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Immune checkpoint inhibitor are standard therapy in metastatic urothelial carcinoma. No predictive biomarker of immune related adverse events (iRAE) exists. Antinuclear antibodies (ANA) can be the sign of a subclinical autoimmune condition that could be enhanced by Immune checkpoint inhibitor. We decided to assess the predictive value of baseline autoantibodies and ANA for iRAE in metastatic urothelial carcinoma patients treated with pembrolizumab and explore their prognostic signification.Data concerning patients treated in our institution between 2015 and 2020 with pembrolizumab for metastatic urothelial carcinoma with available baseline value of ANA and other autoantibodies was collected. ANA with titer1/80 were defined positive.A total of 68 patients were included. Fifty-five (80%) had ANA1/80 and among them 21 patients (30%) had ANA1/160. Seven patients with ANA160 (33%) presented iRAE vs. 5 patients (10%) in the rest of the population. Presence of ANA160 was significantly associated with iRAE (P = .029) and limiting toxicity (P = .048) in univariate analysis. iRAE tend to occur earlier, before the third cycle, for patients with ANA1/160 as compared to rest of the patients (28% vs. 6%, P = .052). Exploratory analysis did not reveal correlation between progression free survival or overall survival and ANA1/160 in univariate or in multivariate analysis including the Bellmunt score (HR = 0.7, 95%CI [0.38-1.35], P = .5).The presence of ANA1/160 is associated with iRAE and limiting toxicity of pembrolizumab.

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.To investigate different clinical and biological profiles of BP.We conducted a retrospective 2-center study including all BP patients seen between January 1, 2015, and February 28, 2021. We performed hierarchical clustering on principal components.Three clusters were identified. Patients in cluster 1 (n = 155) were older than those in clusters 2 (n = 89) and 3 (n = 35; P .0001), more frequently presented pauci-bullous BP (n = 63 [41%] vs 14 [16%] and 2 [6%], respectively; P .0001) and had anti-BP230 antibodies in 87% of cases. More than 100 blisters were observed in 14 patients (40%) from cluster 3, versus 3 (2%) from cluster 1 and 0 (0%) from cluster 2 (P .0001). Frequency of mucosal involvement was higher in cluster 3 (n = 32 [91%, including epiglottis in 40%] vs 11 [7%] and 34 [38%]; P .0001). In clusters 2 and 3, 70% and 74% of patients had antibodies targeting only BP180. Those in cluster 3 received more lines of systemic treatment and experienced more relapses.Retrospective study without immunoelectron microscopy.We identified 3 different BP clusters, including one corresponding to severe BP180

Supplementary Figure 2 from Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H2O2), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H2O2 is controlled by catalase. N-acetylcysteine, which decreases H2O2 levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H2O2 concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H2O2 levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.

Supplementary Figure 1 from Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species

Supplementary Figure 3 from Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species

INTRODUCTION: Antiphospholipid antibodies (APA) clinical relevance in COVID-19 is controversial. We aimed to investigate the prevalence and prognostic value of conventional and non-conventional APA in COVID-19 patients. METHODS: This study was a multi-centric, prospective observational French cohort of patients hospitalized for COVID-19 suspicion. RESULTS: 249 patients were hospitalized for suspected COVID-19, including 154 with confirmed COVID-19 and 95 not confirmed. We found a significant increase in lupus anticoagulant (LA) positivity among COVID-19 positive patients (60.9% versus 23.7% in non-COVID19 patients, p

There is an increasing body of evidence suggesting a direct pathophysiological role of anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA), and immunological remission could be a target for treatment. However, data related to the ability of biologics to reduce ACPA titres are contradictory.We aimed to evaluate the changes in ACPA titres after treatment with different biologics in patients with RA.As a first step, a systematic review of the literature available on 3 biologics (TNFi, abatacept and rituximab) and ACPA in patients with RA was performed in Pubmed and Cochrane. As a second step, a retrospective study was performed: all RA patients treated with the 3 above-mentioned biologics were identified. To be included in the analysis, patients had to have at least two titres of ACPA (one before and one after biologic treatment) available. ACPA titres were compared before and after treatment in each of the treatment groups.As a result of the literature review, 24 articles were retained confirming that the data on change in ACPA under biologics is contradictory, particularly for abatacept and TNFi. 144 RA patients (79.3% female, mean age: 56 years) were included in the retrospective analysis: 59 patients had received rituximab, 31 abatacept, 55 TNFi. ACPA titres decreased significantly with rituximab but not with abatacept nor TNFi. Modelling of ACPA titres over follow-up confirmed the significant decrease of ACPA over time rituximab.In this real-life study, ACPA titres only significantly decreased after treatment with rituximab.

International audience; Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods and results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 mu g/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 mu g/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 mu g/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab.

Objective To help identify homogeneous subgroups among patients with anti-PM-scleroderma-antibodies (PM-Scl-Abs) positive auto-immune diseases regardless of diagnostic classifications. Material and methods This multicentric (four hospitals) retrospective study collected all consecutive patients (from 2011 to 2021) with positive testing for anti-PM-Scl-Abs in a context of CTD. Subgroups of patients with similar clinico-biological phenotypes were defined using unsupervised multiple correspondence analysis and hierarchical clustering analysis of the features recorded in the first year of follow-up. Results One hundred and forty-two patients with anti-PM-Scl-Abs were evaluated and 129 patients were included in the clustering analysis and divided into three clusters. Cluster 1 (n = 47) included patients with frequent skin thickening, digestive involvement and interstitial lung disease (ILD) with non-specific interstitial pneumonia (NSIP). They were more likely to develop progressive fibrosing ILD. Cluster 2 (n = 36) included patients who all featured NSIP with frequent organizing pneumonia–associated pattern and mechanic’s hands. This subgroup had increased risk of relapse and ILD was characterized by a good functional outcome. Cluster 3 (n = 46) was characterized by predominant or isolated musculoskeletal involvement and frequently matched UCTD criteria. Although very frequent among anti-PM-Scl-Abs positive patients, muscle involvement was less discriminating compared with skin thickening and ILD pattern to classify patients into subgroups. Conclusion Anti-PM-Scl-Abs associated auto-immune diseases are segregated into three subgroups with distinct clinical phenotype and outcomes. Skin thickening and NSIP are determinant predictors in segregation of theses populations.

