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RESUME La polyarthrite rhumatoide (PR), la spondyloarthrite (SPA) et le rhumatisme psoriasique (RP) constituent les rhumatismes inflammatoires chroniques (RIC) les plus frequents et severes. Le traitement de ces maladies a ete considerablement ameliore au cours des deux dernieres decennies par les traitements biologiques «de fond» (en anglais, biological disease-modifying antirheumatic drugs (bDMARDs)). En2018, de nombreux bDMARDs efficaces sont disponibles, ayant des cibles differentes en particulier les inhibiteurs du facteur de necrose tumorale (en anglais, tumor necrosis factor : TNF)(iTNF), le blocage de co-stimulation des lymphocytes T, l’inhibition du recepteur de l’interleukine 6 (IL-6),la depletion des lymphocytes B, dans la PR, ainsi que des medicaments biologiques ciblant l’interleukine 17 (IL-17), l’interleukine 12 (IL-12), l’interleukine 23 (IL-23) dans les RP et SPA. Le cout de ces bDMARDs est tres eleve et a ete recemment reduit par l’utilisation des medicaments biosimilaires (disponibles actuellement pour certains de ces medicaments). Malgre l’efficacite remarquable et la tolerance satisfaisante de ces bDMARDs, un nombre significatif de patients n’atteint pas l’objectif ideal de remission clinique ou de « faible activite » de la maladie. Ceci justifie la poursuite des recherches fondamentales et cliniques pour le developpement de nouveaux bDMARDs ou de medicaments synthetiques cibles (en anglais, targeted synthetic DMARDs (tsDMARDs) ayant de nouvelles cibles therapeutiques, une meilleure efficacite et tolerance, et un cout plus faible.

Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX.Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin6g/L and4g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia.134 patients met inclusion criteria and were followed-up for 79.5 ± 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 ± 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels8g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% CI: 0.08-0.87], P = 0.03).Our results show that gammaglobulin levels of less than 8g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX.

Objective To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors. Methods In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored. Results 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n=47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.94±2.20 vs. 3.18±2.21, p=0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was re-established in 47/59 patients (80%). Conclusion No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences.

Objective To study the mortality profile of patients with rheumatoid arthritis (RA) in France. Methods Data were collected between 2000 and 2011 from the French Epidemiological Center for the Medical Causes of Death database; all death certificates from adults that either mentioned RA as an underlying cause of death (UCD) or as an associated cause of death (ACD) were evaluated using multiple-cause-of-death analysis. The different causes of death and their frequency were reported, together with the ratio of observed/expected number of death (O/E ratio) to measure the strength of association between RA listed as an ACD and the corresponding UCD. Results During the study period, 13,208 deaths related to RA were identified. The mean ± SD age at death was 79 ± 9 years (51% with ≥80 years) and the female/male ratio was 3.2. When RA was the UCD ( n = 4597), the main causes of death were cardiovascular (29%) and infectious diseases (22%). When RA was an ACD ( n = 8611), the most common UCDs were cardiovascular diseases (35%), neoplasms (14%), respiratory disease (9%), and infectious diseases (7%). The overall O/E ratio was >1 for infectious (3.58), respiratory (1.38), and cardiovascular diseases (1.25), but was Conclusion We provide the most recent national multiple-cause-of-death analysis assessing the mortality profile of RA patients. Our results show that mortality related to cardiovascular, respiratory, and infectious diseases is highly associated with RA. These data support the need to expand new strategies to prevent infectious and cardiovascular diseases in order to improve survival of RA patients.

Objective Digital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc remains controversial. Methods To measure concomitantly in SSc patients with and without active DU: (i) the Augmentation Index of the reflected wave (Aix_75) by radial applanation tonometry, an index of small and medium arterial function; (II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness). Results Sixty-three consecutive SSc patients were included (49 females, aged 60 [49–65] years, disease duration of 8.5 [5–13] years), including 10 (15.9%) with active DU. Patients with active DU versus those without had increased Aix_75 (35% [28–38] versus 28% [20–34], P = 0.041) whereas no difference existed in PWV (7.0 m/s [6.7–10.1] versus 7.6 m/s [6.8–8.7], P = 0.887), in systolic, diastolic, as well as aortic pulse pressure ( P = 0.126, 0.592, and 0.161, respectively). When compared to patients in the low tertile, patients having Aix_75 in the highest tertile had 10-fold more DU (OR = 10.23; 95% CI 1.12 to 93.34, P = 0.039). Conclusion The presence of DU is associated with increased Aix_75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix_75 is predictive of further DU remained to be studied.

Resume Objectif Il existe peu d’etudes evaluant la qualite de vie liee a l’etat de sante (health-related quality of life [HR-QoL]) chez les adultes ayant souffert d’arthrite juvenile idiopathique (AJI), et aucune menee depuis l’avenement des biotherapies. L’objectif de notre etude est d’evaluer l’impact de l’arthrite juvenile idiopathique sur la qualite de vie (QdV) dans une grande cohorte en phase de transition, d’evaluer les facteurs qui influencent cette qualite de vie dans l’arthrite juvenile idiopathique et de determiner le questionnaire a utiliser dans la pratique. Methodes Cette etude a inclus tous les patients atteints d’arthrite juvenile idiopathique, vus a l’âge adulte et consecutivement dans le cadre d’un programme de soins de transition. Les donnees demographiques, cliniques et biologiques ont ete collectees. Les questionnaires de qualite de vie suivants ont ete utilises : SF-36 et EuroQoL. Des temoins apparies selon l’âge et le sexe (exempts de maladie rhumatismale) ont ete inclus. Resultats Cent soixante et un patients atteints d’arthrite juvenile idiopathique (120 femmes et 41 hommes) et 76 (51/25) temoins ont ete inclus. Soixante-cinq sur 161 (40 %) patients etaient consideres en remission. L’arthrite juvenile idiopathique a eu un impact important sur les echelles physiques de la QdV. La douleur paraissait etre le principal facteur affectant la QdV dans les cas d’arthrite juvenile idiopathique. Aucune difference significative n’a ete observee entre les sous-types d’arthrite juvenile idiopathique. Conclusion Dans cette grande cohorte de patients en phase de transition a l’ere des biotherapies, l’arthrite juvenile idiopathique a eu plus d’impact sur le critere physique que psychique/mental des echelles d’evaluation de la QdV. Le principal facteur ayant des repercussions sur la QdV a ete la douleur. Les sous-types d’arthrite juvenile idiopathique ne semblent pas avoir d’influence sur la QdV.

