituximab est repris en association avec le CELLCEPT. Une amelioration clinique est observee, il est decide de poursuite le traitement par rituximab en entretien. Le traitement est ainsi poursuivi avec un bilan annuel a la recherche de neoplasie. Sous traitement l’etat clinique de la patiente reste stable, les recherches pour une pathologie neoplasique restent negatives et des imageries cerebrales, IRM notamment, ne montrent pas d’evolution. Les anticorps anti-neurones restent positifs mais ne presentent aucune specificite. Le traitement ne sera pas modifie jusqu’au printemps 2018, et l’arret du CELLCEPT. Le bilan est repris a l’ete 2018 devant l’apparition de troubles digestifs a type de selles liquides, d’une part, avec la recherche de pathologie infectieuse en lien avec l’immunodepression, et d’autres part, avec la recherche d’anticorps anti-neuropiles : presence d’anticorps anti-DPPX confirmee a deux reprises. Conclusion Les manifestations neurologiques des encephalites a DPPX sont diverses, multifocales et parfois intermittentes. Les manifestations les plus frequentes comprennent une perte de poids, des troubles neuropsychiatriques et une dysautonomie. Les patients semblent bien reagir aux debuts precoces d’une immunotherapie. Un traitement immunosuppresseur semble necessaire a long terme [2] . Ce cas clinique permet de rappeler le polymorphisme des encephalites, et l’interet de reevaluer regulierement des situations cliniques complexes.

Key messages #### What is already known about this subject? #### What does this study add? #### How might this impact on clinical practice? Raynaud’s phenomenon (RP) in systemic sclerosis (SSc) can be severe with active digital ulceration (ADU) and gangrene. RP physiopathology includes early endothelial cell injury, vascular dysfunction and sometimes microvascular thrombosis.1 Antiphospholipid antibodies (aPL) activate endothelial cells and platelets by complexes of beta-2 glycoprotein 1 (β2GP1) and anti-β2GP12 and could therefore contribute to the initiation of and/or aggravate SSc-related RP. aPL prevalence seems increased in patients with SSc compared with controls,3 but aPL-associated clinical features are often contradictory. The aims of this study were to assess aPL and antiphospholipid syndrome (APS) prevalence in patients with SSc and their association with ADU. Consecutive patients aged more than 18 years, fulfilling the American College of Rheumatology/EULAR classification criteria for SSc4 and followed in seven French expert centres for autoimmune diseases labelled by the French national network for autoimmune disease care, were enrolled prospectively during 8 months. Patients with other associated autoimmune disease were excluded. All patients provided written informed consent. SSc subtype was classified based on LeRoy and Medsger’s criteria,5 and skin involvement was assessed according to the modified Rodnan skin score (mRSS).6 Interstitial lung disease …

Background Precise epidemiology of myositis epidemiology remains largely unknown (1). Surveys based solely on administrative claims benefit from large case ascertainment but may be influenced by miscoding and misdiagnosing. The use of medical records with charts review benefit from accurate diagnosis but exhaustive ascertainment is difficult to achieve because numerous specialists are involved and cases may concern both inpatients and outpatients. To overcome these difficulties we undertook a capture–recapture survey that takes advantage of a multi-sources case ascertainment to estimate the number of cases missed by any one source and to correct the prevalence rate (2). Objectives To assess the incidence and prevalence of myositis in Alsace, a region of eastern France. Methods Alsace, region of eastern France, is home to about 2 million inhabitants benefiting from high access to healthcare and a labialized referral center for myositis. Seeking care outside is uneasy because of peculiar geography. Myositis patients were retrieved through three separate sources: i) all general practitioners and community specialist ii) Muscle pathology center records, iii) all public and private hospitals records, vi) all public and private laboratory records. Incident and prevalent cases fulfilling the ACR/EULAR criteria for myositis were included. Results The responses to the questionnaires sent to the physicians (n=3452), yielded 105 potential myositis cases. All hospital centres contacted (n=13) participated in the study and 1335 potential myositis patients were recorded by this source. 263 potential myositis cases were identified through muscle pathology center records. 13 laboratories participate in the studies and 324 potential myositis patients were recorded by this source. We thus received 1863 records of suspected myositis after excluding duplicates within each sources. The thorough review of the corresponding medical charts is currently ongoing and at this stage 10% of the potential cases fulfilled the ACR/EULAR criteria for myositis. Conclusion This first study based on a multi-sources capture-recapture methodology and ACR/EULAR criteria is very likely to provide an accurate estimation of myositis epidemiology. References [1] Incidence and prevalence of inflammatory myopathies: a systematic review. [2] Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J. [3] Rheumatology (Oxford). 2015;54:50-63. [4] Brief Report: Spatial Heterogeneity of Systemic Sclerosis in France: High Prevalence in the Northeast Region. [5] Meyer A, Chifflot H, Chatelus E, Kleinmann JF, Ronde-Ousteau C, Klein D, Jegu J, Geny B, Hirshi S, Canuet M, Blaison G, Kieffer P, Lipsker D, Martin T, Sauleau E, Velten M, Sibilia J. Arthritis Rheumatol. 2016;68:1731-7. Disclosure of Interests None declared

