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Resume Introduction L’hypertension arterielle pulmonaire (HTAP) est une complication grave des connectivites. Les donnees d’utilisation des prostanoides dans cette population sont peu nombreuses. L’objectif de cette etude etait de decrire les caracteristiques des patients traites par prostanoides dans cette indication, et de rapporter les donnees d’efficacite et de tolerance. Methodes Il s’agit d’une etude retrospective multicentrique. Les patients traites depuis 2006 ont ete identifies dans 5 centres hospitaliers. Les donnees concernant l’HTAP et la connectivite sous-jacente ont ete recueillies avant introduction des prostanoides et sous traitement. Resultats Vingt-et-un patients ont ete inclus, dont 20 (95 %) avaient une sclerodermie systemique cutanee limitee. Dix-neuf patients etaient traites par mono- ou bitherapie orale avant adjonction du prostanoide. Le treprostinil etait la molecule la plus utilisee (57 % des patients). A l’introduction du prostanoide, 19 patients (90 %) etaient consideres a haut risque de mortalite. Parmi les patients ayant eu un catheterisme cardiaque droit de reevaluation, il n’y avait pas de difference significative des parametres hemodynamiques par rapport a l’evaluation avant prostanoide. Aucune aggravation extrarespiratoire de la connectivite n’a ete constatee sous traitement. La survie a 1 an de l’introduction de prostanoide etait de 62 %. En analyse univariee, la classe fonctionnelle NYHA etait correlee a la survie sous traitement. Conclusion Cette etude presente des donnees originales d’utilisation des prostanoides dans une cohorte composee majoritairement de patients avec une sclerodermie systemique sous-jacente. Elle souligne la difficulte d’effectuer un suivi standardise sous traitement, chez des patients fragiles. La tolerance des prostanoides est superposable a celle rapportee dans l’HTAP idiopathique.

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD). Data on use of prostanoids in this particular subset of patients are lacking. We aimed to describe the characteristics of patients with PAH-CTD treated with prostanoids and the outcomes under treatment.In this multicenter retrospective study, all patients treated with prostanoids since 2006 were included. Data on PAH and CTD were collected at the time of prostanoid introduction and under treatment.Twenty-one patients were included, of whom 20 (95%) had limited cutaneous systemic sclerosis. Nineteen patients were treated with oral monotherapy or combination before addition of prostanoid. Treprostinil was the most used molecule (57% of patients). At the time of prostanoid introduction, 90% of patients were considered at high risk for death. Among patients who had right heart catheterization during follow-up, there was no significant difference in haemodynamics. No extrarespiratory worsening of the CTD was reported. The 1-year survival under prostanoid was 62%. In univariate analysis, NYHA functional class was associated with survival under treatment.This study provides original data on use of prostanoids in a cohort consisting mainly of systemic sclerosis. It underlines the difficulty to achieve a standardized assessment in this subset of patients. Safety profile was comparable with data reported in idiopathic PAH.

Introduction Le traitement des vascularites associees aux ANCA (VAA) repose sur l’utilisation de corticoides et d’immunosuppresseurs ou immunomodulateurs. En cas de formes refractaires aux traitements conventionnels, la combinaison de deux immunosuppresseurs constitue une option therapeutique pour obtenir une remission. L’objectif de cette etude est d’evaluer l’efficacite et la tolerance d’une combinaison de rituximab et de methotrexate (RTX/MTX), administree pour une forme refractaire de VAA. Patients et methodes Nous avons inclus retrospectivement des patients adultes avec un diagnostic de granulomatose avec polyangeite (GPA) ou de polyangeite microscopique (PAM) selon les criteres de l’ACR et/ou la nomenclature de Chapel Hill, et ayant recu une combinaison de RTX/MTX pour une forme refractaire de vascularite. Les donnees cliniques, biologiques et therapeutiques des patients ont ete recueillies a l’aide d’un cahier de recueil standardise, ainsi que les donnees d’efficacite et de tolerance. Resultats Nous avons inclus 17 patients atteints de GPA traites par rituximab et methotrexate. L’âge median etait de 45 (IQR 32-53) ans, le ratio femme/homme de 1,4. Treize (76 %%) patients avaient des ANCA, dont 7 (41 %) avec une specificite anti-proteinase 3 (PR3). La GPA evoluait depuis une duree mediane de 4,0 (IQR 1,0-8,2) ans, et les patients avaient presente en mediane 3,0 poussees anterieures (IQR 2,0-4,0). Quinze patients (88 %) etaient refractaires au rituximab et 7 (41 %) au cyclophosphamide (administre par voie intraveineuse ou orale). Lors de l’introduction de RTX/MTX, tous les patients avaient une vascularite active malgre un traitement en cours par corticoides a une dose mediane de 14 mg par jour (IQR 9-20), RTX pour 13 (76 %) patients et MTX pour 3 (18 %). Les manifestations cliniques refractaires etaient principalement des manifestations granulomateuses avec des stenoses sous-glottiques ou bronchiques (35 %), des masses orbitaires (35 %), des infiltrations du systeme nerveux central (12 %), des nodules pulmonaires (12 %). La combinaison RTX/MTX comportait du MTX a une dose mediane de 0,31 mg/kg (IQR 0,28-0,33) par semaine, administre dans 88 % par voie sous-cutanee, et du RTX selon un schema a 4 injections de 375 mg/m2/semaine pour 14 (71 %) patients. Tous les patients recevaient egalement des corticoides a une dose mediane de 40 mg (IQR 25-60) par jour. A 6 mois du debut du traitement, 15 patients (88 %) avaient une reponse au traitement dont 4 (24 %) une reponse complete. Apres un suivi median de 11 mois (IQR 11-26), 16 patients (94 %) avaient une reponse au traitement dont 5 (29 %) une reponse complete avec une dose mediane de corticoides de 5 mg/jour (IQR 5-10). Sept patients (41 %) ont eu au moins un effets indesirable grave (grade 3 ou 4) dont des infections pour 4 (24 %) patients, des hepatites pour 2 (12 %) patients. La combinaison a du etre interrompue chez 4 (24 %) patients mais jamais en raison d’un effet indesirable en lien avec cette combinaison. La dose de methotrexate a ete diminuee chez 5 (29 %) patients, dont 2 (12 %) patients en raison d’effets indesirables. Un patient est decede d’une cause indeterminee. Conclusion Notre etude suggere que la combinaison de rituximab et methotrexate pourrait etre une option therapeutique efficace au cours des GPA refractaires, en particulier les formes infiltratives ou granulomateuses telles que les sous glottiques ou bronchiques ou les masses orbitaires, avec un profil de tolerance acceptable.