OBJECTIVE Cutaneous telangiectasia (CT) are common in systemic sclerosis (SSc) patients, but their ability to stratify patients by risk is poorly known. We aimed to determine whether the number and size of CT were associated with the pattern of microvascular lesions assessed by nailfold videocapillaroscopy (NVC) and markers reflecting the severity of SSc-related vasculopathy. METHODS We performed a cross-sectional study, including consecutive SSc patients over a 6-month period. We also considered 3 predefined subsets of patients according to the number of hand or face CT: absence, ≤10, or >10 hand or face CT (profuse CT). Pseudotumoral CT were defined as CT with >5 mm diameter. RESULTS A total of 87 patients were included, of whom 75 (86%) had CT (27 with profuse and 19 with pseudotumoral CT). Profuse and pseudotumoral CT were both associated with capillary loss (P < 0.001 and P = 0.002, respectively) and severe neoangiogenesis (P = 0.015 and P = 0.041, respectively), 2 hallmarks of the late NVC pattern. In multivariate analysis, profuse CT were independently associated with past or current digital ulcers (odds ratio [OR] 2.95 [95% confidence interval (95% CI) 1.09-19.63]), and pseudotumoral CT were independently associated with the late NVC pattern (OR 4.84 [95% CI 1.32-26.19]) and with precapillary pulmonary hypertension (OR 12.60 [95% CI 1.68-94.53]). CONCLUSION We demonstrate that the number and size of CT are associated with the most severe NVC pattern. In addition, profuse and pseudotumoral CT identify a subset of patients with a more severe vascular phenotype. Further prospective studies should determine whether CT number and size could serve as an early clinical biomarker for the development of severe vascular disease.

OBJECTIVE To determine whether calcinosis and acro-osteolysis are related to specific nailfold videocapillaroscopy (NVC) features in patients with systemic sclerosis (SSc; scleroderma). METHODS NVC and bilateral hand radiographs were systematically performed in 155 consecutively recruited patients with SSc during a 24-month period. Radiologic assessment of calcinosis and acro-osteolysis was performed blinded for the results on NVC features. RESULTS Patients with calcinosis (n = 29) or acro-osteolysis (n = 25) on radiographs were more likely to have the late pattern on NVC, defined by severe loss of capillaries and neoangiogenesis (P = 0.003 and P < 0.001, respectively). A reduced number of capillaries was significantly found in patients with calcinosis (mean ± SD 3.55 ± 1.76 versus 5.53 ± 2.32 capillaries per finger; P < 0.001) and acro-osteolysis (mean ± SD 2.88 ± 1.30 versus 5.60 ± 2.26 capillaries per finger; P < 0.001). In addition, neoangiogenesis was more frequently observed in patients with severe acro-osteolysis (P = 0.021). Multivariate logistic regression analysis confirmed the independent association between the late NVC pattern and calcinosis (odds ratio [OR] 3.04, 95% confidence interval [95% CI] 1.20-7.68) or acro-osteolysis (OR 4.57, 95% CI 1.66-12.55), together with history of and/or active digital ulcers. CONCLUSION Acro-osteolysis and calcinosis are independently associated with the late NVC pattern and particularly with severe capillary loss. These results strengthen the link between these radiographic lesions and digital destructive vasculopathy. Moreover, severe acro-osteolysis was more likely to occur with neoangiogenesis, which may suggest an attempt to compensate bone resorption. Further studies are now needed to better understand the physiopathology of calcinosis and acro-osteolysis and determine whether any agent may modify the course of these lesions by influencing vessel damages.

Heart involvement in systemic sclerosis (SSc) is a strong prognostic factor. Our aim was to examine left ventricle (LV) and right ventricle (RV) involvement.We examined LV and RV, systolic and diastolic functions, using echocardiography and Tissue-Doppler echocardiography (TDE) indexes, in a cohort of 212 consecutive SSc patients seen during a 9-month period at 2 institutions (Paris, France and Los Angeles, USA). They were compared to 50 healthy controls.When compared to controls, SSc patients had consistently impaired RV indices that include reduced RV contractility (p0.001), larger right atrial area (p = 0.027) and overall RV diastolic dysfunction (25% of SSc patients versus 0% of controls; p0.001). Patients also exhibited alterations in LV contractility and diastolic function (p0.001 each). In multivariate analysis, RV contractility as expressed by the TDE S(T) parameter was associated with TDE LV contractility S(M) (p = 0.030), DLCO (p = 0.013) whereas RV diastolic impairment was associated with systolic pulmonary artery pressure (p = 0.015). A subgroup of 27 patients had proven pulmonary arterial hypertension (PAH); comparison between SSc-PAH versus SSc free of PAH patients revealed reduced LV diastolic function (transmitral E/A ratio, p = 0.045 and E(A)10 cm/s, p = 0.029), reduced overall RV contractility (21.5% versus 4.5%; p = 0.03) and reduced RV diastolic function (transtricuspid E/A ratio; p = 0.014 and 68% versus 29% with impaired function; p = 0.001).Our data show that RV is commonly affected in SSc with predominant impaired diastolic function. Several factors, including primary heart, lung vascular disease and pulmonary hypertension, contribute to such impairment.

Objective Few studies have assessed Health-Related Quality of Life (HR-QoL) in adults following juvenile idiopathic arthritis, and none since the advent of biotherapies. The aim of our study is to assess the impact of juvenile idiopathic arthritis on quality of life in a large transitional cohort, evaluate which factors influence quality of life in juvenile idiopathic arthritis, and determine which questionnaire should be used in practice. Methods All consecutive juvenile idiopathic arthritis patients followed during adulthood in a transitional care program were included. Demographical, clinical and biological data were collected. The following quality of life questionnaires were administered: SF36 and EuroQoL. Age- and sex-matched controls (without rheumatic disease) were included. Results One hundred and sixty-one juvenile idiopathic arthritis (120 women and 41 men) and 76 (51/25) controls were included. Out of 161, sixty-five (40%) were considered to be in remission. Juvenile idiopathic arthritis had a large impact on the physical scales of quality of life. Pain seemed to be the most important factor affecting quality of life in cases of juvenile idiopathic arthritis. No significant difference was found between sub-types of juvenile idiopathic arthritis. Conclusion In this large transitional cohort of patients at the era of biotherapies, juvenile idiopathic arthritis has a larger effect on physical than mental scale of quality of life measures. Pain was the main factor influencing quality of life. Sub-types of juvenile idiopathic arthritis do not seem to influence quality of life.

Resume L’acro-osteolyse est rare et survient au cours de plusieurs affections. L’examen clinique, des explorations complementaires paracliniques et parfois la realisation de tests moleculaires peuvent aider a etablir un diagnostic. Nous rapportons le cas d’une femme âgee de 36 ans qui a ete adressee a notre service pour une douleur aigue de l’extremite de l’index gauche. L’examen clinique avait revele la presence de doigts courts avec un pseudohippocratisme associe a une acro-osteolyse. De plus, la presence d’une osteoporose severe, d’un visage legerement dysmorphique, d’une hypermobilite articulaire, associes a la normalite du bilan biologique et de l’histoire clinique, avait amene a poser le diagnostic de syndrome de Hajdu-Cheney. L’analyse moleculaire avait confirme le diagnostic d’une mutation du gene NOTCH2. La patiente avait recu un traitement par bisphosphonates et une amelioration biologique est survenue 12 mois plus tard.