Objective Alsace is a region in eastern France with a population of ∼2 million. All residents have high access to health care and an accredited referral center for SSc. Seeking care outside of this region is difficult because of the peculiar geography. The aim of this study was to assess the prevalence and spatial variation of systemic sclerosis (SSc) in eastern France. Methods Data for SSc patients were obtained from 3 sources (all general practitioners and community specialists, capillaroscopy centers, and all public and private hospital records) and were used to estimate the prevalence of SSc. Surviving patients who resided in Alsace on January 1, 2008 and fulfilled the American College of Rheumatology and/or the LeRoy and Medsger criteria were included in this study. The clinical characteristics of the patients were also assessed. Potentially incomplete case ascertainment was corrected by capture–recapture analyses. Geographic disparities were assessed by spatial cluster analysis and by comparing our results with those for other geographic areas in the world for which data derived using similar methodology were available. Results The review of 499 potential cases identified a total of 244 SSc patients. A trend toward a west-to-east gradient was observed but did not reach statistical significance. According to log-linear modeling, an estimated 83.87 additional cases were missed. Thus, the SSc prevalence was 228.42 cases per million adult inhabitants of Alsace (95% confidence interval 203.70–253.14); this prevalence was significantly higher than that in 2 other regions of France and comparable with the reported prevalence in Detroit, Michigan. Conclusion The stringent methodology used in the current study is very likely to provide an accurate estimation of the prevalence of SSc. Design similarity with 3 other surveys extends the scope of the results by identifying geographic disparities that were previously indistinguishable due to methodologic differences.

Cardiac neonatal lupus syndrome is due to anti-SSA or SSB antibodies and mainly includes congenital heart block (CHB) and dilated cardiomyopathy (DCM). Its optimal management is still debated. We report a large series of autoimmune high degree CHB.Inclusion criteria in this retrospective study were fetuses or neonates with high-degree CHB associated with maternal anti-SSA/SSB antibodies.214 CHB were included: 202 detected in utero at a median term of 23 weeks' gestation (WG) [range 16 to 39 WG] and 12 neonatal cases diagnosed at a median age of 0 days [range birth to 8 days]. The 214 cases of CHB included 202 (94.4%) third-degree CHB, 8 (3.7%) second-degree CHB, and 4 (1.9%) intermittent CHB. In multivariate analysis, the factors associated with feto-neonatal deaths (15.7%) were hydrops (p0.001; hazard ratio [HR] 12.4 [95% confidence interval (95%CI) 4.7-32.7]) and prematurity (p=0.002; HR 17.1 [95%CI 2.8-103.1]). During a median follow-up of 7 years [birth to 36 years], 148 of 187 children born alive (79.1%) had a pacemaker, 35 (18.8%, one missing data) had DCM, and 22 (11.8%) died. In multivariate analysis, factors associated with child death were in utero DCM (p=0.0157; HR 6.37 [95%CI: 1.25-32.44]), postnatal DCM (p0.0001; HR 227.58[95%CI: 24.33-2128.46]) and pacemaker implantation (p=0.0035; HR 0.11[95%CI: 0.02-0.51]). The use of fluorinated steroids was neither associated with survival nor with regression of 2nd degree CHB.In this second largest series of CHB, we confirm some of the previous results. We were unable to find data supporting the routine use of in utero fluorinated steroids.

ObjectiveSystemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%–40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined.Methods998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×106/L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia.Results208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57–10.3)), lymphopaenia (OR 4.41 (2.51–11.5)) and low C3 (OR 1.91 (1.03–4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers.ConclusionThis study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren’s disease.

OBJECTIVE Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. METHODS Patients from the Lupus BioBank of the upper Rhein, a large German-French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. RESULTS A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25-75: 34-52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0-4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39-16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60-7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05-2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00-1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00-1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). CONCLUSION Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.

Background Fatigue is an important issue in systemic lupus and has a major impact on quality of life of the patients. Data are controversial about the factors associated with this complex symptom.1 Objectives To identify the factors associated with fatigue and severe fatigue in patients with systemic lupus erythematosus (SLE) in a large cohort using a multivariate model to precise the importance of each parameter in this multidimensional symptom. Methods We used the LBBR data base, a German French data base of SLE patients. All patients fulfilled the 1997 ACR criteria for SLE. The Fatigue Scale for Motor and Cognitive Functions (FSMC) was used to assess fatigue and severe fatigue. The depression and anxiety were measured with Hospital Anxiety and Depression Scale (HADS). Tests were performed at sampling. Results A total of 570 patients were included (89.1% female). The median age was 42 years (QR25–75: 34–52). The median value of the SELENA-SLEDAI was 2 (QR25–75: 0–4) and 136 patients had a SELENA-SLEDAI score >6. Fatigue was reported by 386 patients (67.7%) including severe fatigue by 209 (36.7%). In univariate analysis among the individual components of the SLEDAI arthritis (p=0.003) and oral ulcers (p=0.002) were associated with severe fatigue. In multivariate analysis fatigue was strongly associated with anxiety (OR: 4.49 [95%CI: 2.60–7.77], p Severe fatigue was strongly associated with depression (OR:6.87 [95%CI: 3.12–15.11], p Conclusions Fatigue is a common symptom in SLE patients and is strongly associated with anxiety and depression. While remission remains an important therapeutic target, these manifestations should also be taken care of with psychological counselling and pharmacological intervention, when needed. Reference [1] Cleanthous S, Tyagi M, Isenberg DA, Newman SP. What do we know about self-reported fatigue in systemic lupus erythematosus?Lupus. 2012Apr;21(5):465–76 Disclosure of Interest None declared

International audience; Background: describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection.Methods: we conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults.Results: data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7–83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1) and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement.Conclusions: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.