To describe the switch to biosimilar etanercept (bETN), evaluate factors associated with this switch, and evaluate the efficacy of this switch in a real-life setting We included patients, from October 2016 to April 2017, with rheumatoid arthritis (RA) and spondyloarthritis (SpA) who received innovator ETN (iETN) for at least 6 months. After receiving information on biosimilars, all physicians were invited to propose a switch from iETN to bETN. Factors associated with bETN discontinuation were explored by univariate and multivariate analyses. We estimated the proportion of patients still on bETN over time by Kaplan-Meier survival analysis. We assessed serum trough concentrations of iETN and bETN and anti-drug antibodies to ETN. Overall, 183 outpatients were eligible for a potential switch; 94 (51.6%) switched from iETN to bETN. The probability of a switch was greater with an older than younger aged physician (mean [SD] age 50.4 [14.3] with a switch vs 44.8 [11.3] with no switch, p = 0.005) and the physician having a full-time academic position than other position (56.4% with a switch vs 13.5% with no switch, p

International audience; Objective: To evaluatre the risk of immunogenicity in patients with chronic inflammatory diseases who experienced successive non-medical swiches to different biosimilars infliximab.Patients and methods: Observational study over a 3-year observation period assessing the risk of immunogenicity in i) patients in maintenance therapy with innovator infliximab who were successively switched to CT-P13, then to SB2 (cohort-1) and ii) biologic-naive patients initiated with CT-P13 before being switched to SB2 (cohort-2). A propotion meta-analysis was also performed, integrating our results to 16 additional studies.Results: Cohort-1 included 265 patients who switched to CT-P13, and 140 patients were subsequently switched to SB2. Among the 235 anti-drug antibody (ADA)-free patients at baseline, 20 patients (8.5%) developed ADA over the 3-year observation period (rate of 3 for 100 patient years). Cohort-2 included 44 patients, of whom 29 subsequently switched to SB2. A total of 11 patients (25%) developed ADA within 3 years (rate of 14 for 100 patients years). We found no influence of the number of biosimilars infliximab received on ADA deveopment in both cohorts. The risk of treatment discontinuation was significantly higher in patients with positive ADA in both cohorts. The meta-analysis including our data exposed an incidence of immunogenicity of 4.7% (95% CI 3.5-6.1%) after the switch from innovator infliximab to biosimilar infliximab and 21.1% (95% CI 13.1-30.3%) in patients initiating biosimilar infliximab.Conclusion: Immunogenicity was not favored by successive non-medical switches to biosimilars infliximab in our study, but was associated with treatment discontinuation.

Background Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. Methods HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ Results The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76–0.94) and specificity of 0.89 (95% CI 0.72–0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level ( Conclusions These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.

To describe the switch to biosimilar etanercept (bETN), evaluate factors associated with this switch, and evaluate the efficacy of this switch in a real-life setting METHODS: We included patients, from October 2016 to April 2017, with rheumatoid arthritis (RA) and spondyloarthritis (SpA) who received innovator ETN (iETN) for at least 6 months. After receiving information on biosimilars, all physicians were invited to propose a switch from iETN to bETN. Factors associated with bETN discontinuation were explored by univariate and multivariate analyses. We estimated the proportion of patients still on bETN over time by Kaplan-Meier survival analysis. We assessed serum trough concentrations of iETN and bETN and anti-drug antibodies to ETN.Overall, 183 outpatients were eligible for a potential switch; 94 (51.6%) switched from iETN to bETN. The probability of a switch was greater with an older than younger aged physician (mean [SD] age 50.4 [14.3] with a switch vs 44.8 [11.3] with no switch, p = 0.005) and the physician having a full-time academic position than other position (56.4% with a switch vs 13.5% with no switch, p 0.001). After a 6-month follow-up, bETN retention rate was 83% (95% CI: 0.76-0.92). The first cause of bETN discontinuation was inefficacy (50%). On multivariate analysis, no factor was independently associated with a bETN switch or discontinuation. Drug trough levels did not significantly differ by discontinuation or continuation of bETN. No patient showed anti-drug antibodies.The probability of switching from iETN to bETN was likely related to physician characteristics.

To study in daily practice the risk of immunogenicity of patients treated with the biosimilar rituximab (RTX) GP2013 used for chronic inflammatory rheumatic disorders.A prospective monocentric routine care study was carried out between September 2018 and May 2021, including consecutive patients treated with the biosimilar RTX GP2013. Biosamples were taken before each infusion to quantify anti-RTX antibodies (ADAbs) and serum RTX trough levels by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag).168 GP2013-treated patients were included (129 who switched from originator RTX and 39 originator RTX naïve). The analysis of 602 samples identified 15 patients (8%) with positive ADAbs including 6 and 9 with transient and persistent ADAbs, respectively. The switch from originator RTX to GP2013 did not increase the risk of immunogenicity, with an incidence rate of 0.8 for 100 patient years. The frequency of persistent ADAs was higher in non-RA patients (5/56, 9% vs. 4/112, 3.5%). Patients with positive persistent ADAbs were more frequently non-caucasian (7/9, 78%, vs. 56/159, 35%, p0.01) and all had detectable circulating B cells (vs. 40% in ADAb-negative patients, P0.001). ADAb positivity was not associated with disease activity or RTX discontinuation but patients with ADAb titers100 ng/mL experienced reduced treatment efficacy or severe infusion-related reaction.Within the study duration, the immunogenicity of GP2013 is a rare event affecting the pharmacodynamics of RTX. Although development of ADAbs had no impact on treatment discontinuation, possible harmful consequences may be observed in patients with high antibody levels.

Although the use of EDTA-containing collection tubes is known to stabilize the complement analytes and to make the results more reliable, no external quality assessment (EQA) scheme based on EDTA plasma samples is available to date in France. Consequently, a number of clinical laboratories currently participate to EQA program on samples whose matrix is different from their routine practice. The aim of this work was to offer a new external quality assessment scheme, as an inter-laboratory exchange (ILE). The ILE samples come from pooled EDTA plasmas of healthy subjects and are diluted to obtain distinct control levels. The protocol has been validated on CH50, C3, C4 and C1-inhibitor measurements, through: (i) a stability study of post-centrifugation storage of EDTA plasma samples at room temperature, 4̊C and -20̊C; (ii) the demonstration of the linearity of the dilution steps; and (iii) a stability study of the diluted samples. Our results demonstrate a four-weeks stability of the ILE samples prepared and stored according to our protocol. Those results are compatible with the ILE implementation constraints, and the program has been implemented in January 2018. The one-year ILE implementation experience is also presented. The newly implemented ILE will be useful for the accreditation of the complement activity of French laboratories using EDTA plasma samples.

