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Among interstitial pneumonia with autoimmune features (IPAF) patients, identifying those at risk to develop a connective tissue disease (CTD) during the disease course is a key issue. The aim of this study was to evaluate the incidence of definite CTD diagnosis in IPAF patients during follow-up.We performed a multicentric cohort study of interstitial lung disease (ILD) from 2010 to 2017 in pneumology and immunology departments of tertiary care centers. Patients with a known cause of ILD (including established CTD) at diagnosis were excluded. Among patients with idiopathic ILD and at least three years of follow-up, two groups (IPAF and non-IPAF) were retrospectively analyzed at time of diagnosis.A total of 249 patients with ILD were enrolled, including 70 IPAF and 179 non-IPAF patients. After a mean follow-up time of 77 ± 44 months, 18/70 IPAF patients (26%) had a CTD diagnosis - 9 antisynthetase syndrome, 8 systemic sclerosis and 1 overlap myositis - compared with 4/179 non-IPAF patients (2%). IPAF patients were at higher risk of CTD occurrence at 3 years of follow-up compared to non-IPAF patients (HR 10.1, 95% CI 3.1-33.1, p 0. 01). IPAF patients progressing to CTD tended to be younger, more often female and have more frequently puffy fingers, capillaroscopy abnormalities and antisynthetase antibodies at diagnosis.We found that a significant proportion of IPAF patients had associated CTD diagnosis during follow-up. Prospective studies are needed to confirm baseline predictive factors of CTD occurrence in IPAF patients.

Resume Introduction Les telomeres sont composes d’une sequence repetee de nucleotides double brin TTAGGG et sont associes a de nombreuses proteines dont le complexe « Shelterin ». Leur role principal est de maintenir la stabilite du genome lors de la replication cellulaire grâce a un mecanisme de copie de la sequence repetee par le complexe telomerase. L’ensemble des pathologies impliquant une deregulation de la maintenance des telomeres sont maintenant reunies sous le terme de telomeropathies. L’objectif de notre etude etait de decrire les caracteristiques clinico-biologiques et therapeutiques dans une cohorte de patients atteints de telomeropathie de recrutement hematologique suivis en medecine interne au centre hospitalier universitaire de Lille. Methodes Il s’agit d’une etude retrospective, unicentrique realisee au sein du service de medecine interne-immunologie clinique, centre de reference des maladies auto-immunes et systemique rares au CHU de Lille entre 2005 et 2020 incluant l’ensemble des patients suivis pour telomeropathie. Resultats Des cas index et des apparentes ont ete inclus. Les 15 patients etudies etaient issus de 10 familles independantes. Soixante pour cent etaient porteurs d’une mutation du gene TERC a l’etat heterozygote. Soixante-sept pour cent avaient une atteinte hematologique comprenant notamment une macrocytose avec anemie et/ou thrombopenie, 20 % une atteinte hepatique et 27 % une atteinte pulmonaire de type fibrosante. L’immunophenotypage lymphocytaire montrait la presence d’une population lymphocytaire T double negative avec une expression de TCR γδ pour 5 (33 %) d’entre eux. Quarante-sept pour cent des patients n’avaient recu aucun traitement. Vingt-sept pour cent etaient sous androgene. Vingt pour cent avaient recu de la ciclosporine et 13 % du serum anti-lymphocytaire dans un contexte de diagnostic errone d’une aplasie acquise. Conclusion Il est important pour le medecin interniste d’etre sensibilise a la complexite des telomeropathies, diagnostic differentiel des aplasies medullaires acquises idiopathiques, pour pouvoir optimiser la prise en charge et eviter les therapeutiques inappropriees. L’allogreffe de cellules souches hematopoietiques est le seul traitement potentiellement curatif. Notre analyse a rapporte des particularites a l’immunophenotypage lymphocytaire non decrites a notre connaissance dont l’imputabilite physiopathologique reste a demontrer.

Resume Objectifs L’hydroxychloroquine (HCQ) est un medicament cle utilise dans le traitement du lupus erythemateux systemique (LES). L’observance est essentielle et doit etre evaluee avec precision pour eviter des substitutions inutiles par un medicament plus couteux ou moins bien tolere. Methodes Un taux eleve de non-observance du traitement par HCQ, defini par une hydroxychloroquinemie Resultats L’etude a inclus 158 patients (86,1 % de femmes) de 42,2 ± 12,6 ans traites par HCQ depuis 9,6 ± 6,9 ans. Le taux sanguin d’HCQ (moyenne ± ecart-type) etait de 1046 ± 662 μg/L a la visite 1 et de 855 ± 577 μg/L a la visite 2. A la visite 1, le taux de non-observance variait de 3,2 % (hydroxychloroquinemie Conclusion Un taux sanguin d’HCQ