Introduction Cette etude avait pour objectif d’etudier les facteurs associes a la fatigue chez des patients atteints de lupus erythemateux systemique (LES) francais a l’aide de 3 questionnaires de fatigue differents. Patients et methodes Nous avons conduit une etude de cohorte prospective multicentrique et recrute des patients dans 10 hopitaux francais entre 2010 et 2014. A partir des donnees recueillies lors du suivi de 336 patients nous avons analyse les donnees de 3 questionnaires auto-administres de fatigue : le domaine fatigue du questionnaire specifique LupusQoL, le domaine vitalite du questionnaire generique SF-36 et le questionnaire generique de fatigue MFI-20. Les donnees demographiques, socioprofessionnelles et cliniques en rapport avec le LES etaient recueillies a l’inclusion. La precarite etait mesuree par le questionnaire EPICES et la depression par le questionnaire CES-D. Les poussees du lupus etaient mesurees par le SELENA-SLEDAI Flare Index-Revised (SFI-R). Les analyses multivariees, sans et avec ajout du facteur depression, ont porte sur les variables significatives en analyse bivariee. Les scores de fatigue utilises variaient de 100 (pas de fatigue) a 0 (plus forte fatigue imaginable) pour les 2 premiers questionnaires et inversement pour le questionnaire MFI-20. Resultats Trois-cent trente-six patients ont ete inclus dont 302 (90 %) femmes. L’âge moyen ± DS (deviation standard) etait de 41 ± 12 ans, la duree d’evolution du LES de 12 ± 9 ans, l’IMC etait de 24,4 ± 5,1 kg/m2. 114 (34 %) patients avaient un niveau d’etude inferieur au baccalaureat, 103 (31 %) etaient sans emploi et 64 (19 %) etaient en situation de precarite selon le score EPICES. Selon le score CES-D, 99 (29 %) patients presentaient un etat depressif avere. Le score de sequelles SLICC/ACR-DI (SDI) etait de 1 ± 1. Les scores de fatigue moyens etaient a 66 ± 25 pour le LupusQoL et 46 ± 21 pour le SF-36. Concernant les domaines du MFI-20, la fatigue etait mesuree a 50 ± 26 pour le domaine fatigue generale/physique (GPF), 35 ± 26 pour le domaine fatigue mentale (MF), 31 ± 28 pour le domaine reduction des activites (RA) et 27 ± 27 pour le domaine reduction de la motivation (RM) du MFI-20. Les facteurs associes a une fatigue plus importante en analyse bivariee et dans les 6 domaines des questionnaires utilises etaient : la precarite, le niveau d’etude bas, le statut sans emploi et un etat depressif avere. Les autres variables significativement associees a des scores de fatigue eleves selon le questionnaire utilise etaient : le sexe feminin, l’âge ≥ 40 ans, le tabagisme actif, l’obesite, une poussee clinique osteoarticulaire, neurologique ou avec des signes generaux, le SDI ≥ 1 et la prise de corticoides ≥ 10 mg/j. L’analyse multivariee, sans inclusion de la depression identifiait la precarite comme facteur significativement associe a la fatigue dans les 6 questionnaires utilises. Les autres facteurs significativement associes aux scores eleves de fatigue etaient le sexe feminin, l’absence d’emploi, l’obesite et les poussees dans les systemes osteoarticulaire et neuropsychiatrique du SFI-R. L’analyse multivariee, en incluant la depression retrouvait celle-ci comme facteur significativement associe a la fatigue dans tous les questionnaires. La precarite n’etait plus significativement associee a la fatigue que dans 2 questionnaires. L’absence d’emploi, l’obesite, les poussees dans les systemes osteoarticulaire et neuropsychiatrique du SFI-R restaient significativement associes a la fatigue selon le questionnaire utilise mais il existait des differences entre les 2 analyses en nombre de questionnaires significativement associes a la fatigue. Conclusion Les facteurs associes a la fatigue dans le LES sont multiples et sujets a de grandes variations selon les questionnaires et la methodologie employee, comme en temoigne la litterature. L’utilisation de questionnaires de fatigue multidimensionnels semble permettre une analyse plus fine de ces facteurs dans le cadre d’etudes epidemiologiques, mais le choix du questionnaire doit etre guide par les objectifs de l’etude. Dans le cadre de notre travail les facteurs associes a la fatigue dans le LES sont sociodemographiques : le sexe feminin ; socioprofessionnels : la precarite et l’absence d’emploi ; certaines comorbidites : la depression et l’obesite ; des facteurs specifiques du LES : les poussees osteoarticulaire et neuropsychiatrique selon le SFI-R. L’effet de la precarite sur la fatigue pourrait etre due a la plus forte intensite des symptomes depressifs chez les patients precaires. La mise en place de strategies interventionnelles visant a corriger les facteurs identifies comme etant associee a la fatigue chez les patients atteints de LES et l’evaluation de leur efficacite devrait etre l’objectif de prochaines etudes.