Introduction Les formes rapidement progressives de PID (RP-PID) sont frequentes au cours des dermatomyosites (DM), en particulier associees a un anticorps (AC) anti-MDA5 (PID-MDA5). Les facteurs predictifs de survenue d’une RP-PID sont mal connus. L’objectif principal etait de determiner les elements facteurs predictifs de survenue des formes RP au cours de PID-MDA5. Methodes Il s’agit d’une etude retrospective multicentrique nationale de patients adultes ayant une PID-MDA5. La RP-PID, a ete definie par une deterioration respiratoire ou Resultats 92 patients ont ete inclus (29 (31 %) hommes, âge median 50,1 ans (38,7–58,6), 57,6 % afro-caribeens, 79,3 % non fumeurs) ( Fig. 1 ). CVF mediane: 68 % (52,2–86,8), DLCO mediane: 47 % (40,5–60,5). Des lesions ulcerations etaient notees chez 42.4 % des patients et 69.6 % etaient amyopathiques. L’extension de la PID etait > 20 % chez 34,8 % des patients. Le pattern initial etait le suivant: PINS (33,7 %), PINS-PO (29,3 %), PID indeterminee (19,6 %) et PIA (7,6 %). Le delai de suivi median etait de 36 mois (7.7-63). Douze patients ont presente un pneumomediastin au cours du suivi. Quarante et un patients (44,5 %) avaient une PID-RP. Les donnees demographiques, le tabac, les signes cutanes et musculaires etaient comparables mais les PID-RP avaient une fievre plus frequente (65.9 vs 29.4 % p = 0,001), et plus de condensations (75.6 vs 49 % p = 0,008). Vingt-neuf patients sont decedes dont 25 dans le groupe PID-RP et 3 ont ete greffes, tous dans le groupe PID-RP. L’extension de la PID, la fievre et la ferritinemie au diagnostic etaient associees a la survenue d’une PID-RP en analyse de regression logistique. La survenue d’une PID-RP etait associee a un pronostic defavorable avec 28 % de survie estimee a 5 ans (p Fig. 1 ). Les patients ayant une forme « limitee » avaient une meilleure survie que ceux ayant une forme « etendue » (p = 0,012). Enfin, en analyse multivariee, l’âge, l’extension de la PID, la ferritinemie etaient des facteurs pronostiques associes a la mortalite. Conclusion Dans cette serie francaise de PID-MDA5, la fievre, la ferritinemie et l’extension de la PID au diagnostic sont associes a la survenue d’une PID-RP.

Introduction Les taux des fractions C3 et C4 du complement, comme d’autres proteines, augmentent au cours la grossesse, y compris chez les patientes atteintes de lupus systemique. Alors que la consommation de ces fractions est prise en compte dans les scores d’activite dont le SLE-Pregnancy Disease Activity (SLEPDAI) [1] , leurs valeurs attendues restent inconnues. Notre objectif etait de decrire les variations des taux seriques du C3 et du C4 dans une cohorte prospective de grossesse chez des patientes lupiques. Patients et methodes Les criteres d’inclusion etaient : – Grossesse incluse dans l’etude prospective observationnelle francaise sur les grossesses et les maladies auto-immunes rares (GR2) ; – Chez des patientes ayant un lupus systemique (criteres SLICC) ; – Grossesse terminee avant le 25 decembre 2020. Pour les femmes ayant plus d’une grossesse incluse dans l’etude, seule la 1ere repondant aux criteres d’inclusion a ete analysee. En cas de mesures multiples des fractions C3 et C4 par patiente, seule la premiere mesure de chaque trimestre a ete prise en compte. Resultats 290 grossesses lupiques ont ete analysees. L’âge moyen des femmes etait 32,2 ± 4,7 ans. 669 valeurs de C3 et 648 valeurs de C4 etaient disponibles. La valeur moyenne de la fraction C3 etait de 0,97 g/L au 1er trimestre, 1,10 g/L au second et 1,24 g/L au 3e trimestre, correspondant a une augmentation de 28 % sur l’ensemble de la grossesse. La valeur moyenne de la fraction C4 etait de 0,18 g/L au 1er trimestre, 0,20 g/L au second et 0,20 g/L au 3e trimestre, correspondant a une augmentation globale de 11 %. En analysant uniquement les patientes avec au moins une valeur disponible a chaque trimestre (n = 96 et n = 101, respectivement), nous avons trouve des resultats tres similaires. Ce meme profil evolutif etait retrouve apres exclusion des patientes ayant fait une poussee de lupus au cours de la grossesse (donnees non presentees). Conclusion Dans cette cohorte prospective de 290 grossesses, la fraction C3 augmente de 28 % et la fraction C4 de 11 % entre le premier et le troisieme trimestre. Ces resultats preliminaires permettront de definir plus precisement le seuil inferieur des valeurs normales du C3 et du C4 selon le trimestre de grossesse, et ainsi renseigner de maniere precise les scores d’activite du lupus chez les patientes enceintes.

Introduction Bien que la sclerodermie systemique (ScS) soit une maladie du reseau microvasculaire, certains patients presentent des complications macrovasculaires graves : coronaropathie, accident vasculaire cerebral et arteriopathie obliterante des membres inferieurs (AOMI). L’occlusion de l’artere ulnaire est decrite chez les patients ScS, alors que l’atteinte macrovasculaire des membres inferieurs est beaucoup moins rapportee. Elle peut conduire a une ischemie critique avec des echecs de revascularisation et une amputation. L’objectif de ce travail etait d’evaluer les caracteristiques de patients atteints de ScS souffrant d’une amputation d’un segment de membre inferieur, afin d’identifier des facteurs de risque associes. Materiels et methodes Nous avons realise une etude retrospective, cas-temoins, multicentrique au sein du GFRS. Chaque patient atteint de ScS ayant subi une amputation d’un segment d’un membre inferieur secondaire a une ischemie critique etait apparie sur le sexe, l’âge (±5 ans) et la forme cutanee a un autre patient ScS sans atteinte macrovasculaire clinique des membres inferieurs. Resultats Vingt-six patients ScS avec amputation d’un segment de membre inferieur ont ete inclus. L’âge moyen etait de 67,2 ans (± 10,9), 20 femmes et 5 formes cutanee diffuse. Le groupe temoin comportait 26 patients ScS sans atteinte macrovasculaire. Les patients ScS avec amputation avaient une duree d’evolution de la maladie plus elevee (15,8 ± 9,4 vs 7,4 ± 5,9 ans), plus d’UD (p = 0,048), et plus d’antecedents d’UD (p = 0,026) que le groupe temoin. Ils avaient egalement un score de Medsger plus eleve, sans tenir compte de l’item « vasculaire » (p = 0,02), du fait d’une prevalence plus elevee de l’hypertension pulmonaire (HTP) (p Conclusion Il s’agit de la plus grande serie de patients ScS avec amputation d’un segment d’un membre inferieur et la premiere comportant un groupe temoin. L’amputation est une complication plutot tardive de la maladie. En comparaison au groupe temoin, l’HTP, le tabac et l’utilisation de corticoides apparaissent comme des marqueurs independants associes a l’amputation. Il est important de detecter et corriger les FRCV des patients ScS, particulierement le tabac, et de ne jamais negliger un trouble trophique du membre inferieur. La place du depistage de la macroangiopathie par echoDoppler arteriel des membres inferieurs devra etre evaluee dans le suivi de la ScS.