Resume Objectif Dans la sclerodermie systemique (ScS) et les myopathies inflammatoires idiopathiques (MII), les auto-anticorps sont utilises dans la pratique quotidienne comme biomarqueurs des phenotypes cliniques. Cette etude vise a estimer la prevalence des anticorps specifiques des myosites (ASM) et des anticorps associes aux myosites (AAM) en utilisant deux tests immunoblots differents dans une cohorte de patients atteints de ScS bien caracterises, puis a etudier leurs associations cliniques. Methodes Dans cette etude transversale, les serums de 300 patients ont ete testes de facon consecutive, avec realisation simultanee des tests immunoblots « myosites » Euroimmun® et D-tek®. Resultats La prevalence des ASM/AAM, ASM et AAM etait respectivement de 17,0 %, 8,0 % et 9,7 %. En combinant les resultats des deux tests, des anticorps anti-PM/Scl 100 etaient presents chez 5,0 % (intervalle de confiance a 95 % : 2,8 ; 8,1) ; anti-PM/Scl 75 et anti-TIF1γ chez 3,7 % (1,8 ; 6,5) ; anti-Ku chez 3,0 % (1,4 ; 5,6) ; anti-MDA5 chez 1,3 % (0,4 ; 3,4) ; anti-Mi-2 β, anti-NXP2, anti-PL-7 et anti-SRP chez 0,7 % (0,08 ; 2,4) ; anti-EJ et anti-PL-12 chez 0,3 % (0,01 ; 1,8) des patients. Aucune reactivite anti-SAE1, Jo-1 ou OJ n’a ete observee. Les anticorps anti-PM/Scl 75 etaient associes a la pneumopathie interstitielle (80 % contre 42 %) et la myosite (27 % contre 3 %) ; les anticorps anti-Ku etaient associes avec la myosite (33 % contre 3 %). Conclusion Dans cette etude transversale portant sur 300 patients atteints de ScS, la prevalence des ASM/AAM, des ASM et des AAM, testes a partir de deux immunoblots differents, etait respectivement de 17,0 %, 8,0 % et 9,7 %. La positivite des AAM etait associee a la pneumopathie interstitielle et a la myosite, mais cette etude n’a pas mis en evidence d’association clinique avec les ASM.

Background Gastrointestinal (GI) involvement was described to be a poor prognostic factor in systemic necrotizing vasculitis. Its prognostic significance may vary according to clinical presentation and vasculitis subtype. Aims This study investigated risk-factors associated to poor outcome in GI-involvement of vasculitis. Methods Patients with systemic vasculitis as defined by the 2012 Chapel Hill Consensus Conference and presenting with GI involvement were retrospectively included. Baseline characteristics, treatments and outcome were recorded. Primary endpoint was a composite of admission to intensive care unit (ICU), emergency surgical procedure, or death. Results Two hundred and thirteen patients were included. Vasculitis were distributed as follows: 41% IgA vasculitis, 27% ANCA-associated vasculitis, 17% polyarteritis nodosa (PAN), and 15% other vasculitis. Eighty-three (39%) patients fulfilled the composite primary endpoint within 6 months. Predictive factors associated with the primary endpoint included PAN subtype (OR 3.08, 95% CI 1.29–7.34), performance status (OR 1.40, 1.05–1.87), use of morphine (OR 2.51, 0.87–7.24), abdominal guarding (OR 3.08, 1.01–9.37), ileus (OR 2.29, 0.98–5.32), melena (OR 2.74, 1.17–6.42), increased leukocytes (per G/L, OR 1.05, 1.00–1.10), low hemoglobin (per g/dL, OR 0.80, 0.71–0.91) and increased CRP (log mg/L, OR 1.21, 0.94–1.56). A risk prediction model for the achievement of primary endpoint had a very good performance [C-statistics 0.853 (0.810 to 0.895], and for overall survival as well. Conclusions Vasculitis presenting with GI involvement have a poor outcome in more than one third of cases. An easy-to-use risk prediction model had a very good performance to predict the admission to ICU, emergency surgical procedure, or death.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Objective To report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors. Methods We analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25–47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model. Results Among 318 TA patients, 16 (5%) died after a median [IQR] follow-up of 6.1 [2.8–13.0] years. The median age at death was 38 [25–47] years with 88% of women. Main causes of death included mesenteric ischemia (n = 4, 25%) and aortic aneurysm rupture (n = 4, 25%). The mortality rate at 5 and 10 years was of 1.9% and 3.9%, respectively. Caucasians (p = 0.049) and smokers (p = 0.002) TA patients were more likely to die. There was an increased mortality in TA (SMR with 95% confidence interval, 2.73 [1.69–4.22]) as compared to age and sex matched healthy controls. We defined high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). In the high risk TA group, the 5-year incidence of death and vascular complication was 48.5% compared to 21.6% (p = 0.001) in those with low risk. Conclusion The overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. We identified specific characteristics that distinguish TA patients at highest risk for death and vascular complications.