Background Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. Patients and methods This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. Results We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24 months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥ 1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36 months, 11 patients died including 5 from intracerebral hemorrhages. Conclusion EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.

International audience; Venous thrombosis affecting thrombocytopenic patients is challenging. We report the case of a woman affected by deep vein thrombosis and pulmonary embolism in a thrombocytopenic context leading to the discovery of a heterozygous mutation in the gene encoding ankyrin repeat domain 26 (ANKRD26) associated with a heterozygous factor V (FV) Leiden mutation. This woman was diagnosed with lower-limb deep vein thrombosis complicated by pulmonary embolism. Severe thrombocytopenia was observed. The genetic study evidenced a heterozygous FV Leiden mutation. Molecular study sequencing was performed after learning that her family had a history of thrombocytopenia. Previously described heterozygous mutation c-127C>A in the 5'untranslated region (5'UTR) of the ANKRD26 gene was detected in the patient, her aunt, and her grandmother. ANKRD26-related thrombocytopenia and thrombosis are rare. This is, to our knowledge, the first case reported in the medical literature. This mutation should be screened in patients with a family history of thrombocytopenia.

International audience; Background: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome.Methods: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months.Results: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality.Conclusions: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

International audience; Evidence before this study We searched PubMed on June 30, 2016, for English-language cohort studies published since Jan 1, 1980, of patients with invasive listeriosis worldwide with the keywords " listeria " , " listeriosis " , " maternal " , and " neurolisteriosis ". Studies had to include epidemiological or clinical data on listeriosis. All clinical forms of infection were included (bacteraemia, neurolisteriosis, and maternal–neonatal infection). Host risk factors for listeriosis have been well identified, but the clinical features and prognostic factors of the disease are based on retrospective studies compiling heterogeneous data or random collected cases. Furthermore, no clinical trial has ever been done and medical management is not evidence based. Added value of the study Our study is the first prospective clinical study focusing on all forms of invasive listeriosis. The study is based on a national mandatory system that allowed the nearly complete capture of microbiologically proven cases. The study shows a higher burden of listeriosis than reported before: more than 80% of infected mothers experienced major fetal or neonatal complications (fetal loss, very high prematurity, early or late onset disease); only 39% of patients with neurolisteriosis survived and fully recovered. The study provides important new data to improve management and predict outcome in listeriosis, such as determination of the time window for fetal losses (

Introduction Les lupus actifs et corticodependants malgre un traitement immunosuppresseur conventionnel, representent un defi therapeutique. Aujourd’hui, si seul le belimumab a ete autorise par une AMM, d’autres biomedicaments sont parfois utilises au lieu a titre derogatoire dans des lupus refractaires. Etant donne le manque de donnees prouvant l’efficacite de ces biomedicaments dans certaines situations rencontrees en clinique, nous avons decide d’etablir des recommandations d’experts pour l’utilisation de biomedicaments dans le lupus erythemateux systemique. Materiels et methodes Nous avons developpe ces recommandations par « consensus formalise d’experts ». Le but de cette methode est de formaliser le degre d’accord entre experts en identifiant, par une cotation iterative avec retour d’information, les points de convergence, de divergence ou d’indecision entre experts. Cette methode comporte plusieurs etapes chronologiques consecutives (phase de pilotage, de cotation, de lecture, de finalisation et diffusion) realisees par des groupes de travail independants. Au travers de 3 reseaux dedies aux maladies auto-immunes systemiques (FLEUR, IMIDIATE, FAI2R) et sous l’egide du CRI, nous avons recueilli les opinions de 59 experts francophones du lupus exercant en Algerie, Belgique, France, Italie, Maroc, Suisse et Tunisie. Les specialites medicales representees etaient la medecine interne (49 %), rhumatologie (34 %), nephrologie (7 %), dermatologie (5 %), pediatrie (3 %) et medecine vasculaire (2 %). Deux methodologistes et 3 groupes d’experts strictement independants ont contribues a ces recommandations : un groupe de pilotage (GP) (n = 9), un groupe de cotation (GC) (n = 28) et un groupe de lecture (GL) (n = 23). Les propositions de recommandations ont ete redigees par le GP et soumises au GC. Chaque membre du GC a indique son degre d’accord de 1 a 9 (1 : totalement inapproprie ; 9 : totalement approprie ; 5 : indecision) et ses commentaires pour chaque recommandation. Apres 2 tours de cotations, le GP a reformule une version initiale des recommandations qui a ete soumise au GL. La distribution des scores et les commentaires du GL ont permis au GP de rediger une version finale des recommandations ( Tableau 1 , Tableau 2 , Tableau 3 , Tableau 4 ). Resultats Dix-sept recommandations finales ont ete elaborees par le GP, en tenant compte de tous les scores et commentaires faits par chaque membre du GC, du GL et des 2 methodologistes de l’etude. Ces recommandations definissent notamment 4 domaines : – le type de patients necessitant un biomedicament ; – le type de biomedicament (belimumab, rituximab, etc.) et de co-traitement a utiliser en fonction de l’atteinte d’organe ; – l’information a donner aux patients ; – la facon d’evaluer l’efficacite du traitement. Un algorithme de choix de biomedicament a ete realise a partir des recommandations finales du domaine 2. Conclusion Dix-sept recommandations pour l’utilisation de biomedicaments dans le lupus erythemateux systemique ont ete formulees par un large panel d’experts pour donner des conseils aux cliniciens dans la pratique quotidienne. Ces recommandations seront regulierement mises a jour en fonction des resultats de nouveaux essais cliniques randomises et de l’experience clinique croissante.