Resume La sclerodermie systemique est une maladie orpheline faisant partie du groupe des connectivites. Elle est caracterisee par des anomalies de la microcirculation, des desordres du systeme immunologique et des depots massifs de collagene et d’autres composants de la matrice extracellulaire dans la peau et dans les organes. Un progres majeur des annees recentes reside dans la validation de nouveaux criteres de classification permettant un diagnostic et un traitement plus precoces, a un stade precedant la fibrose irreversible et les atteintes viscerales (« fenetre d’opportunite »). Le phenomene de Raynaud, qui est habituellement le premier signe de la maladie, est considere comme le principal signe d’appel pour identifier les formes tres precoces de sclerodermie systemique. La sclerodermie systemique est cliniquement heterogene et son pronostic reste imprevisible. Il depend de l’atteinte cardiopulmonaire et des etudes recentes ont tente d’identifier des facteurs biologiques ou genetiques predictifs de la severite de l’atteinte viscerale. De plus, le suivi prospectif de grandes cohortes de patients a permis et permettra encore de degager des facteurs pronostiques puissants. Si l’evolution des manifestations vasculaires a ete recemment amelioree par des traitements cibles, des donnees recentes montrent que la mortalite n’a pas ete modifiee au cours des 40 dernieres annees. Ceci traduit l’inefficacite des traitements actuels a eviter le processus de fibrose. Neanmoins, plusieurs traitements biologiques ayant une efficacite prouvee dans d’autres pathologies immunologiques sont sur le point d’etre etudies dans la sclerodermie systemique. Des resultats prometteurs ont ete rapportes dans des etudes ouvertes de faibles effectifs. Cette mise au point presente les progres recents concernant les criteres de classification, la physiopathologie, les atteintes viscerales, le pronostic et les traitements actuels et futurs de la sclerodermie systemique.

Objective To measure plasma concentrations of high-sensitivity cardiac troponin T (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with systemic sclerosis (SSc; scleroderma) and age- and sex-matched healthy control subjects, and to examine the contribution of traditional cardiovascular risk factors and SSc features to the concentrations of these 2 cardiac biomarkers. Methods Plasma HS-cTnT and NT-proBNP concentrations were measured using the electrochemiluminescence method and sandwich immunoassay, respectively. Results The study group comprised 161 unrelated patients with SSc and 213 matched control subjects. HS-cTnT and NT-proBNP plasma levels were significantly increased in SSc patients compared with controls (both P 14 ng/liter. Increased NT-proBNP concentrations were associated only with the presence of precapillary pulmonary hypertension (P Conclusion HS-cTnT and NT-proBNP concentrations are increased in patients with SSc, even in those who are free of cardiovascular risk factors. These easily obtained biomarkers may be useful for systematic evaluation and stratification of SSc patients, especially to identify those at risk of pulmonary hypertension.

Objective.Systemic sclerosis (SSc) is associated with an increased risk of osteoporosis and fractures. To date, the etiology of bone loss in SSc is unclear. Trabecular bone score (TBS) provides an indirect measurement of bone microarchitecture, independent of areal bone mineral density (aBMD). The aims were to assess bone involvement in SSc using TBS in comparison with a “high-risk” population with rheumatoid arthritis (RA) and controls, and to investigate the determinants of a low TBS.Methods.This was a cross-sectional study of 65 women with SSc, 138 age-matched female patients with RA, and 227 age-matched female controls. Spine and hip aBMD were assessed using dual-energy X-ray absorptiometry. TBS was calculated from the anteroposterior image of the spine aBMD.Results.TBS was significantly lower in SSc compared to controls (p < 0.0001) and did not differ from RA (p = 0.128), despite lower cumulative and daily glucocorticoid (GC) dose (p < 0.0001). Further, patients with SSc receiving GC ≥ 5 mg/day had a significantly lower TBS than those receiving GC < 5 mg/day (p = 0.001). Multivariate analysis revealed that a low TBS was independently associated with daily GC dose (OR 5.6, 95% CI 1.7–19.2) and a T score ≤ −2.5 SD (OR 5.0, 95% CI 1.5–7.0) in SSc. No association between GC and TBS was found in RA.Conclusion.Our results support the development of a combined approach using both TBS and aBMD for the assessment of bone microarchitecture in inflammatory rheumatic diseases. Our study showed that SSc-related bone involvement is characterized by an impairment in bone quality in addition to reduced bone quantity, and highlights that TBS can identify the negative effect of GC on bone microarchitecture.

Objective.Anticyclic citrullinated peptide antibodies (anti-CCP) are considered specific markers of rheumatoid arthritis (RA) and have been included in the revised classification criteria for RA diagnosis. However, these antibodies have also been detected in patients with other types of chronic inflammatory rheumatism. Our objectives were to identify the prevalence of positive anti-CCP patients in non-RA diseases, to determine the diagnostic value of anti-CCP for the diagnosis of RA, to specify the clinical characteristics of non-RA patients positive for anti-CCP, and to determine the discriminatory value of the levels of anti-CCP in patients among the various diseases.Methods.We carried out an observational and descriptive study. All the determinations of anti-CCP requested by the 2 rheumatology departments at Cochin Hospital over a period of 18 months were analyzed. Such determinations were requested for 1162 patients in total. Anti-CCP levels were determined with the Euro Diagnostica ELISA kit, with values ≥ 25 U for this test being considered positive. The diagnosis of rheumatic conditions was the responsibility of the treating physician.Results.Anti-CCP antibodies were detected in 357 (30.7%) of the 1162 patients. The prevalence of anti-CCP was 292/417 (70.0%) in RA, 13/122 (10.6%) in patients with psoriatic arthritis, 13/62 (20.9%) in patients with unclassified rheumatism, 11/33 (33.3%) in patients with primary Sjögren syndrome, 5/30 (16.6%) in patients with systemic lupus erythematosus, 3/28 (10.7%) in patients with mixed connective tissue disorder, 3/36 (8.3%) in patients with systemic sclerosis, 7/44 (15.9%) in patients with juvenile arthritis, and 6/220 (2.7%) in patients with noninflammatory diseases. In the population of patients positive for anti-CCP, mean anti-CCP levels were 869.4 (± 978.4) U/ml, with no significant difference between RA [854.8 (± 959.8) U/ml] and any of the non-RA conditions [922.7 (± 1070.0) U/ml].Conclusion.Anti-CCP are a hallmark of RA, but may be observed in other inflammatory, systemic, or mechanical diseases. In this large cohort of patients, the presence of second-generation anti-CCP (anti-CCP2) antibodies is useful in diagnosing RA (70% sensitivity, 91.3% specificity), but examining the levels of these antibodies does not appear to offer further discriminatory power among patients who are anti-CCP2-positive.

To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc).Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)-derived endothelial cells (ECs) obtained from patients with SSc-associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme-linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos-related antigen 2-transgenic (Fra-2-Tg) mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling.Microarray experiments revealed that the matrix metalloproteinase 10 (MMP-10) gene was the top up-regulated gene in SSc-associated PH EPC-derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc-associated PH and in the lungs of Fra-2-Tg mice. Daily treatment of Fra-2-Tg mice with neutralizing anti-MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet-derived growth factor signaling axis.Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate gene in SSc-associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-associated PH, and its blockade alleviates PH in the Fra-2-Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder.