Background:Active Systemic Lupus Erythematosus (SLE) during pregnancy is associated with poor obstetrical outcome but it is still not clear if remission, lupus low disease activity state (LLDAS) is the best target to achieve at conception. Besides, the effect of damage on pregnancy outcome has not been studied.Objectives:Our aim was to determine the 1st trimester risk factors for adverse pregnancy outcome (APO).Methods:Inclusion criteria were: 1) women≥18 years enrolled in the prospective GR2 study; 2) with SLE (SLICC criteria); 3) and an ongoing singleton pregnancy at 12 weeks (only 1 pregnancy per patient). We used the following definitions: DORIS1, DORIA2, clinical SLEDAI-2K=0, LLDAS3 (for SLE activity), SFI4 (for flares), and SLICC-damage index5 (for damage). APO included: foetal death, neonatal death, placental insufficiency with premature deliveryrd percentile).Results:238 patients were included. 234 (98.3%) women were on hydroxychloroquine (HCQ) and 206 (86.5%) had a clinical SLEDAI-2K=0. Regarding pregnancy outcome, 230 (96.6%) patients had a live birth (mean term 37.7 weeks). Thirty-four (14.3%) patients developed at least 1 APO: placental insufficiency (n=22), foetal death (n=7), neonatal death (n=1), and SGA (n=5). Two different regression logistic models were assessed, one for DORIA and one for LLDAS. We found that only SLICC-Damage index and lupus anticoagulant (LAC) were associated with APO (p=0.02, OR 1.8, 95% CI: 1.1-2.9; p=0.001, OR 4.2, 95% CI: 1.8-9.7 respectively for DORIA model; p=0.03, OR 1.7, 95% CI:1.1-2.8; p=0.002, OR 3.7, 95% CI: 1.6-8.7 respectively for LLDAS model).Conclusion:We confirmed that LAC predicts APO. We found for the first time that chronic damage at 1st trimester also predicted APO. No effect of remission/LLDAS was observed in this cohort of patients on HCQ with a stable and well-controlled SLE.References:[1]van Vollenhoven R, et al. ARD 2017.[2]Zen M, et al. ARD. 2015.[3]Franklyn, K. et al. ARD 2016.[4]Petri M, et al. NEJM 2005.[5]Gladman DD, et al. Arthritis Rheum, 1997.Table 1.Univariate analysis for APOMaternal featuresTotal (N=238)APO (N=34)Non-APO (N=204)P valueAge, mean (SD)31.6(4.5)30.7(4.8)31.7(4.4)0.22Secondary APS34(14.3)10(29.4)24(11.8)0.01Previous renal phenotype67(28.2)13(38.2)54(26.5)0.16At least 1 flare during pregnancy37(15.5)6(17.4)31(15.2)0.80Positive anti-DNA (N=222)104(46.8)21(67.7)83(43.5)0.01Hypocomplementemia (N=216)57(26.4)13(40.6)44(23.9)0.05LAC (N=232)41(17.7)15(44.1)26(13.1)Triple aPL (N=232)17(7.3)5(14.7)12(6.1)0.0824h-proteinuria>0.5g/day9(3.8)3(8.8)6(2.9)0.12Activity/DamageSLEDAI-2K, median (IQR) (N=212)2(0-3)2(2-4)2(0-2)0.01SLICC-DI, median (IQR) (N=236)0(0-0)0(0-0)0(0-0)0.007PGA, median (IQR)(N=235)0.1(0-0.2)0.1(0-0.41)0.1(0-0.2)0.06DORIA remission*154(64.7)17(50.0)137(67.2)0.05DORIS remission**147(61.8)17(50.0)130(63.4)0.13LLDAS (N=219)157(71.7)19(57.6)138(74.2)0.05Clinical SLEDAI-2K=0206(86.5)28(82.4)178(87.3)0.44TreatmentPrednisone (PDN)119(50.0)23(67.7)96(47.1)0.03PDN (mg/day) median (IQR)7(5-10)0(0-6)5(0-10)0.007Immunosuppressants57(24.0)13(38.2)44(21.6)0.04Hydroxychloroquine234(98.3)34(100.0)200(98.0)1.00Low dose aspirin165(69.3)29(85.3)136(66.7)0.03Low molecular weight heparin61(25.6)15(44.1)46(22.6)0.01Legend: APS: antiphospholipid syndrome; aPL: antiphospholipid; PGA: Physician global assessment. *: DORIA definition of remission = clinical SLEDAI=0 and prednisone ≤5 mg/day; **: DORIS definition of remission = clinical SLEDAI=0, prednisone ≤5 mg/day, and PGADisclosure of Interests:None declared.

Introduction La granulomatose eosinophilique avec polyangeite (GEPA) associe une vascularite des petits vaisseaux, un asthme a debut tardif et une hypereosinophilie sanguine et tissulaire. Malgre des progres recents dans la comprehension de la physiopathologie, les mecanismes conduisant a la maladie restent inconnus. L’objectif de cette etude etait d’etudier l’hypothese d’une contribution genetique grâce a l’analyse du sequencage complet d’exome d’une famille multiplex atteinte de GEPA, afin d’en extraire des genes candidats et de les etudier sur une cohorte de patients atteints de GEPA sporadique. Patients et methodes Nous avons realise un sequencage complet d’exome par Next Generation Sequencing (NGS) d’une famille multiplex atteinte de GEPA, le pere et un fils etant atteints selon les criteres de classification de l’ACR et la mere et une fille etant indemnes de toute affection. Un sequencage Sanger des genes candidats precedemment identifies a ensuite ete realise chez 119 patients atteints de GEPA sporadiques afin de rechercher une recurrence de variants dans ces genes au sein de la cohorte. Resultats L’analyse des donnees de sequencage basee sur l’hypothese d’une transmission autosomique dominante et sur l’etablissement de filtres selectionnant les variants tres rares ou rares dans la population generale et predits comme probablement deleteres par les outils de prediction bioinformatique a permis d’identifier 3 genes candidats : EPX, LCN2 et FLT3. Le sequencage Sanger des genes LCN2 et FLT3 chez les 119 patients avec une GEPA sporadique n’a pas mis en evidence de variants d’interet. En revanche, le sequencage du gene EPX a permis d’identifier 22 variants distincts chez 31 patients. Parmi ces 22 variants, 8 variants identifies chez 16 patients etaient classes comme benins et 5 variants chez 5 patients etaient classes comme de signification inconnue. Les patients avec variants de signification inconnue etaient exclus de l’etude comparative pour limiter les biais. Dix patients (8,4 %) presentaient donc un variant considere comme possiblement pathogene. Ces 10 patients etaient des hommes dans 60 % des cas, avec un âge median au diagnostic de 46 [IQR 42–51] ans. Comparativement aux patients avec GEPA sans mutation ou avec un variant benin (n = 104), les patients avec variant d’EPX potentiellement pathogene presentaient plus d’atteinte cardiaque [6/10 (60 %) versus 28/104 (27 %)], plus d’infiltrats pulmonaires [6/10 (60 %) versus 52/104 (50 %)], un chiffre maximal d’eosinophiles plus eleve (mediane a 9420/mm3 [IQR 5844–178925] versus 6000/mm3 [3500–11980]) mais moins de neuropathie peripherique [5/10 (50 %) versus 62/104 (59,6 %)], moins de purpura vasculaire [2/10 (20 %) versus 34/104 (32,7 %)], moins d’ANCA positifs [2/10 (20 %) versus 30/104 (29 %] et aucune atteinte renale alors qu’elle etait presente chez 8 (7,7 %) patients sans variant. Conclusion Pour la premiere fois, un sequencage complet d’exome d’une forme familiale de GEPA a permis d’identifier un gene candidat dont des variants predits deleteres ont ete retrouves chez 8,4 % des patients d’une cohorte de GEPA sporadique. Les patients porteurs d’un variant potentiellement pathogene presentaient un phenotype clinique plus « hypereosinophilique » que « vascularitique ». Des etudes fonctionnelles des variants affectant cette enzyme eosinophile peroxydase seront necessaires pour confirmer la contribution de ce gene dans la physiopathologie de la GEPA.