Summary Objective: The aim of our study was to evaluate the diagnostic contribution of 18F-fluoro-deoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. Patients and methods: We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. 18F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. Results: 18F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal 18F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal 18F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering 18F-FDG-PET/CT. We considered that 18F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. Conclusions: Our study supports the potential interest of 18F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, 18F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.

Introduction La cohorte LBBR est une cohorte franco–allemande de patients ayant un lupus erythemateux systemique (LES). Les patients ont ete inclus prospectivement entre 2011 et 2015 dans 17 centres avec un recueil de sang a l’inclusion afin de constituer bio-banque. L’objectif de cette etude est de decrire les caracteristiques demographiques, cliniques et biologiques de cette cohorte. Patients et methodes Pour etre inclus les patients devaient etre majeurs et avoir consulte dans un des 17 centres participants. Un phenotypage detaille etait recueilli a l’inclusion en meme temps que le prelevement sanguin. La bio-banque conserve du plasma, des cellules et de l’ADN de tous les patients inclus. Les patients devaient avoir un lupus selon les criteres ACR ou SLICC ou 3 criteres et un diagnostic pose par un centre expert. Par ailleurs, un certain nombre de patients avec un syndrome d’Evans et des ANA positifs ont ete inclus. Les donnees etaient monitorees par les investigateurs. Resultats Au total, 1077 patients ont ete inclus, avec un âge moyen au moment de l’inclusion de 43,6 ans ( ± 16,8). Il y avait une majorite de femme (88,6 %). L’origine ethnique etait frequemment caucasienne (84,3 %), mais on notait egalement des patients d’origine nord-africaine (7,0 %), asiatique (2,8 %) et africaine (2,4 %). Il y avait 78 patients avec un cas familial de lupus systemique au premier degre. Parmi les patients, 30,6 % avaient une autre maladie auto-immune associee. Huit-cent-cinquante-huit (79,7 %) patients remplissaient les 4 criteres ACR ou les criteres SLICC. Le score SLEDAI moyen a l’inclusion etait de 4,07 ( ± 4,7). Les principales manifestations cliniques etaient : des arthrites (n = 743), une photosensibilite (n = 643), un erytheme malaire (n = 549), une nephropathie lupique (n = 348), des serites (n = 255), des manifestations neurologiques (n = 150). Au niveau biologique on notait des Ac antinucleaire positifs chez 95,1 % des patients, des Ac anti-DNA natifs positifs chez 75,7 % et des Ac anti-Sm chez 14,8 %. Une lymphopenie inferieure a 1500/mm3 et une thrombopenie Conclusion Il s’agit de la premiere description d’une grande cohorte franco–allemande de patients avec un lupus systemique. Les caracteristiques cliniques de cette cohorte sont comparables avec celles d’autres cohortes de patients ayant un lupus systemique comme RELESSER et GLADEL. L’analyse genetique couplee a ces donnees phenotypiques detaillees permettra d’avoir plus d’information sur l’impact de la genetique sur le developpement et le pronostic de la maladie. Cette bio-banque est ouverte a tout investigateur pour realiser des projets de recherche.

Key points Idiosyncratic drug-induced agranulocytosis is a potential adverse event of most drugs, rare but life-threatening. Its annual incidence does not exceed 10 cases per million population in Europe and has remained stable over the past two decades. Its pathogenesis is poorly understood . The principal drugs associated with it are antithyroid drugs, antibiotics including trimethoprim, sulfamethoxazole, and beta-lactamines, ticlopidine, sulfasalazine and dipyrone. Clinical presentation is highly variable but a severe infection is observed in more than one third of cases. Poor prognostic factors include a neutrophil count under 100/mm 3 , age > 65 years, septicemia or shock, and severe comorbidity. Improvement in the management of infectious complications and the use of hematopoietic growth factors in severe cases helps explain that mortality rate has fallen to less than 5%.

Alsace is a region in eastern France with a population of ∼2 million. All residents have high access to health care and an accredited referral center for SSc. Seeking care outside of this region is difficult because of the peculiar geography. The aim of this study was to assess the prevalence and spatial variation of systemic sclerosis (SSc) in eastern France.Data for SSc patients were obtained from 3 sources (all general practitioners and community specialists, capillaroscopy centers, and all public and private hospital records) and were used to estimate the prevalence of SSc. Surviving patients who resided in Alsace on January 1, 2008 and fulfilled the American College of Rheumatology and/or the LeRoy and Medsger criteria were included in this study. The clinical characteristics of the patients were also assessed. Potentially incomplete case ascertainment was corrected by capture-recapture analyses. Geographic disparities were assessed by spatial cluster analysis and by comparing our results with those for other geographic areas in the world for which data derived using similar methodology were available.The review of 499 potential cases identified a total of 244 SSc patients. A trend toward a west-to-east gradient was observed but did not reach statistical significance. According to log-linear modeling, an estimated 83.87 additional cases were missed. Thus, the SSc prevalence was 228.42 cases per million adult inhabitants of Alsace (95% confidence interval 203.70-253.14); this prevalence was significantly higher than that in 2 other regions of France and comparable with the reported prevalence in Detroit, Michigan.The stringent methodology used in the current study is very likely to provide an accurate estimation of the prevalence of SSc. Design similarity with 3 other surveys extends the scope of the results by identifying geographic disparities that were previously indistinguishable due to methodologic differences.

