PURPOSE:To evaluate the long-term efficacy of and tolerance to adalimumab in patients with juvenile idiopathic arthritis-associated uveitis (JIA-U). METHODS:This retrospective study included patients with JIA-U who completed the ADJUVITE trial with at least 2 years and up to 5 years of follow-up after the end of the trial (i.e. at least 3 years and up to 6 years of follow-up after randomization). Data, including treatment course, visual and anatomical outcomes, uveitis activity evaluated by laser flare photometry, and safety were collected from medical records. RESULTS:Forty-one eyes of 25 participants with a mean age of 10.5 ± 4.0 years at the end of the trial were enrolled. Twenty-one patients (84%) responded to adalimumab during a mean follow-up period of 68.0 ± 21.6 months (range 26-109 months, post-trial), and among the responders, one patient could discontinue adalimumab without further uveitis relapse. Five years after the end of the trial, the mean BCVA improved to 0.07 ± 0.39 logMAR (vs. 0.14 ± 0.20 logMAR, p = 0.048) and the mean anterior chamber flare decreased to 29.9 ± 19.1 ph/ms (vs. 37.2 ± 35.0 ph/ms, p = 0.170). The mean dose of methotrexate decreased significantly from 11.3 ± 4.4 mg/week at the end of the trial to 5.2 ± 6.2 mg/week at the last follow-up (p = 0.002). Four patients did not respond to adalimumab and required other biologics. Adalimumab was well-tolerated in all patients. CONCLUSIONS:Adalimumab was effective in maintaining long-term uveitis control in patients with JIA-U, with a good safety profile. However, complete discontinuation was not possible in most cases, confirming the suspending effect of adalimumab.

OBJECTIVE:Kawasaki disease (KD) is an acute systemic vasculitis predominantly affecting coronary arteries of infants and children. We recently identified leucin-rich α-2-glycoprotein 1 (LRG-1) as known transforming growth factor β1 (TGFβ1) signal-modulating molecule, orchestrating endothelial activation and cardiac remodeling, as associated with interleukin-1β (IL-1β) signaling in KD. In the present study, we aimed to assess the role for LRG-1 as part of a multimediator inflammatory environment as a possible direct mediator of human coronary artery endothelial activation. METHODS:Human coronary artery endothelial cells (HCAECs) were treated with a blood inflammatory matrix, with or without targeted inhibition of several inflammatory mediators, including LRG-1, and were analyzed for inflammatory activation or endothelial-to-mesenchymal transition (EndMT) on gene expression level. Proteomic profiling of the inflammatory matrix, treatment-naïve KD (n = 11), or healthy control serum samples (n = 10) was performed by proximity extension assay (n = 184 markers) and Luminex. RESULTS:Proteomic analysis of KD serum samples and the inflammatory matrix revealed elevation of 37 versus 50 inflammatory proteins, respectively, with 19 significantly up-regulated markers shared. The HCAEC culture with the inflammatory matrix resulted in inflammatory endothelial activation, which was most efficiently abrogated by IL-1 receptor type 1 (IL-1R1) inhibition compared to all other tested drugs. Whereas inflammatory endothelial activation can also link to TGFβ-driven EndMT, which was supported by respective signatures in our KD serum proteomics, we observed that in vitro inflammatory matrix-induced EndMT was partly impaired by both IL-1R1 and tumor necrosis factor inhibition compared to other tested drugs. CONCLUSIONS:Collectively, our observations in the context of a multimediator inflammatory environment indicate a prominent role of a specific clinically relevant cytokine signaling axis in inflammatory coronary artery endothelial activation and EndMT in the context of KD.