Introduction Une etude retrospective anterieure a suggere une superiorite des glucocorticoides (GC) plus rituximab (RTX) par rapport aux GC seuls pour induire une reponse clinique complete au cours des vascularites cryoglobulinemiques non infectieuses (VasCryo). Cependant, la combinaison de GC et RTX etait associee a des infections severes plus frequentes, alors que le taux de mortalite ne differaient pas entre les schemas therapeutiques. L’essai ESBAM ( NCT02556866 ) visait a evaluer l’efficacite et la tolerance de RTX en association aux GC pour le traitement de VasCryo mixtes actives non infectieuses. Patients et methodes Nous avons mene un essai multicentrique randomise, en double aveugle, de superiorite du RTX par rapport au placebo pour l’induction de la remission au cours des VasCryo mixtes actives non infectieuses. Pour etre inclus, les patients devaient avoir un VasCryo active definie par une cryoglobuline serique positive et une vascularite active, et devaient etre des patients naifs ou en rechute. Les patients etaient randomises pour recevoir la prednisone plus le RTX administree par perfusion intraveineuse a 375 mg/m2 aux jours (j) 1, 8, 15 et 22 ou la prednisone plus placebo administree selon le meme calendrier. Les GC etaient reduits progressivement de maniere protocolaire. Le critere d’evaluation principal etait la remission de la VasCryo sans prednisone a la semaine (S) 24. Il etait initialement prevu que cette etude inclut 79 patients par groupe. Resultats Entre juillet 2015 et juillet 2017, 15 patients ont ete inclus dans l’essai ESBAM et 14 ont ete randomises (un patient est decede avant la randomisation) : 5 pour recevoir RTX et 9 pour le groupe placebo. L’âge median etait de 62 ans [45 ; 71], 73 % etaient des femmes et 73 % etaient des patients en rechute. Les principales manifestations de la VasCryo incluaient : purpura (71 %), neuropathie (43 %), arthralgies (36 %) et glomerulonephrite (29 %). Les caracteristiques des patients etaient comparables entre les groupes. A la semaine 24, 4/5 (80 %) avaient une vascularite inactive dans le groupe RTX contre 6/8 (75 %) dans le groupe placebo. Une remission sans prednisone etait obtenue chez 1/5 (20 %) dans le groupe RTX contre 0/8 dans le groupe placebo. Les doses cumulees de GC a S24 et a S48 etaient comparables entre les deux groupes. Au cours du suivi jusqu’a 48 semaines, 7 rechutes de vascularite sont survenues, 3 dans le groupe RTX et 4 dans le groupe placebo. Les taux de survie sans rechute a S48 etaient de 40,0 % [IC 13,7–100 %] dans le groupe RTX contre 41,7 % [IC 15,9–100 %] dans le groupe placebo. Le score de sante physique du SF-36 s’est significativement ameliore dans le groupe RTX par rapport au groupe placebo, en particulier a S36 et a S48 (p = 0,02 et p = 0,04, respectivement). La cryoglobulinemie est restee positive dans les deux groupes pour la majorite des patients, et l’evolution de la fraction C4 du complement etait comparable entre les groupes au cours des 48 semaines. Vingt evenements indesirables graves ont ete enregistres, dont une infection severe patiente dans le groupe RTX et 2 dans le groupe placebo. Aucun patient n’est decede apres la randomisation. Conclusion L’association de glucocorticoides plus rituximab, comparativement aux glucocorticoides plus placebo, semble induire des taux de remission similaires a la 24e semaine au cours des VasCryo mixtes actives non infectieuses.

Lenalidomide is an immunomodulating drug structurally similar to thalidomide. It is indicated for patients with relapsing or refractory multiple myeloma in combination with dexamethasone, and for patients with myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality. It is also used to treat other myelodysplastic syndromes such as myelofibrosis and lymphoma. We report a case of organizing pneumonia leading to acute respiratory distress syndrome (ARDS) after long-term administration of lenalidomide, along with a review of the literature.

Introduction Des associations dilatations des bronches (DDB) et vascularite a ANCA (VAA) ont ete ponctuellement rapportees [3] . L’evolution favorable des DDB sous traitement immunosuppresseur interroge sur un lien physiopathologique entre DDB et genese de la vascularite [1] , [2] . Notre objectif etait de decrire les caracteristiques cliniques, biologiques et radiologiques de patients atteints de DDB et de VAA, ainsi que leur profil evolutif et leur pronostic. Patients et methodes Il s’agissait d’une etude retrospective observationnelle et descriptive, a partir d’une serie de patients ayant une VAA selon les criteres de l’American College of Rhumatology (ACR) et des DDB confirmees radiologiquement. Les cas ont ete selectionnes dans la cohorte du Groupe francais d’etude des vascularites (GFEV) et par appel national a observations aupres des societes francaises de pneumologie et de medecine interne. Ils proviennent de 13 centres hospitaliers francais. Resultats Parmi les 61 patients inclus, 27 (44 %) avaient une polyangeite microscopique (PAM), 26 (43 %) une granulomatose avec polyangeite (GPA), 7 (2 %) une granulomatose eosinophilique avec polyangeite (GEPA), et un une VAA indifferenciee. Quarante-cinq patients (74 %) avaient des symptomes respiratoires au diagnostic de la VAA. Les autres manifestations etaient renales (n = 20, 33 %), neurologiques (n = 26, 43 %), rhino-sinusiennes (n = 31, 51 %) et rhumatismales (n = 29, 48 %). Les DDB etaient considerees comme idiopathiques chez 40 patients (65,5 %) et post-infectieuses chez 15 patients (24,5 %). La mediane de survie etait de 7 ans (4–13), avec 9 deces (15 %). Trois d’entre eux etaient dus a une insuffisance respiratoire (33 %) et trois a une complication directe de la VAA (33 %). Au moins une rechute de VAA est survenue chez 26 patients (43 %). Une ou plusieurs surinfections de DDB necessitant une antibiotherapie ou une hospitalisation est survenue chez 32 patients (52 %). Le taux median de surinfections de DDB etait de 0,35 par an (0,2–1). Les DDB ont ete classees en deux groupes : soit anterieures au diagnostic de VAA (25 cas, 41 %), soit diagnostiquees parallelement a la vascularite ou apparaissant durant le suivi (36 cas, 59 %). Les caracteristiques radiologiques, estimees selon le score radiologique de Bhalla, etaient comparables dans les deux groupes. Les DDB connues avant la VAA etaient plus souvent de cause post-infectieuse (48 % versus 8 %, p Conclusion Notre serie d’associations VAA et DDB suggere que les DDB apparaissant au cours d’une vascularite pourraient etre specifiques de la VAA. La preexistence de DDB avant le diagnostic de vascularite influence la presentation phenotypique des VAA et leur pronostic. Les complications infectieuses mortelles ne sont pas liees a la presence de DDB qui ne contre-indiquent pas la prescription des immunosuppresseurs sous couvert d’une prophylaxie adaptee.