Resume Propos. – Le but de cette etude est de determiner le tableau clinique actuel de la maladie de Biermer (MB) en medecine interne. Methode. – Il s'agit d'une etude retrospective (de 1996 a 2002), multicentrique (5 services de medecine interne), incluant 49 observations de MB averee avec une carence en vitamine B12 (B12) documentee. Resultats. – L'âge median des patients etait de 74 ans (25–93), le sex-ratio H/F de 13/36. Trente-cinq pour cent des patients avaient des antecedents et/ou de maladies auto-immunes evolutives ou dysimmunitaires. Des manifestations cliniques variees, neurologiques mais egalement cutaneomuqueuses et thrombotiques etaient trouvees chez 65,4 % des patients, au moins une anomalie hematologique chez 100 %. La B12 serique et l'homocysteinemie moyennes etaient respectivement a 73 pg/ml (20–196) et 42,9 μmol/l (7,8–124). Les anticorps (Ac) antifacteur intrinseque etaient positifs chez 87,5 % des patients, les Ac anticellules parietales gastriques chez 62 % (au moins un des deux Ac chez 96 %). Le test de Schilling affirmait le diagnostic de MB dans 86 % des cas. Le traitement par B12 intramusculaire (n = 27) ou administree par voie orale (n = 5) s'est revele constamment efficace. Conclusion. – L'association de la MB a des maladies auto-immunes et/ou dysimmunitaires est tres frequente ; les tableaux cliniques et les manifestations biologiques de la MB sont extremement varies ; et le traitement par B12 per os peut etre une alternative therapeutique a la voie parenterale.

Introduction Cette etude avait pour objectif de decrire les facteurs demographiques, socio-economiques et les caracteristiques du lupus systemique (LS) associes a la qualite de vie (QDV) mesuree par deux instruments generiques (Medical Outcome Study Short Form 36 [SF-36] et World Health Organisation Quality of life [WHOQOL]) et 2 questionnaires specifiques du LS (LupusQoL et SLEQOL) administres simultanement. Patients et methodes Nous avons conduit une etude de cohorte prospective multicentrique dans 10 hopitaux francais entre 2010 et 2014. L’activite de la maladie evaluee par le questionnaire SELENA-SLEDAI Flare Index Revised (SFI-R) a ete enregistree par le medecin interniste assurant le suivi habituel chez des patients atteints de LS selon les criteres ACR 1997, recrutes consecutivement. Les echelles de qualite de vie ont ete remplies par les patients et les variables socio-economiques recueillies par auto-questionnaire. La precarite sociale a ete evaluee grâce au score « EPICES ». Les variables associees a la QDV (cotee comme un score de 0 a 100 dans chacun des domaines, 100 correspondant a la meilleure QDV) ont ete etudiees a l’aide d’un modele de regression lineaire multiple. Resultats Les 336 patients inclus sur la periode d’etude etaient de sexe feminin dans 90 % des cas, et d’âge moyen (ecart-type) 41(11,9) ans. Le SLEDAI median (intervalle interquartile) etait de 4 (0–8), et 39 % des patientes avaient une poussee moderee dans au moins un organe/systeme d’apres le SFI-R. Cinquante-neuf pour cent des patients etaient traites par corticoides et 1/3 par immunosuppresseurs. D’apres le score EPICES, 38 % des patients etaient en situation de precarite sociale, 62 % des patients avaient un niveau d’etude superieur au baccalaureat et 31 % etaient sans emploi. En regression lineaire multiple, l’origine ethnique n’etait pas associee a la QDV. La precarite sociale etait fortement associee avec le score de qualite de vie dans tous les domaines des questionnaires generiques et specifiques, avec une diminution estimee de la QDV entre −6,5 (domaine « fonction physique » du SF-36, p = 0,02) et −17,84 (domaine « humeur » du SLEQOL, p p p = 0,01]), a l’exception des domaines « psychologique » et « environnement » du WHOQOL. Les signes neuropsychiatriques etaient plus fortement associes aux questionnaires specifiques. Un âge plus eleve etait associe avec une QDV plus faible dans les domaines physiques des questionnaires specifiques, mais pas avec les questionnaires generiques. L’obesite etait associee avec une diminution significative de la QDV dans les domaines physiques du SF-36 (−12,9, p = 0,02 dans le domaine « fonction physique »), a l’exception du domaine « image du corps » du LupusQoL (−8,57, p = 0,02). Par ailleurs, le tabagisme etait associe a une moindre qualite de vie dans certains des domaines physiques des questionnaires generiques, mais pas avec les questionnaires specifiques. Conclusion L’environnement social est fortement associe a la QDV chez les patients atteints de LS, quel que soit l’instrument utilise. Les questionnaires generiques et specifiques pourraient enregistrer des informations differentes et complementaires. Les questionnaires specifiques pourraient etre plus fortement correles avec certains aspects de la maladie et etre utiles pour distinguer le retentissement du LS de celui d’autres comorbidites, comme les pathologies liees au tabagisme, ou a l’obesite.