Background: Systemic lupus erythematosus (SLE) is characterized by a difficult-to-predict fluctuation of disease activity which makes it difficult for patients to promptly identify a flare. Furthermore, SLE is characterized by an impaired of quality of life with a need to better evaluate and improve patient-reported outcomes (PROs). Therefore, patient-centered tools to self-evaluate disease activity and disease burden are a necessary step toward self-empowerment of SLE patient. Objectives: To develop and to evaluate the characteristics of a self-administered questionnaire (LUPIN) to assess SLE disease activity and lupus-relevant PROs. Methods: Patient representatives from a national lupus association (AFL+) and lupus experts developed a self-administered questionnaire which included several domains of SLE perceived activity (Figure 1) and the SF-36 quality of life questionnaire. Prior to a medical consultation, the patient filled the questionnaire which was sealed. Subsequently, the physician evaluated the patient (blindly of the patient responses) and filled patient characteristics, a physician global assessment (PhGA) and a SLE disease activity Index 2K (SLEDAI-2K). The questionnaires were distributed nationally to 31 centers of metropolitan France and overseas territories. Correlations between patient response in individual domains and physician assessment were evaluated using Spearman’s regression and the p-values were adjusted for multiple testing using the Bonferroni method. Results: 325 questionnaires were analyzed at the time of the submission. The mean age was 44 (±14.4) years and 85,2% were women. The mean duration of disease was 12.7 (±9.42) years. Most patients had history of articular and cutaneous involvements (86.6% and 72.6%, respectively) and 34.4% had history of lupus nephritis. The mean SLEDAI was 3 (±3.70) and 67 (20.6%) patients had a clinical SLEDAI ≥ 4. The PhGA correlated moderately with the cSLEDAI (r = 0.52). As expected, there was a weak albeit statistically significant correlation between components of the LUPIN questionnaire and the SLEDAI/clinical SLEDAI and PhGA (r < 0.25 for all; Figure 2). However, there were very good correlations between several components of the LUPIN questionnaire and several of the SF-36 questionnaire domains (r = -0.68 for pain evaluation; r = -0.65 for physical activity evaluation; r = -0.60 for fatigue evaluation; p < 0.0001 for all). Conclusion: Several components of the LUPIN questionnaires have significant correlation with domains of the SF-36 quality of life questionnaire making LUPIN a patient-friendly tool to evaluate patient-reported outcomes now that it has been implemented on smartphones. As expected in a cross-sectional study, there were only weak correlations between domains of the LUPIN questionnaire and physician-assessed disease activity. However, the changes in LUPIN scores assessed prospectively may be more sensitive to detect disease activity fluctuation, which is currently evaluated in a follow-up study. REFERENCES: NIL. Acknowledgements: All patients and physicians who participated in the study. The AFL+ patient association represented by her president Marianne Riviere. Disclosure of Interests: Marc SCHERLINGER Amgen, AstraZeneca, Biogen, BMS, Fresenius Kabi, Galapagos, GSK, Nordic Pharma, Novartis, Sandoz., Jean-François KLEINMANN: None declared, Antonin FOLLIASSON: None declared, Marianne RIVIERE: None declared, Raphaëlle Rybak: None declared, Sabine Malivoir: None declared, Jean-François Viallard: None declared, Frédéric RENOU: None declared, Estibaliz Lazaro: None declared, Christophe Richez: None declared, Pascal Roblot: None declared, Mathieu Puyade: None declared, Clara Baverez: None declared, Arnaud Hot: None declared, Christophe Deligny: None declared, Nicolas Baillet: None declared, Daniel Wendling: None declared, Julien Campagne: None declared, Christian Agard: None declared, Roland Jaussaud: None declared, Thomas MOULINET: None declared, Denis WAHL: None declared, Gilles Blaison: None declared, Elisabeth Diot: None declared, Nicole Ferreira-Maldent: None declared, Isabelle Marie: None declared, Nicolas Girszyn: None declared, Laurent Perard: None declared, Marc André: None declared, Pauline Orquevaux: None declared, amelie servettaz: None declared, François Chasset: None declared, Baptiste HERVIER: None declared, Thierry Martin: None declared, Cécile Fermont: None declared, Emmanuelle David: None declared, LOIC RAFFRAY: None declared, Ludovic Trefond: None declared, Perrine Smets: None declared, Julie Lescanff: None declared, Jacques-Eric Gottenberg: None declared, Xavier Mariette: None declared, Zahir AMOURA: None declared, Jean SIBILIA: None declared.Figure 1The LUPIN questionnaire (paper or electronic form). Figure 2Spearman’s correlation matrix between components of the LUPIN questionnaire, the SF-36 questionnaire and the physician’s assessment of disease activity. Each value corresponds to the spearman r value, in bold when there is a statistically significant correlation after adjusting p-value for multiple testing using the Bonferroni method.

Objective To analyse in routine practice the efficacy of targeted therapies on joint involvement of patients with rheumatoid arthritis/systemic sclerosis (RA/SSc) overlap syndrome. Methods This was a retrospective analysis of medical records of two academic centres over a 10-year period. Joint response to targeted therapies was measured according to EULAR criteria based on Disease Activity Score (DAS)-28. In addition, changes in CRP level and glucocorticoid consumption were recorded. Results Nineteen patients were included. Methotrexate (n=11) and hydroxychloroquine (n=4) were the most used first-line treatments. Targeted therapies were frequently used (n=14). Tocilizumab was the most selected therapy (n=8), then rituximab (n=5), abatacept and anti-tumour necrosis factor (n=4). Twenty-one treatment sequences were assessed, including 18 with EULAR response criteria. Responses were "good" or "moderate" in 100% (4/4) of patients treated with abatacept, 80% (4/5) with rituximab, 40% (2/5) with tocilizumab, and 25% (1/4) with anti-TNF. T and B lymphocyte-targeted therapies (abatacept, rituximab) resulted more frequently in a "good" or "moderate" response compared to cytokine inhibitors (tocilizumab, etanercept, infliximab) with a significant decrease in DAS-28 at 6 months (-1.75; p=0.016) and a trend to a lower consumption of glucocorticoids. Conclusion In patients with RA/SSc overlap syndrome refractory to conventional synthetic-DMARDs, T and B lymphocyte-targeted therapies seem to be a promising therapeutic option to control joint activity.