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.

Background:The bioequivalence between rituximab (RTX) originator and its biosimilar GP2013 has been demonstrated in rheumatoid arthritis (RA) (1). A recent randomized controlled trial suggested in a selected population a very low immunogenicity of GP2013 in RA (Objectives:To study in daily practice the risk of immunogenicity of patients treated with GP2013 for their chronic inflammatory rheumatic disorder.Methods:Prospective routine care study carried out between September 2018 and August 2020 in the Rheumatology department of Cochin Hospital. We consecutively included patients treated with the biosimilar RTX GP2013, systematically used in the department since March 2018. Samples were taken before each infusion in order to detect anti-RTX antibodies (Ab) and RTX residual concentrations by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag).Results:We included 159 consecutive patients treated with GP2013 (124 women, 78%) with a mean age of 59±13 years and a mean disease duration of 18±11 years. Among these 159 patients, 108 (68%) had RA and 51 had another disease (16 systemic sclerosis (SSc), 15 mixed connective tissue disease (MCTD), 5 systemic lupus (SLE), 5 inflammatory myopathies (MI), 5 undifferentiated polyarthritis, 2 juvenile idiopathic arthritis (JIA) and 3 primary Sjögren’s syndromes). 137 patients (86%) were receiving associated disease-modifying therapy (DMARD), mainly methotrexate (111/137 patients, 81%). 120 patients (75%) were in maintenance therapy with originator RTX (cumulative dose of RTX: 3.5±6g) before the switch to GP2013 in March 2018. Originator RTX was not re-established during the entire treatment period. The other 39 patients (25%) treated with GP2013 were naïve of originator RTX.The analysis of the first sample, performed before the second GP2013 infusion, identified 8 patients (5 RA, 1 SLE, 1 MCTD and 1 SSc) with positive anti-RTX antibodies (prevalence 5%), with rates varying between 6 and >100ng/mL and undetectable residual RTX concentrations. Among these 8 patients, 6 had previously received originator RTX and 2 were RTX-naïve patients. There was a trend for higher body mass index in patients with positive anti-RTX antibodies (28±7 vs. 25±6 kg/m2, p=0.12), and no association was observed between anti-RTX immunization and age, disease duration, combination with conventional DMARD, mean interval between infusions or cumulative RTX dose.Among the 8 immunized patients, two groups could be isolated: i) a group of 5 patients (3 RA, 1 SLE, 1 SSc) with low antibody levels (6-22 ng/mL) and no significant clinical consequences (absence of treatment discontinuation and loss of efficacy after 13±4 months of follow-up, only one minor allergic reaction) and ii) a group of 3 patients (2 RA, 1 MCTD) with a high antibody levels (≥100ng/mL) and meaningful clinical consequences: one severe allergic reaction during the second GP2013 infusion leading to treatment discontinuation, and a loss of efficacy with incomplete B depletion in 2 patients leading to RTX dose escalation from 500 mg to 1 g. Among the 151 patients not immunized at the time of the first sample, no severe allergic reaction and 6 minor allergic reactions were noted under GP2013.Conclusion:The immunogenicity of patients treated with RTX is a rare event with possible clinical and biological consequences, especially in patients with high antibody levels.References:[1]Smolen et al, Ann Rheum Dis 2017[2]Tony et al, Arthritis Care Res 2019Disclosure of Interests:None declared

Introduction Les anticorps (Ac) anti-polymyosite/sclerodermie (anti-PM/Scl) ont ete rapportes comme pouvant etre associes a la sclerodermie systemique (ScS). Cette cohorte etudie le profil de patients francais avec une ScS et des Ac anti-PM/Scl en les comparant a des patients atteints de ScS sans Ac anti-PM/Scl. Patients et methodes Etude retrospective menee a l’Hopital Cochin entre 2005 et 2019 incluant tous les patients ayant des Ac anti-PM/Scl positifs associes a une ScS selon les criteres, datant de 2013, de l’American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR). Les cas ont ete apparies a des patients ayant une ScS et des Ac anti-PM/Scl negatifs (2 controles pour 1 cas). L’objectif principal de l’etude etait de decrire le phenotype et le profil evolutif des patients ayant une ScS et des Ac anti-PM/Scl positifs. Resultats Cinquante-trois patients avec Ac anti-PM/Scl positifs ont ete compares a 102 patients negatifs pour les Ac anti-PM/Scl. Quatre-vingt-quatorze patients (60,6 %) avaient une ScS de forme cutanee limitee (lScS) et 61 (39,4 %) une forme cutanee diffuse (dScS). En analyse univariee, le nombre de patients presentant une atteinte musculaire (66 % versus 39 %, p = 0,002) et une forme lScS (72 % versus 55 %, p = 0,042) etait plus importants dans le groupe avec positivite des Ac anti-PM/Scl. La presence d’un phenomene de Raynaud (88 % versus 100 %, p = 0,001) et d’Ac anti-centromeres (ACA) (6 % versus 34 %, p Conclusion Dans notre cohorte, les Ac anti-PM/Scl etaient associes aux ScS cutanee limitee et a la presence d’une atteinte musculaire mais, pas a la presence d’ACA. Les Ac anti-PM/Scl semblent constituer un phenotype a part chez les patients sclerodermiques.