Introduction Nous rapportons le cas d’une toxocarose revelee par des nodules pulmonaires excaves au scanner. Observation Une femme de 27 ans, d’origine caucasienne, se presentait a la consultation de medecine interne pour decouverte de micronodules pulmonaires dissemines, dont certains excaves, mis en evidence sur un examen scannographique. Elle avait en effet remarque une lesion nodulaire au niveau de son sein gauche depuis environ 4 ans, avec quelques fois un aspect inflammatoire de la peau et une exteriorisation purulente. Son medecin traitant avait demande une mammographie, interpretee comme normale, un bilan biologique qui retrouvait une hypereosinophilie a 1500/mm3 et une radiographie thoracique qui mettait en evidence un syndrome interstitiel micronodulaire bilateral. L’interrogatoire retrouvait un amaigrissement involontaire de 20 kg en deux ans, des episodes febriles intermittents depuis 6 mois, avec des pics jusqu’a 39 °C, des sueurs nocturnes, avec un etat general conserve. Une toux ancienne semblait par ailleurs persister. Il n’y avait pas de notion de voyage en zone tropicale. Elle avait travaille un an dans la marine, ou elle avait voyage en Ecosse uniquement. La patiente possedait en revanche un chat et un chien depuis plusieurs annees. Ses principaux antecedents comprenaient un tabagisme recemment sevre a 12 paquets-annees et une allergie aux acariens, phaneres d’animaux et pollens de gramines. L’examen clinique etait normal en dehors une lesion pigmentee centimetrique d’allure ancienne au niveau du sein gauche. Le bilan biologique etait marque par une hypereosinophilie (1,5 G/L), une elevation des IgE totales a 460 kUI/L. On ne notait pas de syndrome inflammatoire et l’electrophorese des proteines plasmatiques etait normale. Fonction renale et bilan hepatique etaient sans particularites. Le bilan auto-immun en particulier etait negatif, le dosage de l’enzyme de conversion de l’angiotensine normal. Les coprocultures bacteriennes et parasitaires (en particulier la recherche d’anguillules) etaient negatives. Les serologies parasitaires Toxocarose larva migrans (IFI A. Suum a 1/60, Western Blot T. canis positif), Trichinellose (IFI T. Spiralis a 1/60) et Ascaridose se revelaient positives (IFI sur A. suum a 1/60, Western Blot sur T. canis positif). Les serologies hydatidose, echinococcose alveolaire, Taenia saginata et T. anguillulose etaient negatives. L’echographie abdomino-pelvienne etait sans particularite. L’echographie des seins concluait a une mastodystrophie d’origine fonctionnelle. La biopsie cutanee de l’areole mammaire retrouvait un infiltrat inflammatoire non specifique sans arguments pour une lesion maligne. Le scanner thoracique sans injection mettait en evidence des micronodules dissemines intra-pulmonaires, predominant en peripherie, avec pour certains un aspect d’excavation, de l’ordre de 8 mm. Il n’y avait pas de lesions kystiques a paroi fine. Le lavage broncho-alveolaire retrouvait une flore normale, pas de bacilles acido-alcoolo-resistants ni d’histiocytes, et la culture (en particulier de mycobacteries, notamment atypiques) etait negative. Un traitement par albendazole per os administre empiriquement avant l’ensemble des resultats biologiques permettait tres rapidement une amelioration clinique, biologique et radiologique : dix jours plus tard, la patiente ne presentait plus aucun symptome. L’hypereosinophilie se normalisait et le scanner thoracique de controle a 3 mois etait strictement normal. Discussion Devant le tableau de granulomatose avec excavations pulmonaires, il n’etait aucunement evident d’evoquer le diagnostic de toxocarose. Il etait d’abord legitime d’eliminer une infection, et en particulier une mycobacteriose. Une histiocytose langerhansienne pulmonaire etait peu probable en l’absence d’images kystiques, et en presence de l’hypereosinophilie. Une maladie de Wegener etait peu probable en l’absence de signes extra-pulmonaires. Les metastases ne pouvaient etre exclues sans documentation histologique. Ici, le diagnostic de toxocarose a ete pose a posteriori sur la base de l’hypereosinophilie biologique, des lesions pulmonaires scannographiques (bien qu’atypiques), des serologies positives, de l’amelioration spectaculaire de la symptomatologie sous traitement anti-parasitaire, et de l’absence d’arguments pour un autre diagnostic. Conclusion La toxocarose peut etre revelee chez le sujet caucasien par un tableau pulmonaire avec des nodules excaves. Il est important de connaitre ce diagnostic peu frequent, car il est accessible a un traitement curatif rapidement efficace.