International audience; BACKGROUND: The aims of the present study were to determine both clinical manifestations and outcome of anti-PL7 patients with antisynthetase syndrome (ASS). METHODS: The medical records of 15 consecutive anti-PL7 patients with biopsy proven ASS were retrospectively analyzed without prior selection. RESULTS: Anti-PL7 patients exhibited polymyositis (n=14) and dermatomyositis (n=1); extra-pulmonary manifestations of ASS included: Raynaud's phenomenon (40%), mechanic's hands (33.3%), joint impairment (26.7%), pericardial effusion (20%) and esophageal/gastrointestinal involvement (20%). The outcome of myositis was as follows: remission/improvement (91.7%) and deterioration (8.3%). Fourteen patients (93.3%) experienced interstitial lung disease (ILD). ILD preceded ASS diagnosis (n=5), was identified concomitantly with ASS (n=8) and occurred after ASS diagnosis (n=1). Patients could be divided into 3 groups according to their presenting lung manifestations: acute onset of lung disease (n=1), progressive onset of lung signs (n=11) and asymptomatic patients exhibiting abnormalities consistent with ILD on PFT and HRCT-scan (n=2). No patient had resolution of ILD, whereas 64.3% and 35.7% experienced improvement and deterioration of ILD, respectively. ILD resulted in respiratory insufficiency requiring O2 therapy in 14.3% of cases. Two patients died. Predictive parameters of ILD deterioration were: DLCO

Objective. We previously showed that DU significantly increased global and hand disability with a significant impact on activities of daily living (ADLs) and work disability. This study aims to evaluate the impact of digital ulcer (DU) healing on disability and daily activity limitations in SSc. Methods. From January 2008 and June 2009, we prospectively evaluated 189 SSc patients for DU history, disability, employment and occupational status during meetings of the French SSc Patient Association (n = 86, 45.5%) or during hospitalization (n = 103, 54.5%)1. Among the 60 patients with at least one active DU at baseline (M0), 40 patients were followed longitudinally over 6 (3) months. These patients were evaluated for DU history, global and hand disability, health-related quality of life (HRQoL), daily activity limitation and employment status. Results. The median (IQR) age was 57.5 (43.5-68) years and the median (IQR) disease duration was 8.3 (3-16.5) years. Twenty-two (55%) patients had diffuse SSc and 34 (85%) were females. At baseline, a mean of 2.9 (2.8) DU per patient was reported. Thirty-three (82.5%) patients had ischaemic DU, 7 (17.5%) patients had >1 DU associated with calcinosis and 13 (32.5%) patients had mechanical DU. Thirteen (32.5%) patients had >4 DU at baseline. Among the 40 patients, 16 (40%) patients showed complete ulcer healing. In these patients with DU, the presence of calcinosis was associated with a lower probability of healing (P = 0.03). Comparison between healed and no-healed DU patients showed an improvement of hand disability provided by an improvement of the Cochin Hand Function score (P = 0.05)) and a trend towards HAQ domain dressing and grooming (P = 0.06) between M0 and M6 (3) visit in healed patients but not in no-healed patients. Concerning HRQoL, there were no difference for Mental and Physical component Scores of SF-36 but significant improvement of Bodily Pain score (P = 0.04) and Physical Role score (P = 0.05) between M0 and M6 (3) visit in patients with healed DU. The absence of healing was associated with significantly decreased work productivity (P = 0.05), whereas the performance in ADL was not significantly decreased (P = 0.15). Patients who were on sick-leave and who received some help for household tasks at the time of active DU were more likely to heal. Conclusion. For the first time, we provide prospective data with evidence that DU healing is associated with an improvement in hand function. Sick leave was associated with better healing of DU

Background To describe the clinical forms and epidemiology of Lyme borreliosis, in French adult patients hospitalized in Indre-et-Loire (Centre region). Methods Patients were recruited from standardized discharge summaries collected in the hospital database. All adult patients, hospitalized in public hospitals of the Indre-et-Loire administrative district, over a period of 8 years (1999–2006), who satisfied the European diagnostic criteria of Lyme borreliosis, were included. Results Encoding of Lyme borreliosis had a poor positive predictive value (65%). Forty-seven adult patients presented with the 50 following clinical forms: erythema migrans (n = 5), neuroborreliosis (n = 32), knee single-joint arthritis (n = 4), acrodermatitis chronica atrophicans (n = 3), carditis (n = 2), ocular borreliosis (n = 2), miscellaneous (n = 2). Three patients had a combination of two different clinical forms. Meningoradiculitis was the most frequent neurologic manifestation. When a cranial nerve was involved, it was constantly the facial nerve, and mainly bilaterally. Few patients in our study had erythema migrans: these patients are usually treated in a general medicine setting. Although the incidence in the Centre region was lower than in some other regions of France and Europe, the clinical spectrum of the disseminated forms was similar. Conclusion This cohort illustrates the diversity of clinical manifestations of Lyme borreliosis in hospitalized patients, particularly at disseminated and late stages as well as the complexity of its diagnosis and its epidemiological surveillance.

Objective.Systemic sclerosis (SSc) is classified among the complex genetic disorders and is characterized by massive extracellular matrix deposits. These may be due to overactivation of transforming growth factor ß that may be in part a result of abnormal remodeling of extracellular matrix and microfibrils. Metalloproteinases (MMP) are a family of proteolytic enzymes, and MMP 2, 9, and 14 contribute to the degradation of microfibrils. Our aim was to determine whether polymorphisms of the MMP2, MMP9, and MMP14 genes confer susceptibility to SSc in a large population.Methods.A case–control study was performed in 659 SSc patients and 511 healthy matched controls from a European Caucasian population. Six Tag single-nucleotide polymorphisms (SNP) of the MMP2 gene and 2 SNP of MMP9 and MMP14 genes were genotyped.Results.All SNP were in Hardy-Weinberg equilibrium in the control population. There was no association between the MMP2, MMP9, and MMP14 variants we investigated and SSc for allelic and genotype frequencies. No association was observed for the different subphenotypes of SSc patients.Conclusion.Our results in a large cohort of European Caucasian SSc patients do not support that MMP2, MMP9, and MMP14 genes are involved in the genetic background of SSc.