Objective To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these changes are associated with overall disease progression and organ involvements. Methods A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions. Results Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) [hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.07–0.93]. Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR = 4.35, 95% CI: 1.87–10.12), occurrence of new DU (HR = 5.33, 95% CI: 1.69–16.71), lung vascular progression (HR = 18.53, 95% CI: 1.28–78.33), progression of skin fibrosis (HR = 4.22, 95% CI: 1.24–14.36), and worsening of the Medsger severity score (HR = 5.26, 95% CI: 1.78–15.52). Conclusion Significant NVC changes are observed in almost half of the patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression.

Objective.To measure concentrations of high-sensitivity cardiac troponin (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis (RA) and to examine correlates.Methods.The plasma concentrations of HS-cTnT and NT-proBNP were measured in consecutive patients with RA and compared to values obtained from age-matched and sex-matched healthy controls.Results.We included 236 unrelated patients with RA (192 females, 57 ± 13 yrs) and 213 controls (170 females, 55 ± 15 yrs). Seventy-one patients with RA were free of cardiovascular (CV) risk factors. HS-cTnT and NT-proBNP concentrations were significantly higher in the total cohort of patients with RA (p = 0.03 and p < 0.0001, respectively) and in the subgroup free of CV risk factors (p = 0.02 and p < 0.0001, respectively) compared to controls. In addition, both the total cohort of patients with RA and the subgroup free of CV risk factors were more likely to have levels above the cutoff concentrations of HS-cTnT (p = 0.003 and p = 0.007, respectively) and NT-proBNP (p = 0.0001 and p < 0.0001, respectively) than controls. Patients with RA and increased C-reactive protein (CRP) levels had higher HS-cTnT (p = 0.03) and NT-proBNP (p = 0.02) concentrations. HS-cTnT levels positively correlated with the 28-joint Disease Activity Score (DAS28-CRP; r = 0.2, p = 0.020). Multivariate logistic regression analysis indicated that increased HS-cTnT levels were independently associated with a DAS28-CRP > 5.1 (OR 11.8; 95% CI 1.6–35.5) and a body mass index > 30 kg/m2 (OR 2.7; 95% CI 1.3–5.5).Conclusion.HS-cTnT and NTproBNP are increased in patients with RA, independent of CV risk factors. The association between HS-cTnT, NT-proBNP, and CRP, together with the correlation between HS-cTnT and disease activity, support the link between myocardial injury/dysfunction and inflammation.

Objectives Several epidemiological studies have revealed the co-occurrence of other autoimmune diseases (AIDs) within patients with systemic sclerosis (SSc). However, some of these studies were based on small cohorts and wide ranges of prevalence have been reported. Therefore to overcome these limitations of individual studies, we sought to perform a meta-analysis to determine the accurate prevalence of polyautoimmunity in SSc. Methods We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to March 2013. All cohort studies reporting on prevalence of other AIDs known to be associated with SSc were analyzed. Prevalence of polyautoimmunity and of each AID were then calculated. Results Ten studies reporting polyautoimmunity were identified corresponding to a total of 6102 SSc patients. Overall 1432 patients with at least one AID were identified corresponding to a weighted prevalence of polyautoimmunity equal to 25.7% CI 95% [20.1%–31.6%]. Overall 208/5139 SSc-patients had at least two additional AIDs resulting in a weighted prevalence of 3.9% [3.3%–4.4%]. The most prevalent associated AIDs were autoimmune thyroid disease (10.4%) followed by Sjogren's syndrome (7.7%) and dermatopolymyositis/polymyositis (5.6%). Conclusion Our results confirm that SSc polyautoimmunity is a frequent condition in SSc affecting a quarter of SSc-patients. The impact on the phenotype and also on the management and therapy will need to be addressed now in further works.

Objective.Radiographic damage was recently identified as a feature of poor prognosis in polyarticular juvenile idiopathic arthritis (pJIA). However, most radiographic studies did not differentiate pJIA from other subtypes of JIA and little is known about pJIA persisting into adulthood. We describe radiological peripheral involvement in young adults with pJIA compared to patients with rheumatoid arthritis (RA).Methods.All consecutive patients with pJIA followed in a transition program were included. Age, sex, disease duration, and medical or surgical treatment information was collected. Laboratory tests and standard radiographs of the hands and wrists, feet, and hips were analyzed by 2 independent radiologists blinded to the diagnosis. One RA control group (age < 55 yrs), matched for sex and disease duration, was recruited.Results.Forty-three patients with pJIA and 59 with RA were included. Radiographs showed hand lesions in 79% of pJIA and 86% of patients with RA, feet lesions in 74% of pJIA and 80% of patients with RA, and hip damage in 35% of pJIA and 17% of patients with RA (p = nonsignificant). Specific to the juvenile forms were lower frequency of proximal interphalangeal joint involvement (51% vs 76%; p = 0.03) and higher risk of bilateral hip damage (86% vs 25%; p < 0.01) than in adult RA.Conclusion.Structural peripheral damage is as common and as severe in young adults with pJIA as in adults with RA. The main specific feature of pJIA seems to be a high risk of bilateral hip damage. This requires a particular monitoring of pJIA patients with unilateral hip involvement to detect bilateralization.

The thymus plays a crucial role in immune system homeostasis. Thymic abnormalities have been reported in many autoimmune diseases, but data for systemic sclerosis (SSc) and rheumatoid arthritis (RA) are sparse. The aim of this study was to evaluate the prevalence and correlates of radiological incomplete involution of the thymus in SSc and RA patients, and in a non-autoimmune group of controls.All patients were at least 40 years old: 96 SSc patients (median age 59 years, 80% women) and 65 RA patients (median age 57 years, 88% women) were compared with 32 control individuals (median age 63 years, 62% women). Pulmonary CT-scans performed for lung assessment were available for all individuals. For the purpose of our study, complete involution of the thymus was defined as the absence of a residual thymus or a gland thickness, corresponding to the short axis on the axial slice, of less than 7 mm. We defined incomplete involution of the thymus as a residual thymic tissue more than 7 mm thick.The frequency of incomplete thymus involution was significantly higher in SSc and RA patients (respectively 15 and 14%) than in the control group (0%; P0.05). Incomplete thymus involution was associated with pulmonary restrictive syndrome in SSc patients, and with biotherapy and an absence of antinuclear antibodies in RA patients.Our findings show that two autoimmune diseases, SSc and RA, are associated with incomplete thymus involution.