Introduction La bioequivalence entre le rituximab (RTX) princeps et son biosimilaire GP2013 a ete demontree dans la polyarthrite rhumatoide (PR) [1] . Un essai randomise controle recent a suggere sur une population selectionnee une tres faible immunogenicite du GP2013 dans la PR ( [2] . Notre objectif a ete d’etudier en pratique courante le risque d’immunogenicite des patients traites par GP2013 pour leur rhumatisme inflammatoire chronique. Patients et methodes Etude prospective de soins courants realisee entre septembre 2018 et aout 2020 dans le service de Rhumatologie de l’hopital Cochin. Nous avons inclus consecutivement les patients traites par le biosimilaire du RTX GP2013, utilise dans le service de facon systematique depuis mars 2018. Des Prelevements systematiques ont ete effectues avant chaque perfusion afin de doser par technique ELISA les anticorps (Ac) anti-RTX et les concentrations residuelles de RTX (Lisa Tracker Duo Rituximab, LTR005, Theradiag). Resultats Nous avons inclus 159 patients consecutifs traites par GP2013 (124 femmes, 78 %) avec un âge moyen de 59 ± 13 ans et une duree moyenne de la maladie 18 ± 11 ans. Parmi ces 159 patients, 108 (68 %) avaient une PR et 51 une autre maladie (16 sclerodermies systemiques (SSc), 15 connectivite mixte (CM), 5 lupus systemiques (LES), 5 myopathies inflammatoires (MI), 5 rhumatismes inflammatoires inclasses, 2 arthrites juveniles idiopathiques (AJI) et 3 syndromes de Sjogren primitifs). 137 patients (86 %) recevaient un traitement de fond associe, principalement du methotrexate (111/137 patients, 81 %). 120 patients (75 %) etaient traites au long cours par RTX princeps (dose cumulee de RTX : 3,5 ± 6 g) avant le switch systematique vers le GP2013 en mars 2018. Aucun retour au princeps n’est survenu pendant toute la periode de suivi. Les 39 autres patients (25 %) traites par GP2013 etaient naifs du RTX princeps. L’analyse du premier prelevement, realise avant la seconde perfusion de GP2013 a identifie 8 patients (5 PR, 1 LES, 1 CM et 1 SSc) avec des Ac anti-RTX positifs (prevalence 5 %), avec des taux variant entre 6 et > 100 ng/mL et des concentrations residuelles de RTX indetectables. Parmi ces 8 patients, 6 patients avaient precedemment recu du RTX princeps et 2 patients etaient naifs de cette molecule. Il etait note une tendance a une association entre immunisation et indice de masse corporel plus eleve (n = 8 ; 28 ± 7 vs 25 ± 6, p = 0,118), mais il n’existait aucune association entre immunisation anti-RTX et l’âge, la duree de la maladie, la prise d’un traitement de fond conventionnel associe, l’intervalle moyen entre les perfusions ou la dose cumulee de RTX. Parmi les 8 patients immunises, deux groupes ont pu etre isoles : – un groupe de 5 patients (3 PR, 1 LES, 1 SSc) avec un faible taux d’Ac (6-22 ng/mL) sans consequence clinique observee (maintien du traitement, absence de perte d’efficacite apres 13 ± 4 mois de suivi, une seule reaction allergique mineure) ; – un groupe de 3 patients (2 PR, 1 CM) avec fort taux d’Ac (≥ 100 ng/mL) caracterise par une reaction allergique severe lors de la seconde perfusion de GP2013 ayant conduit a l’arret du traitement chez un des 3 patients et une perte d’efficacite clinique avec effet fin de dose et absence de depletion B chez les 2 autres, avec pour consequence l’augmentation des doses de RTX de 500 mg a 1 g. Parmi les 151 patients non immunises lors du premier prelevement, aucune reaction allergique severe et 6 reactions allergiques mineures ont ete notees sous GP2013. L’analyse des prelevements ulterieurs (pour l’instant 97 patients avec 2 prelevements, 27 patients avec 3 prelevements) est en cours. Conclusion L’immunogenicite des patients traites par RTX est un phenomene rare, mais avec de possibles consequences cliniques et biologiques lors d’une immunisation avec un taux eleve d’Ac.

Background There is an increasing body of evidence suggesting a direct pathophysiological role of ACPA in Rheumatoid Arthritis (RA). Therefore, on the top of clinical, biological and imaging remission, one target could be immunological remission, defined as the normalization of the ACPA titers after therapy. In this sense, data related to the capacity of different biologics to normalize ACPA are contradictory. Objectives To evaluate the changes in ACPA titers before and after treatment with different biologics. Methods RA patients treated with biologics were identified via the hospital’s pharmacy and/or the Electronic Medical Record of the patients; thereafter, for each patient, ACPA titers before/after treatment were retrieved from the department of biology. To be included, patients had to be diagnosed with RA, to have received a biologic (either abatacept IV or SC, TNF-inhibitors(TNFi) (Infliximab iv and Etanercept SC), or Rituximab IV) and to have at least two dosages of ACPA (at least one before and one after biologic treatment). ACPA titers were compared before and after treatment in each of the treatment groups. A mixed model analysis including an interaction between the drug and time was also performed. Results Among the 328 selected RA patients 92 patients (female: 84%, mean age: 62 years) had enough biological data to be included for the analysis: 36 patients had received rituximab, 21 abatacept, 35 TNFi. Mean (Standard deviation) ACPA levels in the whole group before treatment was 924.8 (1164.6) UI/L. ACPA titers (summarized in figure 1) decreased significantly after Rituximab (from 1287 (1322) to 301(387) UI/L; p Conclusion In this real-life study, ACPA titers decrease slightly only after Rituximab therapy. These data suggest that there is potentially a huge unmet need in RA if the target is to achieve an immunological remission. Disclosure of Interests Stephane Hilliquin: None declared, Loriane Gutermann: None declared, Claire Goulvestre: None declared, Jerome Avouac: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Anna Molto: None declared

Background: In order to assess the pharmacokinetic/pharmacodynamic relationship of hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus (SLE), HCQ levels have been measured in whole blood as well as in serum but both methods have never been compared. In addition, cut offs for non-adherence (classically 200ng/ml but also 100 ng/mL) have been established only in whole blood. Objectives: The aims of this study were (1) to compare these two pharmacological approaches, and (2) since it would be very interesting to retrospectively assess severe non-adherence in clinical trials or in large cohort of patients in which only serum samples are usually available, to determine if serum HCQ level cut offs could be established for identification of severe non-adherent patients. Methods: The HCQ and desethylchloroquine (DCQ) levels were measured in serum and whole blood from 573 SLE patients. The risk factors for active SLE (SLEDAI score >4) were identified using multiple logistic regression. HCQ serum level was also measured in 51 non-adherent patients (whole blood HCQ level Results: The mean HCQ and DCQ levels were 916 ± 449 and 116 ± 55 ng/mL in whole blood, respectively; and 469 ± 223 and 63 ± 31 ng/mL in serum, respectively. The mean ratio of serum/whole blood level for HCQ and DCQ were 0.53 ± 0.15 and 0.57 ± 0.21, respectively. A strong positive correlation was found between serum and whole blood levels of HCQ (rho=0.837 [CI95% 0.810-0.860], p Given the mean ratio of serum/whole blood level for HCQ was 0.53, we extrapolated that serum HCQ level cut offs of 106 and 53 ng/mL would correspond to the previously used cut-off of 200 and 100 ng/mL of HCQ in whole blood. Using HCQ serum level cut off of 106 ng/mL, 43 of 51 patients (84%) with blood HCQ levels Of these 51 patients, 25 patients (49%) exhibited HCQ whole blood concentration below 100 ng/mL. Using HCQ serum level cut off of 53 ng/mL, 23 of 25 patients (92%) with HCQ whole blood level Conclusion: Our data support the use of whole blood rather than serum as the matrix for drug monitoring of HCQ levels in SLE patients. However, when whole blood is not available, our results support the use of HCQ serum level to assess non-adherence with a cut off of 106 ng/mL corresponding to 200 ng/ml in whole blood. Disclosure of Interests: None declared