Introduction Les donnees prospectives concernant les grossesses chez des femmes atteintes d’un lupus systemique (LS) et/ou d’un syndrome des antiphospholipides (SAPL) sont peu nombreuses. Une large etude prospective francaise multicentrique (etude du GR2), mise en place en mai 2014, devrait permettre d’ameliorer nos connaissances dans ce domaine. Nous en presentons les premiers resultats. Patients et methodes Les criteres d’inclusion dans l’etude du GR2 sont : (1) un diagnostic de lupus systemique selon les criteres SLICC et/ou un syndrome des antiphospholipides selon les criteres de Sydney ; (2) Une grossesse evolutive ≤ 12 semaines d’amenorrhee (SA) ; et (3) le recueil d’une non-opposition. Le recueil des donnees est prospectif. Nous avons analyse ici l’ensemble des grossesses signalees jusqu’a fin decembre 2016. Les grossesses en cours n’ont pas ete analysees. Les dossiers comportant des donnees manquantes ont ete exclus. Resultats Sur 170 grossesses, 155 ont ete analysees. La pathologie sous-jacente etait un LS (n = 81), un SAPL (n = 55) ou une association des deux (n = 19). Une naissance vivante a ete obtenue dans 80,6 % des cas (n = 125), survenant apres 36 SA dans 83,9 % des cas (n = 104 ; donnees manquantes [DM] = 1). Trente pertes foetales ont ete observees (19,4 %) au cours des 13 premieres semaines d’amenorrhee (SA) dans 66,7 % des cas (n = 20), entre 13 et 22 SA dans 20 % des cas (n = 6) et apres 22 SA dans 13,3 % des cas (n = 4). Aucun BAV n’a ete constate parmi les 26 grossesses dont les meres avaient des anticorps anti SSA et/ou anti SSB. Detail des 100 grossesses chez les patientes ayant un LS ± SAPL : cliniquement, le LS etait caracterise par une atteinte renale (anterieure ou actuelle) dans 30 cas : classe I (n = 1 ; 4 %), classe III (n = 10 ; 40 %), classe IV (n = 6 ; 24 %), classe V (n = 8 ; 32 %) (DM = 5). Une poussee de LS a ete observee 20 fois dans l’annee precedant la grossesse, dont une seule avec atteinte renale. Le score SLEDAI a l’inclusion etait ≥ 4 dans 19 cas (29,7 % car DM = 36). Quatre-vingt-quinze grossesses (95 %) ont ete traitees par de l’hydroxychloroquine, 30 (30 %) par de l’azathioprine et 45 (52,3 % ; DM = 14) par corticosteroides, dont 12 avec plus de 7,5 mg/j (26,7 %). Une poussee de lupus est survenue 27 fois (37,0 % ; DM = 27)principalement articulaire ou cutanee. Aucune poussee renale n’a ete observee. Detail des 74 grossesses avec SAPL ( ± LS) : les manifestations cliniques du SAPL etaient une thrombose arterielle (n = 9 ; 12,2 %), veineuse (n = 46 ; 62,2 %) et un syndrome catastrophique (n = 1 ; 1,4 %). Le SAPL etait uniquement obstetrical 32 fois (43,2 %). La biologie montrait un anticoagulant circulant lupique (n = 49 ; 66,2 %) voire, une triple positivite antiphospholipides (anticoagulant circulant lupique plus anticorps anticardiolipine plus anticorps anti-Beta2GP1 ; n = 27 ; 36,5 %). L’aspirine a dose antiagregante a ete prescrite 71 fois (95,9 %), une heparine de bas poids moleculaire 37 fois (89,2 %), a dose therapeutique (n = 27, 42,9 %), intermediaire (n = 4, 6,3 %) ou prophylactique (n = 32, 50,8 % ; DM = 3). Les complications obstetricales en rapport avec le SAPL etaient une insuffisance placentaire (n = 13, 24,5 %, DM = 21) dont un retard de croissance in utero (n = 5, 41,7 %), une preeclampsie (n = 7, 58,3 %) et/ou un hematome retroplacentaire (n = 1, 8,3 %)(DM = 1). Une seule complication thrombotique est survenue, en post-partum alors que le traitement etait inadequat (du fait de la patiente). Conclusion Les resultats observes chez 155 patientes montrent un pronostic favorable de la grossesse dans la plupart des cas. L’amelioration de l’exhaustivite des donnees et le rythme des inclusions qui se sont acceleres (82 grossesses lupiques et/ou SAPL incluses depuis janvier 2017) permettront d’obtenir, prochainement, des donnees plus precises et de faire des analyses plus completes, notamment, sur nos strategies therapeutiques.

Objective To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene–gene interactions between BANK1 and IRF5 as well as STAT4. Methods BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. Results The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64–0.93) and an OR of 0.73 (95% CI 0.61–0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57–0.86], P = 3.39 × 10−4) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06–1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. Conclusion Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

Objective There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjogren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. Methods The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. Results In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18–2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr] = 0.04, OR 1.59, 95% CI 1.16–2.17) and fibrosing alveolitis (Pcorr = 0.001, OR 2.07, 95% CI 1.38–3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti–topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P = 0.029, OR 1.92, 95% CI 1.07–3.44). Conclusion The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.

Objective To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single-nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta-analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc. Methods Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti–topo I) and for anticentromere antibodies (ACAs). Results The co-occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 × 10–7) and a protective haplotype carrying the 1858C allele (P = 2.20 × 10–16) in our French Caucasian population. The meta-analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 × 10–3, OR 1.08 [95% CI 1.02–1.15]) and mixed (P = 3.11 × 10–3, OR 1.09 [95% CI 1.04–1.16]) populations, particularly in the anti–topo I–positive subset. Conclusion Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.

Resume Objectif Decrire les differentes modalites therapeutiques de la localisation sous glottique d’une maladie de Wegener. Materiel et methode Nous rapportons le cas d’une femme âgee de 26 ans qui presentait une localisation sous glottique d’une maladie de Wegener. Cas clinique Madame B. a presente une maladie de Wegener a localisation renale, cutanee, naso-sinusienne, oropharyngee et sous glottique. Le traitement medical a permis une regression de l’ensemble des lesions a l’exception de la stenose sous glottique. Devant un retentissement de la stenose sur les activites quotidiennes, un traitement endoscopique a ete realise. La dilatation endoscopique et une injection intralesionelle de corticoide ont ete renouvelees a deux reprises a quelques semaines d’intervalle pour permettre une reprise des activites quotidiennes et sportives. Un an apres l’injection intra-lesionelle de corticoide, la patiente est stable et la SSG ne retentit plus sur les activites quotidiennes de la patiente. Conclusion L’apparition d’une symptomatologie respiratoire haute dans le cadre de la maladie de Wegener doit alerter et faire rechercher une stenose sous glottique. L’injection intralesionelle de corticoides est une methode recente et moins invasive que les dilatations. Elle semble donner des resultats satisfaisants.

Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

We report a case of a 76-year-old woman with isolated unilateral Raynaud phenomenon revealing giant-cell arteritis with diffuse arterial lesions and bilateral renal artery stenosis. Doppler ultrasonography showed bilateral stenosis of the subclavian and axillary arteries. Angio-CT PET enlightened diffuse arterial lesions, mainly involving the aorta and the brachial and femoral arteries as well as bilateral renal ostial stenosis with right kidney ischemia. Diagnosis of giant-cell arteritis was made on the temporal artery biopsy. Corticosteroid therapy led to rapid clinical and radiological improvement. Clinical manifestations of giant-cell arteritis may be atypical. Diffuse arterial disease may exist in the absence of cephalic symptoms or significant inflammatory biological features. Ostial renal artery stenosis may induce potentially threatening renal ischemia.