Resume Objectifs Le thymus joue un role crucial dans l’homeostasie du systeme immunitaire. Des anomalies du thymus ont ete rapportees dans de nombreuses maladies auto-immunes mais les donnees sur la sclerodermie systemique (ScS) et la polyarthrite rhumatoide (PR) sont rares. Le but de cette etude etait d’evaluer la prevalence et la correlation entre l’involution radiologique incomplete du thymus chez les patients porteurs de sclerodermie systemique et de polyarthrite rhumatoide compares a un groupe temoin d’affections non auto-immunes. Methode Tous les patients etaient âges d’au moins 40 ans : 96 ScS (âge moyen 59 ans, 80 % de femmes) et 65 PR (âge moyen 57 ans, 88 % de femmes) et ont ete compares a 32 sujets temoins (âge moyen 63 ans, 62 % de femmes). Des tomodensitometries pulmonaires etaient disponibles pour tous les sujets. Dans le but de cette etude, une involution complete du thymus a ete definie par l’absence de thymus residuel ou d’une epaisseur de la glande de moins de 7 mm sur le petit axe de la coupe axiale. Nous avons defini l’involution incomplete du thymus comme un tissu thymique residuel de plus de 7 mm d’epaisseur. Resultats La frequence de l’involution thymique incomplete est significativement plus importante dans la sclerodermie systemique et la polyarthrite rhumatoide (respectivement 15 % et 14 %) que dans le groupe temoin (0 % ; p Conclusion Nos resultats montrent que deux maladies auto-immunes, la sclerodermie systemique et polyarthrite rhumatoide, sont associees a une involution thymique incomplete.

Objectives Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc. Methods and results This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54 ± 13 years, mean disease duration 8 ± 9 years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3 years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF)

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

Objectives Specific cardiac involvement in granulomatosis with polyangiitis (GPA) is probably underestimated since many of these conditions are subclinical. The objective of this study was to assess the prevalence and patterns of cardiac abnormalities detected by cardiac MRI (CMRI) in patients with GPA. Methods Thirty-one consecutive patients with newly diagnosed or relapsing GPA underwent CMRI to assess morphological, functional, perfusion at rest and delayed enhancement abnormalities. Results At least one abnormality was observed on CMRI for 19 of 31 patients (61%). Four patients (13%) had an impaired left ventricle ejection fraction (LVEF). LV regional wall motion abnormalities were found in 11 patients (35%). Late gadolinium enhancement (LGE) was detected in 10 of 31 patients (32%). LGE was mostly nodular ( n = 9). Myocardial early contrast enhancement was detected in 5 of the 31 patients (16%), which was systematically associated with LGE in the same territory. CMRI detected pericarditis in eight patients (26%). GPA with

Rituximab seems well tolerated in patients with rheumatoid arthritis (RA). However, variations in the gammaglobulin profile that might increase the infection risk have been reported. Here, our objective was to evaluate gammaglobulin concentrations and the infection risk in patients receiving rituximab therapy for RA in everyday practice.Prospective single-center observational study of 65 patients with refractory RA (median age, 59 years; range, 26-83) treated with rituximab 1 g twice 15 days apart, with or without a further 1-g dose at least 6 months later depending on the clinical response. Gammaglobulins were assayed before each rituximab dose.The median cumulative rituximab dose was 4 g (1-16) and the median time to retreatment was 8 months (6-16). Rituximab therapy significantly improved the DAS-28 score. The gammaglobulin concentration decreased significantly between the first and last rituximab dose (from 11.6 g/L [5-26] to 8.2 g/L [3-20], a -2.6 g/L difference; P0.05). The decrease was larger in the 24 patients with cumulative rituximab doses greater than 5 g than in the 41 other patients (difference of -4 vs. -2.7 g/L; P0.05). Three patients experienced severe infections, two in the high-dose group and one in the other group (P=0.5).These data obtained in everyday practice constitute further evidence that rituximab is well-tolerated in patients with RA. Rituximab therapy was associated with a decrease in gammaglobulin concentrations that was greater in patients receiving higher cumulative doses.

Resume Objectif Le rituximab (RTX) semble bien tolere au cours de la polyarthrite rhumatoide (PR). Il a toutefois ete montre un impact sur le profil des gammaglobulines pouvant modifier le risque infectieux. Determiner l’impact sur les concentrations de gammaglobulines et le risque infectieux de l’utilisation en pratique courante du RTX dans la PR. Methodes Serie prospective monocentrique de 65 patients atteints de PR refractaire (âge median 59 ans [26–83]). Les patients ont recu 1 g de RTX renouvele a 15 jours d’intervalle, puis un re-traitement par 1 g apres un intervalle minimum de six mois, defini selon la reponse apres le premier cycle. Des dosages de gammaglobulines etaient effectues avant chaque perfusion. Resultats La dose mediane de RTX administree a ete de 4 g (1–16), le delai moyen de re-traitement de huit mois (6–16). Le RTX a permis une amelioration significative du score d’activite DAS28. La concentration de gammaglobulines a baisse significativement entre la premiere et la derniere cure de RTX (11,6 g/L (5–26) versus 8,2 g/L (3–20) ; delta = 2,6, p p Conclusion Ces resultats obtenus en pratique courante confortent la bonne tolerance clinique du RTX dans la PR, mais egalement une tendance a une baisse des gammaglobulines avec une influence de la dose cumulee.

Objective.To assess the prevalence of autoimmune diseases in first-degree relatives of patients with systemic sclerosis (SSc), and to compare those results with control families in order to identify patterns of autoimmune diseases in relatives.Methods.A retrospective case-control postal questionnaire survey was performed in France to recruit patients with SSc belonging to an association of patients with SSc and unrelated age-matched and sex-matched controls. Each participant was asked to self-report on the existence of autoimmune diseases in their first-degree relatives. The prevalence of autoimmune diseases in the families of patients with SSc was compared with the corresponding prevalence in the families of controls.Results.A total of 121 families out of 373 (32.4%) with a member having SSc reported at least 1 autoimmune disease in 1 or more first-degree relatives. The most frequent autoimmune diseases in SSc families when adjusted for family size were autoimmune thyroid disease (AITD; 4.9%), rheumatoid arthritis (4.1%), psoriasis (3.9%), and type 1 diabetes mellitus (2.9%). Compared with control families, AITD and connective tissue diseases (SSc, systemic lupus erythematosus, or Sjögren’s syndrome) were more likely to occur in families with SSc (p = 0.01 and p = 0.01, respectively), with OR of 3.20 (95% CI 1.25–8.18) and 5.20 (95% CI 1.22–21.8). In contrast, inflammatory bowel disease was less likely to occur within families with SSc (p = 0.02, OR 0.29, 95% CI 0.11–0.80). In addition, the coexistence of more than 1 autoimmune disease in the index SSc case was associated with familial aggregation of autoimmune diseases.Conclusion.Our results show that autoimmune diseases cluster within families of patients with SSc. This supports the notion that these diseases might arise on a shared genetic basis underlying several autoimmune phenotypes.