Background Objectives To determine whether the successive switches from innovator infliximab to a first then a second biosimilar infliximab increase the risk of immunogenicity during a 3-year observation period. Methods This is a usual care study performed in Cochin Hospital, Paris, France. First switch from innovator infliximab to a first biosimilar infliximab occurred in October/December 2015 and the second switch from the first to the second biosimilar infliximab started in December 2017. The end of the observation period was December 2018. Immunogenicity was defined by the detection of positive anti-drug antibodies (ADA >10 ng/mL), at least at two consecutive time points. The primary outcome of the study was the development of immunogenicity during the observation period. Secondary outcomes were i) the point prevalence of positive ADA at baseline, ii) the influence of the successive switches to biosimilars on the risk of immunogenicity and iii) the retention rate of biosimilar infliximab at the end of the observation period. Results Our prospective cohort consisted on 265 patients on maintenance therapy with innovator infliximab (135 axSpA, 64 with inflammatory bowel diseases, IBD, 31 with RA, 21 with PsA, 8 with uveitis and 6 with other chronic inflammatory diseases) who switched to biosimilar infliximab. Then, 140 patients switched to the second biosimilar infliximab, 26 remained treated with the first biosimilar, and innovator infliximab was re-established in 55 patients. 29 patients (15 females, 14 males) had positive ADA at baseline (point prevalence: 12.4%), before the switch to biosimilar infliximab. Among these 29 patients, 15 had axSpA (11%), 6 RA (19%), 6 IBD (9%) and 2 PSa (10%). Among the 236 patients with no ADA at baseline, 20 patients developed ADA during the observation period, corresponding to a rate of 3 for 100 patient years. The mean time to positive ADA detection was 21.2±13.7 months. Kaplan Meyer curve showed no influence of the number of biosimilars infliximab received on immunogenicity (Figure 1A). Among the 20 patients with positive ADA, 4 were back to innovator infliximab at the time of ADA detection, 10 patients were exposed to the first biosimilar and 6 to the second. The risk of treatment discontinuation was significantly higher in patients with positive ADA at baseline or during follow-up compared to patients without ADA (Figure 1B, Hazard Ratio 2.27, 95% confidence interval 1.33-3.89). No predictive factor of immunogenicity was identified (including type of disease, age, sex, BMI or concomitant DMARD intake). The retention rate of biosimilar infliximab (Figure 1C) was 58% (154/265) at the end of observation period, including 131 patients treated with the second biosimilar and 23 who remained treated with the first biosimilar. Conclusion In this usual care study with a 3-year observation period, the development of immunogenicity was low (3 for 100 patient years) and not favored by the switch to biosimilars infliximab. Thus, immunogenicity does not constitute a barrier to interchangeability between biosimilars infliximab in chronic inflammatory diseases. Disclosure of Interests Ambre Lauret: None declared, Anna Molto: None declared, Vered Abitbol: None declared, Loriane Gutermann: None declared, Ornella Conort: None declared, Francois Chast: None declared, Claire Goulvestre: None declared, Claire Le Jeunne: None declared, Stanislas Chaussade: None declared, Christian Roux Grant/research support from: Alexion, Amgen, UCB, Frederic Batteux: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Jerome Avouac Grant/research support from: research grant from Pfizer

Introduction Il existe de plus en plus de donnees en faveur du role physiopathologique des anticorps anti-peptide citrullines (CCP) dans le developpement de la polyarthrite rhumatoide (PR). La remission immunologique, qui viendrait s’ajouter a la remission clinique, biologique et l’absence de progression radiographique, pourrait etre un nouvel objectif des traitements. Or, les donnees de la litterature concernant la diminution des taux d’anti-CCP sous traitements biologiques cibles sont contradictoires. L’objectif de cette etude etait d’evaluer les variations du taux d’anticorps anti-CCP chez des patients suivis pour une PR et traites par biotherapies. Materiels et methodes Les patients suivis pour une PR dans le service de rhumatologie de 3 hopitaux de region parisienne (Cochin, Bicetre et Corbeil-Essonnes) et traites par biotherapie ont ete identifies par le registre de la pharmacie hospitaliere ou le dossier medical informatise. Pour chaque patient, un taux d’anticorps anti-CCP, avant et apres traitement, a ete obtenu de maniere retrospective via le laboratoire de biologie de l’hopital. Pour etre inclus, les patients devaient etre suivis pour une PR, devaient avoir recus au moins une biotherapie (abatacept, anti-TNF alpha ou rituximab) et devaient avoir au moins deux dosages d’anticorps anti-CCP disponibles, avant et apres initiation du traitement. Les taux d’anticorps anti-CCP ont ete compares avant et apres introduction pour chaque biotherapie. Nous avons etudie la relation longitudinale entre la variation du taux d’anticorps anti-CCP et chaque traitement grâce a un modele mixte incluant l’interaction entre le traitement et le temps. Resultats Parmi les 1477 patients suivis pour une PR, 144 patients avaient des donnees necessaires pour etre inclus dans l’analyse (79,3 % de femme, âge moyen: 59 ans): 59 patients avaient recu un traitement par rituximab, 31 par abatacept, 54 par anti-TNF alpha. La moyenne du taux d’anticorps anti-CCP du dosage pre-therapeutique de l’ensemble de la cohorte etait de 712,8 ± 1039,8 U/mL ( Fig. 1 ). Il existait une diminution significative du taux d’anticorps anti-CCP apres traitement par rituximab (de 1187,3 ± 2282,0 a 417,1 ± 564,6 U/mL; p Conclusion Dans cette etude de vie reelle, le taux d’anticorps anti-CCP diminue de maniere significative seulement apres traitement par rituximab, et suite au traitement par abatacept ou anti-TNF alpha.