Patients with HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) experience systemic inflammatory symptoms and polyclonal lymphoproliferation due to an unknown etiology. Schnitzler's syndrome (SS) is characterized by recurrent urticarial rash, monoclonal IgM gammopathy, and other clinical signs of inflammation. To our knowledge, we report the first case of iMCD associated with SS and the fourth case of anakinra inducing a complete response for an iMCD patient. A forty-four year old woman with a history of a recurrent urticarial rash, presented to our hospital complaining of 6 months of night sweats, fever, chronic urticaria, iliac bone pain, and generalized lymphadenopathy. An IgM Kappa monoclonal component was measured at 7.8g/L. A lymph node biopsy revealed histopathological features consistent with the plasma cell variant of iMCD. She was diagnosed with SS and iMCD. Anti-IL-1 treatment with anakinra (100mg/day) was introduced. Within 48h, we observed improvement in the fever and the urticarial rash. By one month, we considered the patient in complete remission. Two years later, the remission is persistent while the patient is still under therapy. Though this is only the fourth reported case of anakinra in iMCD, this is yet another case demonstrating the effectiveness of anti-IL-1 blockade in SS. We hypothesize that uncontrolled cytokine production is responsible for both the SS and the iMCD. The etiologies of SS and iMCD are unknown, and future research is necessary.

Background Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE). Methods We identified all patients with SLE and PAH (SLE-PAH) who were enrolled in the French Pulmonary Hypertension Registry with a diagnosis confirmed by right heart catheterization (RHC). A control group of 101 patients with SLE without known PAH was selected from SLE expert centers participating in the Pulmonary Hypertension Registry. Survival was estimated by the Kaplan-Meier method. Hazard ratios associated with potential predictors of death were estimated using Cox proportional hazard models. Results Of the 69 patients with SLE-PAH identified in the French Pulmonary Hypertension Registry, 51 were included in the study. They did not differ from the control group regarding age, sex, or duration of SLE at the time of the analysis but had a higher frequency of anti-SSA and anti-SSB antibodies. The delay between SLE diagnosis and PAH diagnosis was 4.9 years (range, 2.8-12.9) years. The 3- and 5-year overall survival rates were 89.4% (95% CI, 76.2%-96.5%) and 83.9% (95% CI, 68.8%-92.1%), respectively. The survival rate was significantly better in patients with anti-U1-RNP antibodies ( P = .04). Conclusions Patients with SLE-PAH have an overall 5-year survival rate of 83.9% after the PAH diagnosis. Anti-SSA/SSB antibodies may be a risk factor for PAH, and the presence of anti-U1-RNP antibodies appears to be a protective factor regarding survival.

Background Dilated cardiomyopathy (DCM), a well-known complication of cardiac neonatal lupus, is associated with high mortality rate. Its risk factors remain unclear. Methods We analyzed occurrence of postnatal DCM among children with high-degree congenital heart block (CHB) and mothers with anti-SSA and/or anti-SSB antibodies. Results Among 187 neonates with CHB, 35 (18.8%, one missing data) had DCM and 22 (11.8%) died during a median follow-up of 7years [range: birth–36years]. On multivariate analysis, factors associated with postnatal DCM were in utero DCM ( P =0.0199; HR=3.13 [95% CI: 1.20–8.16]), non-European origin ( P =0.0052; HR=4.10 [95% CI: 1.81–9.28]) and pacemaker implantation ( P =0.0013; HR=5.48 [95% CI: 1.94–15.47]). Postnatal DCM could be categorized in two subgroups: neonatal DCM (n=13, diagnosed at a median age of 0day [birth–4days]) and late-onset DCM (n=22, diagnosed at a median age of 15.2months [3.6months–22.8years]). Factors associated with neonatal DCM were in utero DCM, hydrops, endocardial fibroelastosis and pericardial effusion, whereas those associated with late-onset DCM were non-European origin, in utero mitral valve insufficiency, and pacemaker implantation. Fluorinated steroids showed no protective effect against late-onset DCM ( P =0.27; HR=1.65 [95% CI: 0.63–4.25]). Probability of survival at 10years was 23.1% for newborns diagnosed neonatally with DCM, 53.9% for those who developed late-onset DCM, and 98.6% for those without DCM. Conclusion Neonatal and late-onset DCM appear to be two different entities. None of the known risk factors associated with neonatal DCM predicted late-onset DCM. Long-term follow-up of cardiac function is warranted in all children with CHB.