Resume Nous rapportons l’observation d’une patiente de 38 ans hospitalisee dans notre service pour le bilan de lesions osteolytiques. Elle presentait des douleurs dorsolombaires et costales apparues dans les suites du diagnostic d’une hyperthyroidie sur goitre multi-heteronodulaire toxique. Les douleurs ont persiste malgre un traitement chirurgical du goitre. L’examen clinique retrouvait des taches cutanees « cafe au lait ». Le bilan phosphocalcique a mis en evidence un diabete phosphate. Les radiographies montraient des lesions lytiques costales ainsi que des fractures vertebrales dorsales. Au scanner, presence de multiples lesions touchant le rachis, les cotes, le sternum, les ailes iliaques et le sacrum avec un aspect typique en verre depoli. Le diagnostic de syndrome de McCune-Albright a ete porte devant cette triade caracteristique. Le traitement a consiste en une supplementation en vitamine D ainsi qu’en de fortes doses de phosphore et de 1–25 OH vitamine D3 pour le diabete phosphate ; un traitement par bisphosphonates intraveineux a ete introduit pour la prise en charge des douleurs osseuses. Nous rapportons une observation inhabituelle de syndrome de McCune-Albright revele tardivement dans les suites d’une hyperthyroidie. Nous pensons que les lesions de dysplasie fibreuse sont devenues symptomatiques du fait de l’hyper remodelage osseux lie a l’hyperthyroidie.

Objective. SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies. Methods. We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis. Results. Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 [95% CI 3.03, 4.11, P < 0.0001; I 2 = 93%, P(het) = 0.001]. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 198090: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement. Conclusion. Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.

Resume Les osteites chroniques multifocales recidivantes (OCMR), egalement appelees osteites chroniques non bacteriennes (OCN), appartiennent au groupe des maladies rares. Cette pathologie se caracterise par des poussees douloureuses inflammatoires osseuses recidivantes, parfois associees a de la fievre traduisant la presence d’une ou plusieurs localisations d’osteite aseptique. Il existe deux formes d’OCMR, mono- ou plurifocale. Les formes monofocales sont un diagnostic differentiel d’osteomyelite septique ou de tumeur, ce qui necessite quasiment systematiquement une biopsie osseuse et souvent l’instauration d’une antibiotherapie d’epreuve. L’OCMR est actuellement consideree comme la forme pediatrique du syndrome SAPHO et les donnees recentes suggerent de classer les OCMR dans la grande famille des maladies auto-inflammatoires. Le traitement des OCMR n’est actuellement pas codifie. Malgre l’absence d’etude randomisee contre placebo, certains consensus peuvent etre etablis : les anti-inflammatoires non steroidiens (AINS) en premiere ligne de traitement, l’efficacite des bisphosphonates et des biotherapies de type anti-TNF alpha pour les formes les plus severes. Bien qu’elle soit consideree comme peu severe, des donnees recentes suggerent que l’OCMR est responsable dans 50 % des cas de sequelles physiques invalidantes, malgre une prise en charge therapeutique bien conduite.

Barrett's oesophagus (BE) is the major risk factor for oesophageal adenocarcinoma (EAC). SSc is associated with an increased risk of BE related to chronic reflux. The aim of this study is to determine the outcomes of BE and estimate the EAC risk in SSc patients over a 3-year prospective study.SSc patients were recruited through EUSTAR network centres. Inclusion criterion was a recent histological finding of BE. The patients were then prospectively followed and, as recommended, a second oesophageal endoscopy was performed according to the presence of BE-related dysplasia at baseline.A total of 50 SSc patients with BE (40 without and 10 with dysplasia) were included and 46 completed the follow-up (138 patient-years). During the 3-year follow-up, 4 of the 46 BE patients (3% per year) were diagnosed with high-grade dysplasia/EAC, of which one developed cardial EAC. EAC incidence in the BE subgroup with dysplasia increased to 4% per year compared with the absence of EAC cases in the BE subgroup without dysplasia at baseline.Our results, in accordance with previous published data suggesting an increased risk of EAC or cardial adenocarcinoma in SSc, highlight the need for accurate follow-up of BE SSc patients at risk of developing adenocarcinoma.

"Primary" myocardial disease is common in patients with systemic sclerosis and appears to be a factor of poor prognosis when clinically evident. An increasing body of evidence suggests that myocardial involvement is due, at least in part, to abnormal vasospasm, with or without associated structural abnormalities, of the small coronary arteries or arterioles. Impaired myocardial perfusion, as well as left and right ventricular dysfunction, have recently been confirmed in this setting, using more sensitive techniques such as tissue Doppler echocardiography and magnetic resonance imaging. Vasodilators such as calcium channel blockers, angiotensin-converting-enzyme inhibitors and an endothelin receptor antagonist improve both myocardial perfusion and functional abnormalities, and their systematic long-term administration might help to prevent these major complications.

ObjectiveTo examine the outcomes of hand radiographic x-rays in patients with systemic sclerosis (SSc) and to identify risk factors for the progression of hand radiographic lesions in a prospective cohort.MethodsDual time-point x-rays were systematically performed after a median interval of 5 years (range 4–7 years) in 103 consecutively recruited patients with SSc. Univariate and multivariate Cox proportional hazards models evaluated predictors of progression of hand radiographic lesions.ResultsRadiographic progression of erosive arthritis, acro-osteolysis, calcinosis and flexion contracture occurred in 24, 22, 27 and 18 patients, respectively. Multivariate Cox regression analysis did not identify any predictor of the progression of erosive arthritis. Digital ulcers were shown independently to predict the progression of acro-osteolysis and calcinosis (HR 12.43, 95% CI 1.97 to 88.40 and 3.16, 95% CI 1.22% to 9.43%, respectively). The diffuse cutaneous subset was shown to be an independent predictor of the progression of flexion contracture (HR 7.52, 95% CI 1.21 to 43.93).ConclusionThe results highlight the striking level of hand radiographic lesions in SSc and suggest close monitoring of patients with the diffuse cutaneous subset for the occurrence or worsening of this complication. The results also show that severe peripheral vascular involvement predicts both acro-osteolysis and calcinosis, highlighting their vascular background.

Objective.Several lines of evidence suggest that the generation of reactive oxygen species (ROS) is of major importance in the pathogenesis of SSc. Protein and lipid damage have previously been demonstrated, but scarce data are available on oxidative damage to DNA. In patients with SSc, we evaluated levels of 8-hydroxy-2’-deoxyguanosine (8-oxodG), the main validated biomarker of endogenous oxidative damage to DNA, compared to levels of F2-isoprostane, a product of free radical-mediated peroxidation of arachidonic acid.Methods.Urinary levels of 8-oxodG and 8-isoprostaglandin-F2α (8-iso-PGF2α) were determined by competitive ELISA method in consecutive SSc patients and controls matched for age and sex.Results.We included 80 unrelated SSc patients (72 women, mean age 56 ± 11 yrs) and 39 controls (33 women, mean age 64 ± 8 yrs). Urinary levels of 8-oxodG/creat and 8-iso-PGF2α/creat in SSc patients were found to be higher than in controls (6.5 ng/mg vs 3.7 ng/mg, p = 0.0001; and 11.4 ng/mg vs 4.2 ng/mg, p < 0.0001). In multivariate analysis, 8-oxodG levels were associated with the presence of pulmonary fibrosis on computerized tomography scan, decreased forced vital capacity, and decreased DLCO/alveolar volume. In patients with the diffuse cutaneous subset, a modified Rodnan skin score > 14 was independently associated with 8-oxodG levels. In SSc, 8-oxodG and 8-iso-PGF2α values were correlated (r = 0.32; p = 0.005).Conclusion.Our study confirmed marked oxidative stress in SSc. We also found increased values of 8-oxodG in SSc patients and a relevant association with a fibrotic phenotype. The predictive value of this marker and its potential influence on fibrotic disturbances remain to be determined.