To analyse in routine practice the efficacy of targeted therapies on joint involvement of patients with rheumatoid arthritis/systemic sclerosis (RA/SSc) overlap syndrome.

L’atteinte neurologique centrale n’est pas décrite dans les grandes séries étudiant les atteintes viscérales de la sclérodermie systémique (ScS). Plusieurs études suggèrent cependant, d’une part, une plus forte prévalence de troubles psychiatriques et de dysfonctionnements cognitifs chez ces patients [1], et d’autre part, des anomalies en spectroscopie par résonance magnétique (SRM) [2]. L’objectif de notre étude était de rechercher et décrire les atteintes neurologiques, psychiatriques et cognitives ainsi que les données de la SRM monovoxel au cours de la ScS et d’évaluer les possibles associations entre ces différentes données. Entre janvier 2011 et août 2016, 79 patients ayant une ScS ont été prospectivement inclus au cours d’un PHRC interrégional dans les CHU de Lille et de Rouen, ainsi que 27 témoins avec un sex-ratio et une distribution d’âge comparables aux patients. L’imagerie était réalisée sur une IRM 3T et comprenait 4 acquisitions monovoxels positionnées de façon bilatérale sur les noyaux gris centraux et dans les centes semi-ovales. Le critère d’évaluation principal était le rapport NAA/Cr (N-acetylaspartate/créatinine, marqueur de densité et de viabilité neuronale). Nous avons recueilli les données démographiques, de l’examen clinique global et neurologique, du bilan biologique, de l’évaluation psychiatrique, des questionnaires de qualité de vie, de l’évaluation cognitive ainsi que des résultats de la SRM. Les comparaisons ont été réalisées par des tests de Wilcoxon–Mann–Whiney et les corrélations avec des tests de corrélation de Spearman. Les caractéristiques démographiques étaient comparables entre les patients ScS et les témoins avec un âge moyen de 52 ± 10,3 ans et 51 ± 9,8 ans, et une proportion de sujets de sexe féminin de 77,8 % et 83,5 % respectivement. Vingt-quatre patients (30,4 %) présentaient une ScS cutanée limitée/sine scleroderma et 55 (69,6 %) une ScS cutanée diffuse. La durée d’évolution médiane de la ScS était de 6,8 ans (2,9 ; 12,8). Vingt et un patients (29 %) présentaient une pneumopathie interstitielle diffuse, 3 (4 %) une HTAP, et 6 (7,6 %) une atteinte digestive grave. Lors de l’interrogatoire, 17 patients (23,6 %) et 2 témoins (7,4 %) décrivaient des difficultés mnésiques. La SRM mettait en évidence une diminution significative du rapport NAA/Cr au niveau des noyaux gris centraux gauches (p = 0,032) et du centre semi-ovale droit (p = 0,025) chez les patients comparés aux témoins. L’analyse cognitive objectivait une altération significative des performances cognitives chez les patients comparés aux témoins (fNART ; 99,7 vs 103,9 ; p = 0,003 et MOCA ; 26,0 vs 27,4 ; p = 0,039) avec une dégradation des fluences verbales (mots en « P » ; 18,9 vs 27,2 ; p < 0,001), de la vitesse de traitement cognitif (test de Stroop planche 1 ; 32,5 vs 29,1 ; p = 0,014) ainsi que des capacités d’apprentissage (apprentissage de couples de desseins score total ; 21,9 vs 30,1 ; p < 0,001). Sur le plan psychiatrique, on observait des scores de dépression (HADS dépression ; 5,0 vs 2,5 ; p < 0,001) et de fatigue (FFS ; 4,3 vs 3,4 ; p < 0,001) plus élevés chez les patients. Enfin, il existait une corrélation entre l’altération de l’index d’asymétrie des rapports NAA/Cr au niveau des noyaux gris centraux (valeur absolue) et les scores d’anxiété, de dépression et l’expression de la plainte cognitive chez les patients (respectivement r = 0,31 ; 0,45 et 0,27 ; p < 0,05). À travers les premiers résultats de cette étude, nous objectivons des anomalies en SRM, une altération cognitive et des scores de dépression plus importants chez les patients ScS que chez les témoins. Cette étude, en accord avec les données récentes de la littérature [3], suggère qu’il existe une atteinte cérébrale organique au cours de la ScS et qu’elle serait corrélée à la sévérité des manifestations neuropsychiatriques.