Between 9000 and 14000 people have systemic sclerosis (ScS) in France. The work is often affected. Our study aims to assess the frequency of professional difficulties (DP) of scleroderma patients, identify these DP, the symptoms involved and the solutions used. A heteroquestionnaire was offered to scleroderma patients the Lille University Hospital. Data were cross-checked with the clinical database of the National Observatory of scleroderma patients. We used 104 questionnaires of which 84% are women. A total of 62.5%, (95% CI [52.5 to 71.8]) patients had experienced DP related to SSc, 55% reported symptoms worsened at work, 41% lower efficiency and a 19% job loss. Symptoms responsible for their DP were mainly asthenia, Raynaud syndrome, arthralgias and finger ulcerations. Only 40% of patients in difficulty were initiating steps with the county home for disabled people and 45% in informing their doctor at work (MT). The MT information absence was related to a misunderstanding of possible aid in 45% of cases, 57% of patients had not found a solution, 41% of them have lost their jobs and 31% of patients in the cohort experienced a drop in income. The impact of SSc the work is important. The aid job retention devices are under-used due to lack of knowledge of steps to take and the role of MT. Taking into account the symptoms responsible for PD must be improved to participate in this retention.

Introduction L’objectif de ce travail est d’etudier les alterations du proteome serique des patients atteints d’hypertension arterielle pulmonaire (HTAP) associee a la clerodermie systemique (SSc), d’identifier les proteines correlees a la severite hemodynamique et determiner leur role potentiel dans la physiopathologie de la maladie. Patients et methodes Les patients eligibles ont ete recrutes dans les centres de reference SSc et/ou HTAP de Boston, Lille, Le Kremlin-Bicetre et Grenoble. Les patients etaient inclus s’ils remplissaient les criteres suivants : diagnostic de SSc selon les criteres ACR/EULAR 2013, forme cutanee limitee, pas de pneumopathie interstitielle diffuse (PID) etendue selon les criteres de Goh, et pas de traitement specifique de l’HTAP. Les patients etaient consideres comme des cas s’ils avaient un diagnostic d’HTAP confirme par catheterisme cardiaque droit (KTD) et un echantillon de serum preleve le meme jour que le KTD. Ils etaient consideres comme des temoins s’ils n’avaient aucun signe evocateur d’HTAP a l’echocardiographie. Resultats Dans une premiere etape exploratoire, l’expression serique de 1129 proteines a ete evaluee chez 15 cas et 16 temoins par analyse proteomique a haut debit (SOMAscan). Nous avons identifie 53 proteines exprimees differentiellement entre les 2 groupes. Parmi ces 53 candidats, seules 2 etaient significativement correlees avec les resistances vasculaires pulmonaires (RVP) : chemerine (p = 0,01, ρ = 0,62) et SET nuclear proto-oncogen (SET) (p = 0,01, ρ = 0,62). Pour valider ces resultats, les taux seriques de chemerine et SET ont ete mesures en ELISA chez 25 cas et 19 controles supplementaires. Les dosages de chemerine etaient de nouveau significativement plus eleves chez les cas (p = 0,01) et correles avec les RVP (p = 0,01, ρ=0,46) dans cette cohorte independante. Dans une deuxieme etape, pour etudier le role physiopathologique potentiel de la chemerine, nous avons realise des marquages en immunofluorescence confocale sur des poumons explantes de temoins sains, de patients SSc-PID sans HTAP et de patients SSc-HTAP. Le marquage du recepteur de chemerine, CMKLR1, etaient significativement augmente sur les cellules musculaires lisses d’artere pulmonaire (CML-AP) de patients SSc-PID et de patients SSc-HTAP. Nous avons ensuite teste l’effet de la chemerine sur la proliferation des CML-AP en stimulant les CML-AP de patients presentant une HTAP idiopathique (HTAPi) avec du serum de patients SSc avec et sans HTAP, en presence ou en l’absence d’un inhibiteur de CMKLR1. On confirmait que les CML-AP d’ HTAPi surexprimaient l’ARNm de CMKLR1 par rapport aux temoins sains (p = 0,03). Le serum des patients SSc-HTAP induisait une proliferation de CML-AP significativement plus elevee (p = 0,005) que le serum des temoins. Cette difference n’etait plus significative (p = 0,69) lors de l’ajout de l’inhibiteur CMKLR1 a-NETA. Conclusion La chemerine semble etre un biomarqueur de substitution valide des RVP dans l’HTAP-SSc. L’elevation de la chemerine circulante et la surexpression de son recepteur, CMKLR1, contribuent a la physiopathologie de l’HTAP-SSc en induisant la proliferation des CML-AP.