Little is known about systemic sclerosis (SSc)-related myopathy. We aimed to compare the clinical and immunological features of SSc patients with or without associated myopathy.Forty SSc patients with myopathy, defined by myalgia or muscle weakness associated with creatine kinase (CK) more than five times the upper limit range or myopathic electromyography (EMG) or abnormal myopathology, were identified from the records of four French hospital centres. For each patient, we selected two SSc controls matched for cutaneous SSc form, sex, age at SSc onset, and disease duration. We performed a case-control study testing clinical and immunological SSc-related features for association with myopathy by conditional logistic regression.Muscle and SSc features of patients with myopathy did not differ significantly among the four centres of origin. Only four (10%) patients with SSc-associated myopathy had anti-polymyositis-scleroderma (PM-Scl) antibodies. Case-control univariate analysis revealed that reduced forced vital capacity (FVC) [odds ratio (OR) 3.0, 95% confidence interval (CI) 1.3-34.9], heart involvement, defined as clinical congestive heart failure, left ventricular ejection fraction (LVEF)60%, arrhythmia or conductive abnormalities (OR 2.9, 95% CI 1.3-6.5), and scleroderma renal crisis (OR 3.0, 95% CI 1.3-34.9) were significantly more frequent in patients with myopathy than in controls. Two autoantibodies were more frequent in patients with myopathy: anti-PM-Scl (OR 5.0, 95% CI 1.1-23.9) and anti-RNP (OR 6.9, 95% CI 1.1-64.4). Multivariate analysis retained two variables associated positively with myopathy [reduced FVC (OR 3.1, 95% CI 1.3-9.8) and heart involvement (OR 2.5, 95% CI 1.1-7.1)], while anti-centromere antibodies were associated negatively (OR 0.11, 95% CI 0.03-0.53).Heart monitoring of SSc patients with myopathy should be undertaken regularly because of the association of myocardial and skeletal myopathies in such patients.

Resume La sclerodermie systemique (ScS) est une connectivite caracterisee par des lesions microvasculaires diffuses et qui comporte une atteinte du tractus digestif dans environ 90 % des cas. Le segment le plus frequemment atteint est l’œsophage mais l’ensemble du tube digestif peut etre affecte. Le reflux gastro-œsophagien est l’atteinte digestive la plus frequente mais des lesions plus inhabituelles peuvent etre rencontrees. L’ectasie vasculaire antrale gastrique (GAVE) ou estomac pasteque fait partie de ces complications rares ; elle releve de modifications des capillaires sous-muqueux qui sont dilates et parfois thromboses et entre dans le cadre de la microvasculopathie de la maladie. Cette complication est une etiologie d’anemie profonde au cours de la ScS a ne pas meconnaitre du fait de sa gravite potentielle. Elle appelle un traitement local specifique adapte.

Resume La sclerodermie systemique (ScS) est une maladie orpheline incurable appartenant au groupe des connectivites. Elle est caracterisee par un processus specifique de fibrose systemique, microvasculaire et tissulaire pouvant aboutir a des defaillances d’organe notamment dans le systeme cardiovasculaire. Son heterogeneite clinique, ainsi que la complexite des variations des differentes atteintes viscerales tout au long de l’evolution de la maladie rendent delicates le choix des criteres a la fois diagnostique et d’evaluation. Les criteres actuellement utilises pour le diagnostic sont des criteres de classification, peu fiables en cas de maladie debutante, rendant necessaire le developpement de nouveaux outils afin d’ameliorer le diagnostic precoce de cette maladie. Le suivi de la maladie s’effectue a l’aide de criteres composites ou de criteres specifiques des differentes atteintes viscerales de la maladie. Nous passerons en revue ici les differents criteres actuellement utilises pour le diagnostic et pour le suivi en pratique courante de la ScS.

Objective.Identification of an association between IRF5 rs2004640 and systemic sclerosis (SSc) has highlighted a key role for type 1 interferon (IFN). Additional functional IRF5 variants have been identified as autoimmune susceptibility factors. Our aim was to investigate whether IRF5 haplotypes confer susceptibility to SSc, and to perform genotype haplotype-phenotype correlation analyses.Methods.We genotyped IRF5 rs377385, rs2004640, and rs10954213 in 1623 individuals of French European Caucasian origin. SSc patient subphenotypes were analyzed according to cutaneous subsets and for SSc-related pulmonary fibrosis.Results.Case-control studies of single markers revealed an association between IRF5 rs3757385, rs2004640, and rs10954213 variants and SSc. We identified an IRF5 risk haplotype “R” (padj = 0.024, OR 1.23, 95% CI 1.07–1.40) and a mirrored protective haplotype “P” (padj = 8.8 × 10−3, OR 0.78, 95% CI 0.68–0.90) for SSc susceptibility. Genotype-phenotype correlation analyses failed to detect any association with a single marker. By contrast, phenotype-haplotype correlation analysis was able to detect intra-cohort association and to discriminate SSc patients with from those without the following clinical traits: “R” and/or “P” haplotypes identified diffuse cutaneous SSc (p = 0.0081) and fibrosing alveolitis (p = 0.018).Conclusion.IRF5 haplotypes are more informative than single markers, suggesting that they could be helpful for risk stratification of SSc patients. Our study provides further evidence of a key role of IRF5 in SSc severity.

Objective To assess the usefulness of routine electrocardiography for heart disease screening in patients with spondyloarthropathy (SpA) or rheumatoid arthritis (RA). Methods We included consecutive patients with SpA or RA or with degenerative joint disease (control group) admitted over a 6-month period and free of cardiovascular events. A 12-lead electrocardiogram (ECG) was obtained and was interpreted by a cardiologist who was unaware of the diagnosis. Results We included 108 patients with SpA (mean duration, 11 ± 10 years), 106 with RA (mean duration, 12 ± 9 years), and 74 with degenerative joint disease (controls). No patient had cardiovascular symptoms or a prior history of cardiovascular disease. The only difference in cardiovascular risk factors across the three populations was a higher prevalence of diabetes in the RA and control groups. We found no differences between the SpA or RA groups and the control group regarding the rates of the following ECG findings: premature beats, atrioventricular block (2.8% in the SpA group, 1.9% in the RA group, and 2.7% in the control group), complete or incomplete left bundle branch block (0.9%, 0.9%, and 2.7%, respectively), complete right bundle branch bloc or left bundle branch block (0.9%, 4.7%, and 4.1%, respectively); and abnormalities suggesting myocardial ischemia (10.2%, 19.8%, and 17.6%, respectively). Conclusion In patients with SpA or RA who have no cardiovascular symptoms or history of cardiovascular disease, a routine ECG shows no increase in the cardiac abnormalities specifically associated with these joint diseases, compared to controls with degenerative joint disease.