A 37-year-old woman was admitted after 3 days of fever, cough and diffuse pain. She had a 6-month history of relapsing polychondritis treated with steroids and, initially, cyclophosphamide. Cyclophosphamide was stopped after the third infusion due to anaphylactic shock and replaced by mycophenolate mofetil. On physical examination, she had dyspnea with serious wheeze, dry cough and …

International audience; OBJECTIVES:Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France.METHOD:An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination.RESULTS:The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud's phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes.CONCLUSIONS:Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.

Pulmonary embolism is the main pulmonary manifestation of primary antiphospholipid syndrome. Other pulmonary manifestations including intra-alveolar haemorrhage are less common. We report a 36-year-old man with a primary antiphospholipid syndrome who presented with an acute respiratory failure due to the association of pulmonary embolism and intra-alveolar haemorrhage. This diagnosis should be systematically considered as it is life threatening and requires a specific therapy.

Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to death or definitive motor weakness. A 38-year-old woman was admitted for an acute and painful tetra paresis occurring after a laparoscopy for an ovarian cyst. She also complained of abdominal pain treated with noramidopyrine, tachycardia, hypertension and hyponatremia. The electrophysiological examination showed a motor axonal neuropathy. The increase of Urine ALA at 268 micromol/l (N

Introduction Les atteintes respiratoires du lupus systemique (SLE) concernent jusqu’a 80 % des patients. Le Shrinking Lung Syndrome (SLS) est une atteinte rare caracterisee par une dyspnee, une elevation des coupoles diaphragmatiques et un syndrome ventilatoire restrictif. Nous decrivons ici une serie de 10 nouveaux cas de SLS au cours du lupus et une revue de la litterature en etudiant particulierement les caracteristiques cliniques, biologiques, fonctionnelles, l’imagerie, la reponse au traitement et le pronostic de cette association rare. Patients et methodes Les criteres d’inclusion etaient un lupus systemique defini selon les criteres de l’ACR, et l’association d’au moins un critere clinique (douleur thoracique, dyspnee) et un syndrome ventilatoire restrictif. Les criteres d’exclusion etaient la presence d’une autre maladie pulmonaire, musculaire ou cardiaque, et un BMI > 30. Les patients etaient recrutes a partir des bases de donnees locales des internistes et des pneumologues sollicites par leurs societes savantes. Les cas de la litterature etaient recherches dans la base Pubmed avec les mots cles « shrinking lung syndrome » et « lupus ». Resultats Les 10 nouveaux cas etaient tous des femmes d’âge moyen 34,2 ans (17–67 ans). Toutes presentaient une dyspnee et une douleur thoracique au diagnostic. Sur les 9 dont le detail des autoanticorps etait disponible, toutes avaient des anticorps antinucleaires, 7 des anti-ADN natif, 8 des anti-SSA, 3 des anti-SSB, 4 des anti-RNP. L’imagerie thoracique etait normale dans 2 cas, montrait une elevation des coupoles diaphragmatiques dans 7 cas, des atelectasies des bases dans 7 cas, un epanchement pleural dans 3 cas, un epaississement pleural dans 2 cas. La capacite vitale forcee (CVF) etait en moyenne a 48 % de la valeur theorique, la capacite pulmonaire totale (CPT) a 60 %, la DLCO a 46 %, le KCO a 98 %. Sept patients etaient traites par corticoides, 4 montraient une amelioration clinique et paraclinique, 2 etaient stables et 1 venait de debuter le traitement. Le Cyclophosphamide etait propose chez 2 patientes permettant une stabilisation de la maladie chez l’une et une amelioration chez l’autre. Une patiente est restee stable sous methotrexate 15 mg/semaine. La physiotherapie a ete utilisee parallelement chez 2 patientes qui se sont ameliorees. Les 155 patients colliges sur Pubmed etaient des femmes dans 86 % des cas, d’âge moyen 34,1 ans (11–69 ans). Le diagnostic de SLS etait porte en moyenne 67 mois apres celui de SLE. Ils se presentaient avec dyspnee (100 %), douleur thoracique (80 %), fievre (42 %), toux (17 %). Neuf patients ont ete exclus car ils etaient associes a une autre connectivite. Un antecedent de pleuresie etait note dans 49 % des cas. Les atteintes d’organe associees les plus frequentes etaient les arthralgies (88 %), les rashs (51 %), les glomerulonephrites (50 %). Les enzymes musculaires etaient normales dans 100 % des cas rapportes. Les autoanticorps presents etaient des antinucleaires (100 %), anti-ADN (75 %), anti-SSA (38 %), anti-SSB (12 %), anti-RNP (15 %). L’elevation des coupoles diaphragmatiques etait le signe radiographique le plus constant (96 %). Il existait un syndrome restrictif dans 99 % des cas, avec en moyenne une CVF a 1,93L (54 % de la valeur theorique), une CPT a 2,88L (56 %), une DLCO a 49 %, une KCO a 95 %. L’echocardiographie etait normale dans tous les cas. Les pressions inspiratoires et expiratoires etaient diminuees dans 82 % et 80 % des cas respectivement. L’EMG diaphragmatique etait normal dans 75 % des cas. Le traitement comportait des corticoides dans 96 % des cas, beta-mimetiques et theophylline dans 8 % des cas chacun, azathioprine dans 30 % des cas, cyclophosphamide dans 18 % des cas, rituximab dans 6 % des cas. L’evolution etait favorable dans 94 % des cas cliniquement, mais aussi sur l’imagerie et les epreuves fonctionnelles respiratoires (82 %). Conclusion Le Shrinking Lung Syndrome est une manifestation respiratoire du lupus systemique dont le diagnostic fait appel a la clinique (dyspnee, douleur thoracique), l’imagerie (elevation des coupoles diaphragmatiques, atelectasies), les epreuves fonctionnelles respiratoires (syndrome ventilatoire restrictif), la biologie (CPK normales) et l’elimination des diagnostics differentiels. Bien que sa physiopathologie ne soit pas encore totalement comprise, le traitement par corticoides, betamimetiques, theophylline, immunosuppresseurs ou plus recemment Rituximab permet, dans la quasi-totalite des cas, une amelioration clinique et paraclinique, mais rarement une recuperation fonctionnelle totale. Les rechutes sont rares mais les sequelles fonctionnelles, limitees par le traitement, restent frequentes.