Resume Introduction L’angiœdeme hereditaire (AOH) est caracterise par des poussees recidivantes d’œdemes de localisations et de severite variables. Une alteration de la qualite de vie des patients atteints d’AOH est decrite par plusieurs etudes. Nous avons etudie l’impact global de la maladie chez les patients suivis pour un AOH de type I, notamment son retentissement sur les activites de la vie quotidienne, la sphere emotionnelle et la qualite de vie. Methodes Un questionnaire a ete distribue aux patients consultant pour un AOH de type I, recueillant les caracteristiques demographiques, les caracteristiques de la maladie, le retentissement sur la vie professionnelle, le score Hospital Anxiety And Depression (HAD), le score SF-36 et le questionnaire de handicap prioritaire McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). Resultats Les 33 patients inclus rapportaient en moyenne de 5,17 crises sur l’annee precedente. Le stress etait le principal facteur declenchant. Un traitement de fond etait rapporte par 58 % des patients, 72 % recevaient un traitement specifique en cas de crise severe. Un absenteisme pendant leurs etudes etait rapporte 33 % des patients, et pendant leur travail par 34 %. Un patient souffrait de symptomes depressifs et dix autres de symptomes anxieux d’apres le questionnaire HAD. Les domaines les plus impactes sur le score SF-36 etaient la perception generale de la sante et de la vitalite. Le score moyen pour le MACTAR etait faible. Conclusion L’AOH a un retentissement encore important dans la vie quotidienne et affective des patients, malgre la disponibilite de traitements preventifs et curatifs des crises.

Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan.ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up.Data were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046).In patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability.

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

International audience; BACKGROUND:As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature.METHODS:46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage >1g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed.RESULTS:We observed a significant improvement of muscle pain (74% vs. 20%, p

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

Objectives Systemic capillary leak syndrome (Clarkson's disease) is a rare entity characterized by recurrent and unpredictable attacks of capillary leakage of plasma fluid and proteins throughout the endothelium. Some cases are secondary. We describe the rare association between secondary capillary leak syndrome (SCLS) and autoimmune diseases. Methods We conducted a nationwide, retrospective, observational, and collaborative study throughout the hospital units of the Club des Rhumatismes et Inflammations network (CRI) between March and August 2015. Inclusion criteria were patients with (1) capillary leakage episodes characterized by edema and elevated hematocrit, low albumin count without proteinuria, or other cause of protein loss; and (2) definite autoimmune diseases according to international classification criteria. Results The clinical and biological data of five patients (three women) were reviewed. Median age was 43.2 (17–55) years. Four patients had Sjogren syndrome. One of them also fulfilled the criteria for systemic sclerosis ( n = 1). The fifth patient had polymyositis. During the 37.2 months of median follow-up (5.4–201), we recorded a total of 24 attacks, yielding an attack incidence of 91/100 patient-years. Laboratory tests revealed that three patients had anti-SSA/Ro antibodies. Only one patient had a monoclonal blood component (IgGκ). Three patients needed ICU support; one died during a flare. Conclusions We reported the first case series of a rare association of SCLS and autoimmune diseases, supporting the idea of some immune mediation in the pathogenesis of the former disease.

Resume Introduction L’amylose AA est une complication classique et grave de nombreux processus inflammatoires chroniques, qu’ils soient d’origine infectieuse, auto-immune, ou neoplasique. Elle se complique frequemment d’une atteinte renale, souvent sous forme d’un syndrome nephrotique. L’arterite a cellules geantes est une arterite inflammatoire frequente chez le sujet âge ; cependant, il est rare qu’elle engendre une amylose AA. Observation Nous rapportons l’observation d’une patiente presentant un syndrome nephrotique et un syndrome inflammatoire chronique, chez qui la biopsie renale revelait une amylose secondaire. L’enquete etiologique concluait a une amylose consecutive a une pan-aortite a cellules geantes, alors qu’il n’y avait pas de signes cliniques typiques en faveur de cette maladie. L’evolution renale et generale etait rapidement defavorable malgre l’instauration du traitement. Conclusion En cas de syndrome inflammatoire chronique inexplique du sujet âge, une aortite compliquant une arterite a cellules geantes doit etre recherchee, car le diagnostic clinique de cette forme de vascularite est difficile, alors que le retard diagnostique expose a des complications graves, voire fatales.

Resume Introduction Les manifestations vasculaires au cours du lupus erythemateux systemique (LES) sont de mecanismes (atteinte inflammatoire ou vascularite, atherosclerose, etc.) et de presentations varies. Observation Nous rapportons l’observation d’un patient de 34 ans avec un LES comportant une atteinte cutanee, articulaire, neurologique et renale. Il presentait un choc hemorragique sur rupture d’un micro-anevrisme de l’artere hepatique gauche dont l’evolution etait favorable apres transfusions, traitement immunosuppresseur et hydroxychloroquine. Conclusion Atteinte rare au cours du LES, une vascularite digestive peut se manifester par des micro-anevrismes notamment hepatiques a l’instar de la panarterite noueuse. Dans la litterature, 10 cas de vascularite des arteres digestives avec micro-anevrismes ont ete rapportes. L’enjeu principal reside dans un diagnostic precoce pour une prise en charge adaptee et une amelioration du pronostic des patients.