Resume L’objectif etait d’evaluer l’interet de l’electrocardiogramme (ECG) systematique, comme outil de detection des anomalies cardiaques au cours des spondylarthropathies (SPA) et de la polyarthrite rhumatoide (PR). Methodes Des malades consecutifs atteints de SPA, PR ou maladies articulaires degeneratives (consideres comme temoins) hospitalises sur une periode de six mois et indemnes d’evenement cardiovasculaire ont ete inclus. Un ECG – 12 derivations – etait realise et interprete par un cardiologue en insu du diagnostic. Resultats Au total, 108 patients avec SPA (duree moyenne 11 ± dix ans), 106 malades avec PR (duree moyenne 12 ± neuf ans) et 74 temoins ont ete inclus. Ceux-ci etaient asymptomatiques sur le plan cardiaque et sans antecedent cardiovasculaire. Les populations etaient homogenes, concernant la presence des facteurs de risque cardiovasculaire, hormis pour le diabete, plus frequent dans les groupes PR et temoin. Les proportions d’extrasystoles, de blocs auriculoventriculaires (2,8 % dans le groupe SPA ; 1,9 % dans le groupe PR ; 2,7 % chez les temoins), de bloc de branche gauche complet ou incomplet (respectivement : 0,9 % ; 0,9 % ; 2,7 %), de bloc de branche droit complet ou de bloc de branche gauche (respectivement : 0,9 % ; 4,7 % ; 4,1 %) et d’anomalie evocatrice d’ischemie myocardique (10,2 % ; 19,8 % ; 17,6 %) etaient similaires chez les patients atteints de PR ou de SPA par comparaison a la population temoin. Conclusion Chez les patients sans antecedent cardiovasculaire, asymptomatiques, la realisation d’un ECG systematique ne permet pas de mettre en evidence le risque accru de complications cardiaques specifiques liees a ces pathologies, chez les patients atteints de SPA et PR.

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.

Objective.To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID).Methods.A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases.Results.We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren’s syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren’s syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers.Conclusion.Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Objective. To assess dermal expression and fibroblast production of fibrillin-1 (FBN-1) in SSc. Methods. In vivo analysis of microfibrillar network was performed using EM from affected and unaffected skin biopsy specimens of dcSSc patients (n = 5) compared with healthy controls (n = 2). FBN-1 matrix deposition and organization by dermal fibroblast cultures from dcSSc (n = 6), healthy (n = 5) and Marfan (n = 4) controls was analysed in vitro by IF with or without TGF-b activation. Finally, production of FBN-1 by cultured dermal fibroblasts was evaluated by western blot (WB) and real-time PCR. Results. We observed a striking decrease of tissue microfibrillar network in the dermis of SSc patients compared with healthy controls affecting both clinically involved and uninvolved skin. In cultures, SSc dermal fibroblasts displayed no apparent in vitro alteration of synthesis, secretion and organization of microfibril network. The WB and real-time PCR analyses showed similar FBN-1 amounts in matrix and FBN1 gene expression in SSc and healthy controls. Conclusions. We observed a striking decrease of in vivo microfibrillar network in clinically affected and unaffected skin in early dcSSc patients. This does not relate to an inability of SSc dermal fibroblasts to produce, secrete and organize microfibrils in vitro. Therefore, the disturbances of microfibrils in SSc may be a secondary event to matrix remodelling that occurs in this disease.

SummaryHeart involvement, including primary myocardial involvement, is very common in systemic sclerosis. There is strong evidence that primary myocardial involvement is related to repeat focal ischaemic injury causing subsequent irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus preclinical identification is highly encouraged. The severity of heart involvement has been confirmed recently. Echocardiography, including pulsed tissue Doppler echocardiography, is the cornerstone of routine heart assessment. Myocardial perfusion may be assessed by single photon emission computed tomography. If available, cardiac magnetic resonance imaging should be considered as it allows simultaneous measurement of ventricular volumes and function and myocardial perfusion, and assessment of possible inflammation and/or fibrosis. Biological variables, such as B-type natriuretic peptides, are highly relevant, valuable markers of global heart involvement in systemic sclerosis and should be considered for screening of patients and/or research purposes.

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.

Resume Le Tumor necrosis factor (TNF)-Receptor Associated Periodic Syndrome (TRAPS), lie aux mutations du gene TNFRSF1A codant pour le recepteur au TNF de type 1, est un syndrome auto-inflammatoire extremement polymorphe. Arthralgies et synovites non erosives font partie des manifestations les plus frequentes. Nous rapportons le cas d’une patiente âgee de 73 ans presentant un tableau de rhumatisme inflammatoire chronique erosif evoluant par poussees. La notion de signes extra-articulaires abdominaux et cutanes moderes et aspecifiques a conduit a envisager le diagnostic de TRAPS, qui a ete confirme par la mise en evidence de la mutation R92Q du gene TNFRSF1A. En dehors de la corticotherapie presentant un effet suspensif sur les symptomes, les traitements de fond par methotrexate et etanercept n’ont pas permis de reduire la frequence des poussees ni d’enrayer la progression structurale. Un traitement par anakinra est desormais envisage. Il s’agit a notre connaissance du premier cas decrit d’atteinte articulaire erosive dans le cadre d’un TRAPS. Ce diagnostic doit etre envisage en cas de rhumatisme inflammatoire refractaire associe a des signes extra-articulaires meme moderes.

The aims of the present study were to identify prognostic factors for systemic sclerosis (SSc)-related interstitial lung disease and to clarify the possible causative role of manometric oesophageal involvement. Consecutive SSc patients underwent pulmonary function tests and oesophageal manometry. They were included in the study if pulmonary function tests were repeated12 months after baseline. The primary end-point was a decrease ofor=10% of the predicted value in forced vital capacity (FVC). The secondary end-points were a decrease ofor=15% pred in lung carbon monoxide diffusing capacity (D(L,CO)) and a decrease ofor=20% pred in FVC. Of the 105 patients (45 diffuse SSc; median disease duration 2.0 yrs), 23 (23%) had a FVC of80% pred, 60 (59%) had a D(L,CO) of80% pred and 57 (54%) showed severe oesophageal hypomotility at baseline. Over 72+/-46 months, 29 (28%) patients displayed a decrease ofor=10% pred in FVC, 39 (40%) of 98 patients displayed D(L,CO) decline and 19 (18%) patients displayed a decrease ofor=20% pred in FVC. On multivariate analysis, diffuse SSc was a significant predictor for a decrease ofor=10% pred in FVC (p = 0.01). No other predictor of a decrease in pulmonary function was identified. Only diffuse SSc was predictive of a decrease in pulmonary function in this early-SSc cohort. This does not support preliminary data suggestive of a causative role of oesophageal involvement.

Objective An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinerAIR-Sclerodermie Study). Methods Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8–3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis. Results A total of 384 patients were followed up for a mean ± SD of 41.03 ± 5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean ± SD age of the patients was 53.1 ± 12.0 years. The mean ± SD duration of SSc at study entry was 8.7 ± 7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20–25 mm Hg at baseline subsequently developed PAH. Conclusion The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.