High resolution computed tomography (HRCT) was recently demonstrated to be as good as open lung biopsy for the diagnosis of pulmonary involvement in patients with scleroderma. Nevertheless, in view of its price and related irradiation, HRCT cannot be recommended as a screening test. Serum III procollagen (sPIIINP) is an aminopropeptide of type III collagen, which is released during conversion into collagen by specific proteases. Increased levels of sPIIINP have been observed in patients with scleroderma. The aim of the present study was to assess the relationship between sPIIINP measurement and pulmonary involvement defined according to HRCT and pulmonary function tests (PFT) with single-breath carbon monoxide transfer capacity (TL,CO) in 28 patients suffering from scleroderma. Patients were divided into two groups for analysis, Group A comprising 16 patients without pulmonary scleroderma and Group B comprising 12 patients with pulmonary scleroderma. All patients had stable cutaneous disease and normal renal and hepatic function. The level of sPIIINP was determined by radioimmunoassay (RIA-gnost P-III-P, Prod. Nr. ODMT; Behring, Marburg, Germany). Mean +/- SD sPIIINP level in Group A was 0.85 +/- 0.21 U.mL-1. Individual values ranged 0.6-1.3 U.mL-1. Mean +/- SD sPIIINP value was 1.30 +/- 0.40 U.mL-1 in Group B and individual values ranged 0.7-1.9 U.mL-1. The difference in mean sPIIINP level between Group A and Group B was significant. Using a cut-off at 1.1 U.mL-1, sensitivity of sPIIINP was 0.66, specificity 0.94, positive predictive value 0.89, negative predictive value 0.79, false positive rate 0.06, and false negative rate 0.33. The value of sPIIINP correlated with HRCT score but not with PFT. This study confirms the relationship between sPIIINP and scleroderma with interstitial lung disease. We suggest that sPIIINP could be measured in patients with scleroderma to screen those patients requiring HRCT. Further studies are necessary to determine the value of sPIIINP in terms of prognosis and follow-up of patients under treatment.

Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes.We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis.We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention.Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups.This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

International audience; The aims of the present study were to: compare the characteristics between antisynthetase syndrome (ASS) patients with anti-Jo1 antibody and those with anti-PL7/PL12 antibody. The medical records of 95 consecutive patients with ASS were reviewed. Seventy-five of these patients had anti-Jo1 antibody; the other patients had anti-PL7 (n=15) or anti-PL12 (n=5) antibody. At ASS diagnosis, the prevalence of myalgia (p=0.007) and muscle weakness (p=0.02) was significantly lower in the group of anti-PL7/PL12-positive patients than in those with anti-Jo1 antibody; median value of CK (p=0.00003) was also lower in anti-PL7/PL12 patients. Anti-Jo1 positive patients developed more rarely myositis resolution (21.3% vs. 46.2%); in addition, the overall recurrence rate of myositis was higher in anti-Jo1 positive patients than in patients with anti-PL7/PL12 antibody (65.9% vs. 19.4%). Anti-Jo1-positive patients, compared with those with anti-PL7/PL12 antibody, more often experienced: joint involvement (63.3%vs. 40%) and cancer (13.3% vs. 5%). By contrast, anti-PL7/PL12 positive patients, compared with those with anti-Jo1 antibody, more commonly exhibited: ILD (90% vs. 68%); in anti-PL7/PL12 positive patients, ILD was more often symptomatic at diagnosis, and led more rarely to resolution of lung manifestations (5.6% vs. 29.4%). Finally, the group of anti-PL7/PL12 positive patients more commonly experienced gastrointestinal manifestations related to ASS (p=0.02). Taken together, although anti-Jo1 positive patients with ASS share some features with those with anti-PL7/PL12 antibody, they exhibit many differences regarding clinical phenotype and long-term outcome. Our study underscores that the presence of anti-Jo1 antibody results in more severe myositis, joint impairment and increased risk of cancer. On the other hand, the presence of anti-PL7/PL12 antibody is markedly associated with: early and severe ILD, and gastrointestinal complications. Thus, our study interestingly indicates that the finding for anti-Jo1 and anti-PL7/PL12 antibodies impacts both the long-term outcome and prognosis of patients with ASS.

Cardiopulmonary involvement in adult-onset Still's disease is not as common as cutaneous and articular involvement. Pleuropericarditis is the most frequent thoracic manifestation. Although difficult, diagnosis of other thoracic manifestations, which may reveal the disease, is crucial, due to the high risk to life and the efficacy of new immunosuppressive agents. The pathophysiology involves essentially immunological factors, Still's disease being increasingly seen as an autoimmune inflammatory disease. Pro-inflammatory cytokines such as interleukine (IL) 1, 6 and 18 play a crucial role in macrophage activation, which is central in the pathophysiology of adult Still's disease. The classification of cardiopulmonary manifestations is based on anatomy. Cardiac lesions may involve all the tissues of the heart and the pulmonary arteries. Respiratory lesions may involve the pleura, the lung parenchyma (organizing pneumonitis, infiltrative lung disease, alveolar damage, amyloidosis), and the respiratory muscles, including the diaphragm. Finally, some manifestations may be provoked by the treatment itself. Steroids, the first-line treatment, are very effective in pleuropericarditis. Methotrexate used to be prescribed when steroids failed, but biotherapies such as IL1 and IL6 inhibitors have transformed the prognosis of forms resistant to these drugs.

Objective Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic factors. With regard to the latter, there has been a recent shift from the “common variant” to the “rare variant” paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc. Methods TREX1 single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls). Results No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low-frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 [95% confidence interval 2.28–5.41], P = 8.58 × 10−9) in the combined populations. Genotype–messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression. Conclusion The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low-frequency functional variants and the critical role of A20 in autoimmunity.

BackgroundRecent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders.ObjectiveTo study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population.MethodsNLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin.ResultsConditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA.ConclusionsOur results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

International audience; Objective. The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell co-stimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. Methods. CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. Results. The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 x 10(-5). The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 x 10(-6), OR 1.82 (95% CI 1.38-2.40), P = 2.16 x 10(-5), and OR 1.61 (95% CI 1.25-2.08), P = 2.73 x 10(-4), respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. Conclusion. Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

Objective Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor β receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. Methods Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. Results The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48–0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13–0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21–0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. Conclusion Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

Objective.Serotonin is a key contributing factor in pulmonary arterial hypertension (PAH) by inducing pulmonary arterial smooth muscle cell (PA-SMC) proliferation. This relates specifically to the internalization process in PA-SMC of the serotonin transporter (SLC6A4 or 5-HTT). A long (L)/short (S) (44 base pair insertion) functional polymorphism within the promoter of the transporter SLC6A4 gene has been reported to be associated with familial and idiopathic PAH. Our objective was to determine whether polymorphisms of SLC6A4 confer susceptibility to SSc and its vascular phenotype.Methods.Three Tag single-nucleotide polymorphisms (SNP) (rs2066713, rs1042173, rs6354) chosen using Hapmap and linkage disequilibrium data were genotyped in a total cohort of 667 SSc patients (56 with PAH, 207 with digital ulcerations) and 447 controls. All individuals were of French Caucasian origin. L/S polymorphism genotyping was determined by polymerase chain reaction in a random subgroup of 364 SSc patients (34 with PAH, 138 with digital ulcerations) and 218 controls.Results.Three polymorphisms (L/S, rs2066713, rs1042173) were in Hardy-Weinberg equilibrium in the control population, but rs6354 deviated. Allelic and genotypic frequencies for these 3 polymorphisms were similar in SSc patients and controls. Subphenotype analyses of subsets with PAH and digital ulceration did not detect any difference between SSc patients compared to controls.Conclusion.These results from a large cohort of European Caucasian SSc patients do not support the implication of SLC6A4 in the pathogenesis of SSc and its vascular subphenotypes. However, serotonin pathways remain good candidates to contribute to the vasculopathy of SSc.