Objective.The clinical spectrum, etiologies, and best therapeutic approaches of type II mixed cryoglobulinemia (MC) not associated with hepatitis C virus (HCV) infection have been poorly described to date. We studied the clinical presentation and outcome of patients with type II MC with no evidence of HCV.Methods.This was a multicenter retrospective study on the clinical presentation and outcome of patients with type II MC without evidence of HCV infection. Only patients with symptomatic MC were included.Results.Thirty-three patients were included (median followup 67.2 mo). Extensive investigations for associated diseases were performed at presentation. MC was related to an autoimmune disease in 14 patients, to a lymphoid malignancy in 4 patients, and to an infectious disease in 2 patients, while MC was classified as essential (primary) in 13. Essential MC tended to be more severe than secondary disease with, in particular, more frequent renal and peripheral nerve involvement. Most patients were treated with steroid with or without immunosuppressive agents, mainly cyclophosphamide. These treatments were unable to induce sustained remission. One patient was successfully treated with lenalidomide. Seven patients with nonmalignant MC were treated with rituximab; 2 had a sustained complete remission, 3 improved greatly but relapsed within 5 months, and 2 experienced a disease flare.Conclusion.An important proportion of non HCV-related type II MC remains essential. Efforts should be made to find other etiologies than HCV, because treatments with steroid and immunosuppressants are not satisfactory, especially in severe forms. In these situations anti-CD20 therapy may present the best option but should be used with caution. New agents such as lenalidomide remain to be evaluated.

Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomas of quiescent lupus patients to normal B cell transcriptomas. When the statistical analysis is performed on the entire group of patients, the differences between patients and controls appear quite weak with only 14 mRNA genes having a false discovery rate ranging between 11 and 17%, with 6 underexpressed genes (PMEPA1, TLR10, TRAF3IP2, LDOC1L, CD1C and EGR1). However, unforced hierarchical clustering of the microarrays reveals a subgroup of lupus patients distinct from both the controls and the other lupus patients. This subgroup has no detectable clinical or immunological phenotypic peculiarity compared to the other patients, but is characterized by 1/an IL-4 signature and 2/the abnormal expression of a large set of genes with an extremely low false discovery rate, mainly pointing to the biological function of the endoplasmic reticulum, and more precisely to genes implicated in the Unfolded Protein Response, suggesting that B cells entered an incomplete BLIMP1 dependent plasmacytic differentiation which was undetectable by immunophenotyping. Thus, this microarray analysis of B cells during quiescent lupus suggests that, despite a similar lupus phenotype, different biological roads can lead to human lupus.

To better understand the structural basis for rheumatoid factor [RF] activity and the origin of autoantibodies in human autoimmune diseases, we isolated the RF producing B cells from the peripheral blood and from the synovial fluid of a patient suffering from rheumatoid arthritis [RA]. We previously demonstrated that a significant fraction of these RF were derived from three V kappa III genes known to encode most of the monoclonal RF light chain variable regions. To get more insight into the actual repertoire of RF-V kappa genes during RA, we analyzed the nucleotide sequences of RF light chain variable regions of other V kappa families. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from RF producing cells from the same patient KRA, we isolated only three different rearranged V kappa-J kappa complexes: slkv5, slkv7 and bkv42, all derived from V kappa I germ-line genes not previously known to be associated with RF activity; this suggests that the repertoire of VL genes coding for RF during RA is more diverse than the one involved in the generation of paraprotein RF during monoclonal lymphoid proliferations, although there remains a possible bias in favor of the V kappa III family. Moreover, each of these genes is somatically mutated with a pattern suggesting a selective pressure of the antigen. Particularly interesting is the additional proline residue at the V kappa-J kappa junction of bkv42, an unorthodox feature that we found previously in more than 50% of RF V kappa III-J kappa gene complexes. Finally, the homogeneity of some non conservative mutations suggests the existence of a restricted set of pathogenic epitopes driving the production of RF during RA.

Much interest was stirred in recent years by the evidence that rheumatoid factors (RF) variable regions are encoded by a restricted set of V genes, with little or no somatic mutations, that are often overexpressed in the fetal repertoire. This is reminiscent of what has been observed for natural autoantibodies. However, these data come from studies of monoclonal RF (mRF) isolated from patients with lymphoproliferative disorders who usually do not present autoimmune symptoms. The molecular characterization of RF during autoimmune diseases such as rheumatoid arthritis (RA) has been hampered for some time because of their polyclonality; recently using the polymerase chain reaction method, we have demonstrated that RF kappa variable regions from a patient with RA were encoded by V kappa III genes known to code for mRF but that these genes had undergone somatic mutations with a pattern suggesting an antigen-driven maturation. Because an important role of the light chain third complementarity-determining region (CDR3) in anti-IgG reactivity and idiotype expression has already been suspected for RF, we now report the molecular characterization of the junction regions of these rearranged V kappa gens. Surprisingly, our data show that in 55% of the cases there is addition of a proline and/or glycine amino acid residue at the recombination site between V kappa and J kappa. The sequence analysis of our patients' germ-line Vg and J kappa 4 genes segments and their flanking regions demonstrates that the additional codons are not readily explicable by recombination between germ-line sequences and probably result from an N addition process. Since we could not find such an additional codon in 15 previously published mRF kappa chains we suggest that "pathogenic" RF during RA and mRF derive from different, although overlapping, B cell subsets. Moreover, since additional codons at the recombination site of V kappa and J kappa seem exceptional in expressed human kappa chains and because the resulting amino acid residue is a proline in most cases, we think that RF kappa chain CDR3 is under a very strong selective pressure during RA.