Introduction Le syndrome de Reynolds (SR) correspond a l’association d’une cholangite biliaire primitive (CBP) et d’une une sclerodermie systemique (ScS). Peu de donnees sur le SR sont disponibles. L’objectif de cette etude est d’etudier la prevalence et de decrire les caracteristiques cliniques, immunologiques, morphologiques et pronostiques du SR. Patients et methodes Nous avons mene une etude retrospective au sein du centre de reference national des maladies auto-immunes et systemiques rares et inclus les patients avec une ScS repondant aux criteres ACR/EULAR 2013 et une CBP repondant aux criteres de l’EASL. Les donnees cliniques, biologiques, therapeutiques et evolutives des patients ont ete analysees et comparees a celles de patients atteints de ScS sans CBP et de patients atteints de CBP sans ScS apparies sur l’âge et le sexe. Resultats Parmi 1028 patients de la cohorte ayant une ScS, 24 (2,3 %) patients avaient un SR et ont ete compares a 96 controles avec une ScS sans CBP et a 48 controles avec une CBP sans ScS. Vingt-deux (91,7 %) patients etaient de sexe feminin avec un âge median [ecart interquartile] de 52,5 [44–67,2] ans. 21 (87,5 %) patients avaient une ScS cutanee limitee et 22 (91,6 %) patients avaient des anticorps anti-centromeres. Huit (33,3 %) patients avaient une CBP diagnostiquee de maniere synchrone a la ScS, 5 (20,8 %) avant le diagnostic de ScS et 11 (45,8 %) apres avec un delai median de 75 [40–157] mois. Les anticorps associes a la CBP etaient des anti-mitochondries chez 21 (87,5 %) patients, des anti-Gp210 chez 3 (12,5 %) patients et des anti-Sp100 chez 2 (8,3 %) patients. Sur le plan de la sclerodermie, les patients avec SR presentaient plus des formes cutanees limitees de ScS (87,5 % versus (vs) 62,4 %, p = 0,03) avec un score de Rodnan modifie plus bas (2 [0–4] vs 4 [2–6], p = 0,004) et une ouverture de bouche plus grande (40 [37,5–47,5] mm contre 36,5 [28,5–41,5] mm, p = 0,04) que les controles. Ils presentaient aussi moins de pneumopathie interstitielle diffuse au scanner thoracique (29,1 % vs 75 %, p Conclusion Les resultats de cette etude retrospective monocentrique montrent que le syndrome de Reynolds est rare et est associe a des formes moins severes de ScS mais qu’il doit etre recherche. En effet, un suivi multidisciplinaire de ces patients est necessaire pour, d’une part, depister regulierement une hypertension pulmonaire, et, d’autre part, debuter un traitement par AUDC des le diagnostic et surveiller l’apparition d’une cirrhose.

Objectives Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation. Results IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor. Conclusion Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA.

Background Biosimilars of originator biologic therapeutics are going to change medical practices. In October 2015, the medical community of Cochin Hospital decided to systematically propose the switch from innovator infliximab to biosimilar infliximab to all treated patients. Objectives To investigate efficacy and safety of switching treatment from innovator infliximab to biosimilar infliximab. Methods This is a usual care study conducted in patients aged >18 years who agreed to switch to biosimilar infliximab, and who received at least 3 infusions of innovator infliximab prior to the switch. The primary outcome of the study was the retention rate of biosimilar infliximab at the time of the third infusion. Secondary outcomes included the factors associated with biosimilar discontinuation, the change between baseline and the last visit (July 2016) in DAS28-CRP (rheumatoid arthritis, RA), BASDAI/ASDAS (axial spondyloarthritis, axSPA) and infliximab trough levels, and the occurrence of adverse events. Results 260 patients fulfilled the inclusion criteria: 182 patients followed-up in Rheumatology (131 with axSPA, 31 with RA, and 20 with other inflammatory rheumatic diseases), 64 in Gastroenterology and 14 in Internal Medicine. The retention rate at the time of the third biosimilar infusion was 82% (149/182 patients), which was lower than the rate observed in patients with inflammatory bowel diseases or uveitis followed-up in Gastroenterology and Internal Medicine, respectively (71/78 patients, 91%). Between baseline and the last visit (mean follow-up: 34±4.5 weeks), 48/182 (26%) patients, including 36 patients with axSPA, discontinued biosimilar infliximab, mainly due to experienced inefficacy (n=47). No clinical or biological factors were associated with biosimilar discontinuation. One infusion reaction led to treatment discontinuation. No serious adverse events occurred. 43 patients restarted innovator infliximab, 2 patients switched to etanercept, 1 to abatacept and 2 maintained biological-free. In RA patients, the mean DAS28-CRP remained stable from baseline to the last visit: 3.38±1.16 to 3.08±1.08 (p=0.217). In axSpA patients, the mean BASDAI increased from 2.94±2.20 to 3.18±2.21 (p=0.046) and the mean ASDAS increased from 1.79±0.90 to 1.99±1.08 (p=0.022). In RA and axSPA, mean CRP levels at baseline (5.95±6.06 and 5.98±11.14 mg/l respectively) and the last visit (6.52±11.32 and 5.03±8.26 mg/l respectively) were not statistically different (p=0.289 and p=0.271, respectively). Mean infliximab trough levels were similar in patients with RA (3.70±5.36 vs. 3.21±4.35 μg/ml, p=0.551) and AxSPA (5.88±5.82 vs. 5.70±5.42 μg/ml, p=0.617) during follow-up. Conclusions In the majority of patients, innovator infliximab can be switched to biosimilar infliximab without changes in efficacy and safety during 34 weeks follow-up. However, 26% of patients discontinued biosimilar infliximab, mainly those with AxSPA due to a subjective increase in BASDAI or ASDAS scores, possibly explained by suggestion or attribution effects rather than pharmacological differences. Disclosure of Interest None declared

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.