Objective In systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), auto-antibodies are used in daily practice as potent biomarkers of clinical phenotypes. This study aimed at estimating the prevalence of myositis-specific (MSA) and myositis-associated (MAA) auto-antibodies in a well-characterised SSc patients cohort using two different immunoblot assays, and studying their clinical associations. Methods In this cross-sectional study, the sera of 300 consecutive patients were tested at the same time with myositis antibodies Euroimmun® and D-tek® immunoblot assays. Results Prevalence of MSA/MAA, MSA and MAA were 17.0%, 8.0% and 9.7%, respectively. When combining results of both tests, anti-PM/Scl 100 were found in 5.0% (95% confidence interval 2.8; 8.1); anti-PM/Scl 75 and anti-TIF1γ in 3.7% (1.8; 6.5); anti-Ku 3.0% (1.4; 5.6); anti-MDA5 in 1.3% (0.4; 3.4); anti-Mi-2 β, anti-NXP2, anti-PL-7 and anti-SRP in 0.7% (0.08; 2.4); anti-EJ and anti-PL-12 in 0.3% (0.01; 1.8) of patients. No reactivity against SAE1, Jo-1 or OJ was observed. Anti-PM/Scl 75 antibodies were associated with interstitial lung disease (80% vs. 42%) and myositis (27% vs. 3%); anti-Ku antibodies were associated with myositis (33% vs. 3%). Conclusion In this cross-sectional study of 300 SSc patients, the prevalence of MSA/MAA, MSA and MAA using immunoblot assays were 17.0%, 8.0% and 9.7%, respectively. MAA positivity was associated with ILD and myositis, but this study did not highlight any clinical associations with MSA positivity.

Subcutaneous immunoglobulin (SCIg) therapy is indicated in primary and secondary immunodeficiency diseases. Its use in practice is being extended to autoimmune diseases. Few studies investigated the feasibility and safety of SCIg in these rare conditions. The aim was to describe the use of SCIg in inflammatory myopathies including polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), in real-life settings. This case series was based upon a retrospective data collection. The primary objective was to assess the feasibility of the SCIg injections for the treatment of autoimmune diseases and adherence to high doses. Secondary objectives included safety and efficacy. Nineteen cases were identified: 7 patients were diagnosed with PM, 7 with IBM, 2 with DM, and 3 with myositis associated with connective tissue disease. Patients were treated and followed-up for a mean duration of 18.8 months (range 4.5-42). They received a median of 64 SCIg infusions and a total of 1215 infusions. Out of 14 patients, 10 showed an improvement in muscle strength, and 7 out of 11 showed an improvement in muscle disability scale. Two patients were lost to follow-up. Few slight adverse reactions were reported including mainly mild headaches and local skin reactions. Any serious adverse event was reported. These results suggest that the use of high-dose SCIg is feasible, beneficial and safe in patients with inflammatory myopathies. SCIg could be an alternative of IVIg in patients with difficult venous access or with insufficient response, and in patients preferring home care setting.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti–MDA5 + -patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti–MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2–positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti–MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

Resume Introduction La maladie de Castleman multicentrique (MCM) peut mimer une maladie de Still de l’adulte. Elle est exceptionnellement associee a une anasarque, une microangiopathie thrombotique et une dysautonomie. Observation Nous rapportons l’observation d’une femme de 32 ans qui presentait a la fois une oligo-anurie avec anasarque, une microangiopathie thrombotique et un tableau compatible avec une maladie de Still. L’evolution etait initialement favorable sous corticotherapie, immunoglobulines polyvalentes et plasmaphereses, avec cependant la persistance de poussees marquees par un syndrome dysautonomique severe et une corticodependance. Le diagnostic de maladie de Castleman de type mixte, HHV8 et VIH negative, etait porte 4 ans apres le debut des symptomes sur une biopsie ganglionnaire. L’evolution etait initialement favorable apres l’introduction de tocilizumab associe a la corticotherapie, puis le remplacement du tocilizumab par l’anakinra permettait un controle durable de la maladie. Conclusion Le tableau de notre patiente correspond partiellement a la description du syndrome TAFRO (Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly) variant de MCM recemment decrit chez des patients japonais.

Resume Le cerveau est l’un des principaux organes touches au cours du syndrome des anticorps antiphospholipides. Le neurologue est donc un acteur important de la prise en charge de ces patients. L’accident vasculaire cerebral ischemique ou l’accident ischemique transitoire sont les manifestations neurologiques les mieux documentees du syndrome des anticorps antiphospholipides, qui en font donc une etiologie classique d’ischemie cerebrale chez le sujet jeune. Poser un diagnostic est un enjeu majeur pour ces patients car ceux-ci sont exposes a risque immediat et prolonge de recidive thrombotique. Ce risque est cependant heterogene et etroitement lie au profil de positivite des anticorps antiphospholipides. De nombreuses autres manifestations neurologiques sont egalement rencontrees chez ces patients, telles que migraine, crises d’epilepsie, troubles cognitifs, troubles psychiatriques, choree, myelite transverse et sclerose en plaques-like syndrome. L’objectif de cet article est de faire un etat des lieux des connaissances actuelles sur les manifestations neurologiques centrales du syndrome des anticorps antiphospholipides, accompagnee d’une mise au point sur la prise en charge de ces patients apres un evenement neurologique, afin de guider le neurologue dans sa pratique quotidienne.

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.

Objective To describe characteristics and long-term outcomes of patients with microscopic polyangiitis (MPA), an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel necrotizing vasculitis. Methods MPA patients from the French Vasculitis Study Group Registry satisfying the European Medicines Agency algorithm were analyzed retrospectively. Characteristics at diagnosis, treatments, relapses and deaths were analyzed to identify factors predictive of death or relapse. Results Between 1966 and 2017, 378 MPA patients (median age 63.7 years) were diagnosed and followed for a mean of 5.5 years. At diagnosis, the main clinical manifestations included renal involvement (74%), arthralgias (45%), skin (41%), lung (40%) and mononeuritis multiplex (32%), with less frequent alveolar hemorrhage (16%), cardiomyopathy (5%) and severe gastrointestinal signs (4%); mean serum creatinine was 217 μmol/L. ANCA were detected in 298/347 (86%) patients by immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA). Among the 293 patients with available ELISA specificities, 272 (92.8%) recognized myeloperoxidase and 13 (4.4%) proteinase-3. During follow-up, 131 (34.7%) patients relapsed and 78 (20.6%) died, mainly from infections. Respective 5-year overall and relapse-free survival rates were 84.2% and 60.4%. Multivariable analyses retained age >65 years, creatinine >130 μmol/L, severe gastrointestinal involvement and mononeuritis multiplex as independent risk factors for death. Renal impairment was associated with a lower risk of relapse. Conclusion Non-renal manifestations and several risk factors for death or relapse were frequent in this nationwide cohort. While mortality was low, and mainly due to treatment-related complications, relapses remained frequent, suggesting that MPA management can be further improved.

Multiethnic studies conducted outside sub-Saharan Africa identify African Black people as the highest-risk group for morbidity and mortality among the 5,000,000 people who are affected by lupus globally. In the meantime, there have bee few attempts to summarize lupus data from sub-Saharan africa. We therefore conducted a systematic review and meta-analysis addressing systemic lupus erythematosus in Native sub-Saharan Africans. This paper both serves as repository for and describes the data obtained by qualitative and quantitative synthesis, notably the pooled prevalence of autoantibodies, the pooled frequency of cumulative drug use, the prevalence of comorbidities/complications and the mortality rate in Native sub-Saharan Africans with systemic lupus erythematosus. These data are interpreted in the research article titled “Systemic lupus erythematosus in Native sub-Saharan Africans: a systematic review and meta-analysis” (Essouma et al., 2019) [1].

Introduction Les pneumopathies interstitielles diffuses (PID) regroupent un ensemble heterogene de maladies caracterisees par un processus diffus inflammatoire et/ou fibrosant [1] . Certains patients atteints de pneumopathie interstitielle diffuse fibrosante, peuvent developper un phenotype a evolution progressive similaire a celui observe dans la fibrose pulmonaire idiopathique (FPI), ces pathologies etant regroupees sous le terme de pneumopathie interstitielle diffuse a forme progressive (PID-FP) [2] . L’objectif de cette etude est de developper des algorithmes pour identifier les patients avec PID-FP non-FPI afin de decrire l’epidemiologie, et le fardeau global de ces maladies en France. Methodes Un algorithme bases sur la CIM-10, et reposant sur des algorithmes americains, a ete developpe en France afin de selectionner entre le 01/01/2010 et le 31/12/2017 les cas prevalents et incidents de PID-FP non-FPI au sein du Systeme national des donnees de sante (SNDS). Un algorithme sera aussi developpe a partir de la cohorte clinique de patients avec PID-FP non-FPI suivis par le Centre national de reference des maladies pulmonaires rares de Lyon. Description des algorithmes Un premier algorithme a ete developpe pour extraire les sejours des patients atteints de PID-FP, base sur la selection de l’ensemble des sejours avec un code de diagnostic de fibrose pulmonaire puis l’exclusion des patients FPI. Les formes progressives seront enfin extraites a partir des donnees de demandes de remboursement pour des traitements specifiques, de consultations chez le pneumologue, d’actes d’imagerie, d’examens de la fonction pulmonaire et/ou d’hospitalisations. La seconde approche consistera a creer un algorithme via une approche par apprentissage automatique grâce au recoupement des donnees du SNDS et de la cohorte clinique. Conclusion Le developpement de ces deux algorithmes par des approches differentes permettra de comparer les resultats obtenus et de choisir l’approche la plus valide pour approfondir les connaissances sur ces pathologies. Cette etude permettra d’estimer le nombre de patients atteints de PID-FP non-FPI, de decrire leur parcours de soins et les couts associes, ainsi que d’explorer la correlation entre la capacite vitale forcee de ces patients et leur morbi-mortalite.