Objective Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE. Methods The study was conducted in the framework of a single-center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol-, formalin-, and methanol-fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme-linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi-square or Fisher's exact tests. Results Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3-ANCAs or MPO-ANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3-ANCAs or MPO-ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti-PR3/anti-MPO–positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P = 0.022), more frequent occurrence of echocardiographic vegetations (P = 0.043), and above-normal serum IgG levels (P = 0.017). Conclusion ANCAs, including PR3- and MPO-ANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.

Background: Subacute cutaneous lupus erythematosus (SCLE) can be induced by numerous drugs. We report 3 cases of SCLE induced by proton pump inhibitors (PPIs). Objective: To highlight a rare cutaneous side effect induced by a frequently prescribed drug such as a PPI. Case Reports: Case 1 was a 30-year-old man who developed multiple annular plaques over the trunk and lower limbs 1 month after the initiation of pantoprazole. Antinuclear antibodies (ANA) were positive with anti-Ro/SSA and anti-La/SSB antibodies, and histology confirmed the diagnosis. Clinical improvement was achieved 8 weeks after the discontinuation of pantoprazole and the introduction of a treatment combining topical steroids and hydroxychloroquine. Lesions relapsed when pantoprazole was accidentally rechallenged. The second case was a 31-year-old woman, 28 weeks pregnant, who presented erythematous annular plaques over the trunk 7 weeks after starting esomeprazole. ANA and anti-Ro/SSA antibodies were positive, and the histology was compatible with SCLE. Fetal ultrasound was normal. She was treated with topical and oral steroids and hydroxychloroquine. Clinical improvement was achieved 4 weeks after the discontinuation of esomeprazole. The third case was a 57-year-old woman with systemic erythematosus lupus presenting annular and psoriasiform lesions on the trunk for 15 months. She was treated successively with hydroxychloroquine, azathioprine, mycophenolate mofetil and methotrexate with prednisone. A review of her drug history revealed the introduction of omeprazole a few weeks before the first appearance of skin lesions and omeprazole was contraindicated. Conclusion: SCLE should systematically be suspected in case of eruption after the introduction of PPI. The risk of fetal cardiac complications is important in pregnant women.

Patients with antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AASV) commonly suffer from arthralgias and, sometimes, polyarthritis during disease flares. Although rheumatoid factor (RF) can be detected in up to 37-50% of AASV patients, anti-cyclic citrullinated peptide (anti-CCP) antibodies are rare. Herein, we describe the clinical features of five P-ANCA-positive vasculitis patients, who had persistent and/or high anti-CCP levels and, more importantly, suffered from remittent non-destructive arthralgias and polysynovitis, independently of the vasculitis course and without evidence of RA. Two were initially thought to have RA rather than microscopic polyangiitis and, at AASV diagnosis, all had kidney involvement and three had alveolar hemorrhages. With a median follow-up of 30 months, one suffered vasculitis relapses, preceded by polysynovitis, and others had remittent arthralgias and polysynovitis, while their vasculitides remained in remission. None of these patients had radiological destructive arthritis. We discuss the challenge of diagnosing these patients positive for anti-CCP and ANCA, and with dominant articular manifestations. AASV patients with anti-CCP antibodies may experience relapsing polysynovitis and non-erosive polyarthritis prior to vasculitis flares, but also independently of the vasculitis course, which is uncommon in AASV, and might represent a small subgroup of AASV patients.

Resume Les patients atteints de vascularite systemique associee aux ANCA (VSAA) souffrent generalement d’arthralgies et, parfois, de polyarthrite durant les poussees. Bien que le facteur rhumatoide (FR) puisse etre detecte chez 37 a 50 % des patients VSAA, les anticorps antipeptides cycliques citrullines (anti-CCP) sont rares. Nous decrivons dans cet article les caracteristiques cliniques de cinq patients atteints de vascularite ANCA-positives qui presentaient anticorps anti-CCP persistants et/ou a taux eleves et d’arthralgies recidivantes non destructrices et de polysynovites, independamment de l’evolution de la vascularite et en l’absence d’evidence de PR. Chez deux d’entre eux, cependant on pensait initialement a une PR plutot qu’a une polyangeite microscopique (PAM). Au moment du diagnostic de la VSAA, tous presentaient une atteinte renale et trois d’entre eux, des hemorragies alveolaires. Avec un suivi median de 30 mois, un patient a eu des poussees de vascularite, precedees d’une polysynovite, et les autres ont eu des arthralgies recidivantes et une polysynovite, alors que leur vascularite demeurait en remission. Aucun de ces patients ne presentait d’arthrite destructrice a la radiographie. Nous discutons ici la difficulte du diagnostic chez ces patients avec ANCA et anti-CCP et presentant des manifestations articulaires predominantes. Les patients VSAA avec des anticorps anti-CCP peuvent presenter des polysynovites et des polyarthrites non destructrices avant les poussees de vascularite, mais egalement independamment de l’evolution de la vascularite, ce qui est moins commun au cours des VSAA. Ces patients constituent un petit sous-groupe au sein des VSAA.

Lung fibrosis is considered a severe manifestation of microscopic polyangiitis (MPA). Antimyeloperoxidase (anti-MPO) antibodies in MPA patients' sera can activate MPO and lead to the production of reactive oxygen species (ROS). While high levels of ROS are cytotoxic, low levels can induce fibroblast proliferation. Therefore, we hypothesised that the oxidative stress induced by anti-MPO antibodies could contribute to lung fibrosis. 24 MPA patients (45 sera) were enrolled in the study, including nine patients (22 sera) with lung fibrosis. Serum advanced oxidation protein products (AOPP), MPO-induced hypochlorous acid (HOCl) and serum-induced fibroblast proliferation were assayed. AOPP levels, MPO-induced HOCl production and serum-induced fibroblast proliferation were higher in patients than in healthy controls (p

Background: Anti-tumor necrosis factor (TNF) agents are increasingly being used for a rapidly expanding number of rheumatic and systemic diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The use of anti-TNF agents has been associated with more and more cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Observations: We report 2 cases of autoimmune bullous skin disease occurring in patients undergoing TNF-targeted therapy: a bullous pemphigoid and a pemphigus foliaceus. Both patients were treated by anti-TNF agents for rheumatoid arthritis and showed improvement following interruption of that treatment. Here, we discuss the relationship between anti-TNF therapy and the occurrence of autoimmune bullous disease. Conclusion: Anti-TNF agents should be considered as a potential cause of drug-induced autoimmune bullous skin disease.

Objective Microscopic polyangiitis (MPA) is a small-vessel vasculitis associated with antimyeloperoxidase (MPO) antibodies in 70% of patients. Anti-MPO antibodies can trigger the release of MPO by neutrophils and monocytes, but their involvement in the pathogenesis of MPA is still questioned. The aim of this study was to investigate whether anti-MPO antibodies can activate MPO to generate an oxidative stress that is potentially deleterious to the endothelium. Methods MPA sera, purified IgG from MPA sera, normal control sera, and purified IgG from normal sera were incubated with MPO coated onto microtitration plates. The peroxidase activity of MPO was evaluated by adding o-phenylenediamine. Production of hypochlorous acid (HOCl) was determined by chemiluminescence. The cytotoxic properties of byproducts of MPO activation were tested on endothelial cells in culture. Results MPA sera with anti-MPO antibodies were found to activate MPO in vitro (P < 0.0001 versus normal sera) and to generate HOCl (P < 0.001), as did IgG purified from MPA sera (P < 0.05). MPA sera without anti-MPO antibodies and MPA IgG absorbed on MPO did not show these activities. The byproducts of MPO activation by MPA sera exerted a strong cytolytic activity on endothelial cells in culture (P < 0.01). Both HOCl production and endothelial lysis were abrogated by N-acetylcysteine (NAC), an antioxidant molecule (P < 0.05 and P < 0.0001, respectively). Conclusion Anti-MPO antibodies could play a pathogenic role in vivo by triggering an oxidative burst, leading to severe endothelial damage. Treatment of MPA patients with NAC might be proposed in an attempt to abrogate these deleterious phenomena.

Objectives To analyze the correlation between serum levels of vascular endothelial growth factor (VEGF) and biopsy findings in patients with a suspicion of prostate cancer. Methods Serum levels of VEGF were measured on frozen, archival serum obtained before prostate biopsy in 47 patients with clinical and/or biologic suspicion of prostate cancer. VEGF-A levels were measured using an enzyme-linked immunosorbent assay. Results The prostate biopsies showed cancer in 27 patients (group 1) and benign tissue in the remaining 20 patients (group 2). No statistically significant difference was found between the two groups in age, digital rectal examination findings, total prostate-specific antigen (PSA) levels, free PSA levels, and complexed PSA levels. The mean prostate volume was significantly lower in group 1 (45.5 g versus 53.9 g; P = 0.04), and the mean percentage of free PSA (free PSA/total PSA) was significantly lower in group 1 (11.3% versus 19%; P = 0.0003). Serum VEGF-A levels were not significantly different between the two groups. The mean VEGF level was 90.6 pg/mL in group 1 and 107.9 pg/mL in group 2 ( P = 0.55). Multivariate analysis showed that VEGF-A levels were not predictive of prostate cancer. Conclusions Our findings suggest that serum VEGF-A is not helpful to predict prostate cancer in patients with clinical and/or biologic suspicion of prostate cancer.

Background/Aims : Acute liver failure (ALF), characterized by massive hepatocyte necrosis, is often caused by drug poisoning, particularly with acetaminophen (APAP). Hepatocyte necrosis is consecutive to glutathione depletion by NAPQI, a metabolite of APAP, and to mitochondrial damages caused by reactive oxygen species (ROS) overproduction. Considering the structure of Mangafodipir, a contrast agent currently used in magnetic resonance imaging of the liver, we hypothesized that this molecule could exert an antioxidant activity and be possibly used as a treatment of APAP-induced ALF. Methods/Results : Mangafodipir is endowed with superoxide dismutase, catalase, and glutathione reductase activities. It can inhibit ROS production by hepatocytes in culture, and protect those cells from oxidative stresses induced by exposure to xanthine oxidase, H 2 O 2 , or UV light. Moreover, preventive or curative administration of Mangafodipir to mice with APAP-induced ALF significantly increases survival rates, and abrogates aspartate aminotransferase elevation and histological damage. Conclusions : Those data point out the potential interest of Mangafodipir in the treatment of toxic ALF in humans.

A critical event in the pathogenesis of experimental autoimmune thyroiditis (EAT) is the entry of thyroid-specific T lymphocytes into the thyroid gland. To investigate the role of soluble mediators in that infiltration, we have assayed the expression of various chemokines in diseased thyroid glands and in cytokine-treated cultures of normal thyroid epithelial cells. MCP-1 (monocyte chemotactic protein-1) and RANTES are produced during EAT and induced in vitro by IFN-gamma, IL-10, TNF-alpha, and IL-1beta. In vitro chemotaxis experiments using immune lymph node (LN) cells showed that RANTES attracted mTg-specific responder LN cells, whereas MCP-1 attracted mTg-specific CD4(+), CD25(+) regulator cells that secreted IL-10. The in vivo transfer of LN T cells attracted in vitro either by RANTES or by MCP-1 confirmed their opposite effects on the course of EAT.

Many autoantibodies have been identified in the serum of systemic sclerosis (SSc) patients, including anti-RNA polymerase III antibodies (ARA), which are associated with diffuse cutaneous SSc (dcSS...

To the Editor: Bartonella henselae and B. quintana are the 2 Bartonella species most commonly involved in human disease and are associated with the formation of vasoproliferative tumors1. Chronic infections are bacteremia (particularly affecting homeless patients), endocarditis, bacillary angiomatosis, and liver peliosis2. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of diseases characterized by necrotizing vasculitis of small vessels and associated with autoantibodies against neutrophil constituents such as myeloperoxidase (MPO) and proteinase 3 (PR3)3. Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MP), and Churg-Strauss syndrome (CSS) are all forms of vasculitis associated with anti-PR3. Several chronic infectious diseases (mycobacterial infections, chronic hepatitis C virus infection, and amoebic liver abscess) have been reported to be associated with a positive ANCA by immunofluorescence, but the specificity was not always defined by ELISA-testing specificity4. A few cases of subacute endocarditis have been reported to be associated with ANCA positivity, mainly anti-PR3. A 40-year-old … Address correspondence to Dr. E. Aslangul, Internal Medicine Department, Hotel Dieu 1, Place du Parvis Notre Dame, 75004 Paris, France. E-mail: elisabeth.aslangul{at}htd.aphp.fr