Resume Propos Les patients de medecine interne presentent souvent des tableaux cliniques inexpliques pour lesquels une origine medicamenteuse peut etre envisagee. La prevalence de patients hospitalises pour iatrogenie est estimee entre 4 a 22 %. Nous avons voulu evaluer l’apport diagnostique du centre regional de la pharmacovigilance pour identifier ou confirmer une iatrogenie dans le service de medecine interne de Lille et caracteriser les facteurs associes a l’iatrogenie. Methodes Il s’agit d’une etude diagnostique prospective monocentrique dans laquelle ont ete incluses toutes les demandes consecutives du service de medecine interne aupres du centre regional de pharmacovigilance du Nord-Pas-de-Calais entre 2010 et 2012. L’iatrogenie selon le centre regional de pharmacovigilance etait retenue sur l’enregistrement de l’effet indesirable medicamenteux dans la base nationale de pharmacovigilance, et analysee en fonction de la conclusion d’iatrogenie retenue par les cliniciens de medecine interne (diagnostic de reference) avec un suivi jusqu’a juin 2013. Les variables concernant le patient, les medicaments et l’evenement indesirable ont ete analysees en regression logistique binaire. Resultats Nous avons analyse 160 contacts, dont 118 cas concordants, 38 faux-positifs (iatrogenie retenue par le centre regional de pharmacovigilance seul), 4 faux-negatifs. L’enregistrement dans la base nationale de pharmacovigilance avait une sensibilite de 96 % (IC95 % [0,92–0,99]), une specificite de 46 % (IC95 % [0,38–0,53]), une valeur predictive positive de 69 % (IC95 % [0,62–0,76]), une valeur predictive negative de 89 % (IC95 % [0,84–0,94]) et un rapport de vraisemblance negatif de 0,1. Les faux-positifs avaient une imputabilite chronologique et semiologique douteuse (RR ajuste = 2,1, IC95 % [1,2,8]). Conclusion Dans notre etude, le centre regional de pharmacovigilance conforte le clinicien dans sa suspicion d’iatrogenie et aide a exclure l’origine medicamenteuse avec une forte valeur predictive negative.

Objective: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). Methods: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. Results: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2±0.5 vs 1.7±2.4 before the use of anti-TNF, p

The clinical efficacy, safety, and acceptability of a new oral saliva equivalent (Novasial) administered four times daily in the treatment of xerostomia in various medical conditions was compared with that of oxygenated glycerol triester oral spray (Aequasyal) and a moisturizing spray (Biotene) in a 2-week, multicenter, randomized, crossover study. Assessment included patient-based evaluation of mouth dryness score (primary endpoint) with a visual analog scale (VAS), blinded assessment of the oral tissue condition by a four-point ordinal scale, and patient-based assessment of tolerability and acceptability.At day 14, Novasial decreased oral mouth dryness by 19.5%, (12.5 ± 22.6 mm, P.0001 versus baseline), versus 10% (6.6 ± 17.9 mm with Aequasyal, P.0001 versus Baseline; and P.0156 versus Novasial) and 13% (8.6 ± 18.9 mm) with Biotene (P.0001 versus baseline). The 50% decrease in the primary endpoint was not achieved, and the overall efficacy of Novasial and Aequasyal were similar with respect to xerostomia. Novasial was preferred to Aequasyal and Biotene in alleviating taste alteration and chewing difficulty. Treatment compliance was higher with Novasial (P = .0014 versus Aequasyal). The treatments improved the oral condition with equal efficacy and were safe and well tolerated (VAS 72-77 mm).Novasial was a safe, well-tolerated, and acceptable treatment in patients with xerostomia induced by various treatments or pathologic conditions.