Background The rheumatoid arthritis (RA)/systemic sclerosis (SSc) overlap syndrome is a rare and understudied association. It affects 5% of patients with SSc. Only open studies evaluating biological drugs (bDMARDs) have reported encouraging results, particularly on joint involvement. The management of these patients is therefore not codified. Objectives The objective was to analyze in real conditions the therapeutic strategy and the response to bDMARDs, with a focus on joint involvement. Methods We retrospectively analyzed over a 10-year period the clinical, biological, radiographic characteristics and therapeutic management of patients meeting the ACR/EULAR diagnostic criteria for RA and SSc in two academic centers. Response to bDMARDs was assessed according to EULAR and if unavailable according to therapeutic maintenance. The evolution of lung function test was also evaluated. Results Twenty-two patients were identified. Interstitial lung involvement was common (n=11). Only 7 patients were treated with csDMARD alone. The most commonly used drug was methotrexate. The use of bDMARDs was frequent (15/22), significantly greater in patients with rheumatoid factors (OR 26.7; p=0.004) and with a trend in patients with higher levels of anti-CCP (160 vs 15 IU; p=0.11) or diffuse interstitial lung disease (OR 10.6; p=0.063). Tocilizumab was the most selected therapy (n = 8) followed by rituximab (n = 5), abatacept, and anti-TNFs (n = 4 respectively). We evaluated 21 treatment sequences, 19 of which were evaluated according to EULAR response criteria. bDMARDS that inhibits the activation of lymphocytes (abatacept, rituximab) generally resulted in a good or moderate response (n = 9/10) with a significant decrease in DAS28 at 6 months (-1.75; p = 0.016). Cytokine inhibitors (tocilizumab, etanercept, infliximab) were less likely to achieve good or moderate control of joint involvement (n = 3/9) with a smaller decrease in DAS28 at 6 months (-0.79; p = 0.36). Two tocilizumab sequences were stopped early due to intolerance and could not be evaluated. One patient received tofacitinib with a good clinical response but was discontinued at 9 months for intolerance. Lung function test data did not change significantly on bDMARD. Conclusion In patients with rheumatoid arthritis (RA)/systemic sclerosis (SSc) overlap syndrome, bDMARDS that inhibits the activation of lymphocytes (abatacept, rituximab) resulted in more frequent and greater improvement in joint involvement than cytokine inhibitors (tocilizumab, etanercept, infliximab). Disclosure of Interests None declared

Background: Rhupus syndrome is better characterized, but uncertainties remain, and therapeutic management must be defined. The objective was to analyze therapeutic procedures with a focus on biologic disease-modifying antirheumatic drugs (bDMARDs). Methods: This 10-year medical records review was based on diagnosis codes (rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) and biological data (anti-CCP testing, anti-dsDNA, and anti-RNP antibodies). Patients fulfilling 2010 ACR/EULAR and 2012 SLICC and/or 2019 ACR/EULAR classification criteria for RA and SLE, respectively, were included. Results: Sixteen patients were identified. Rheumatoid arthritis most often preceded rhupus, with predominant articular pattern; 11 of them had erosive arthropathy. Skin involvement was the most frequent associated manifestation (n = 12). Serious events were reported, including active glomerulonephritis (n = 3), ischemic stroke (n = 1), and myocardial infarction (n = 1). Immunological profiles showed positivity for antinuclear (n = 16), anti-dsDNA (n = 9), and anti-CCP (n = 9). Ten patients required bDMARDs. All types of RA-approved bDMARDs were used. Abatacept was considered effective in 3 of the 4 patients, with 1 primary failure, 1 secondary escape, and 2 therapeutic maintenances, whereas primary or secondary failure was observed under tocilizimub and TNF-blocking agents. Rituximab was the most prescribed (n = 9) and the most effective with a sustained response in 6 patients. Conclusions: In rhupus refractory to conventional treatment, T or B lymphocytes targeted therapies, and particularly rituximab, seem to be a relevant therapeutic option unlike anticytokine biologics.

Le syndrome de chevauchement polyarthrite rhumatoïde (PR)/sclérodermie systémique (ScS) est une association rare et peu étudiée. Elle concerne 5 % des patients atteints de ScS. Seules des études ouvertes ayant évalué les biomédicaments (bDMARDs) ont rapporté des résultats encourageants, notamment sur l'atteinte articulaire. La prise en charge de ces patients n'est donc pas codifiée. L'objectif était d'analyser en conditions réelles la stratégie thérapeutique et la réponse aux bDMARDS, avec un focus sur l'atteinte articulaire. Nous avons analysé rétrospectivement sur une période de 10 ans les caractéristiques cliniques, biologiques, radiographiques et la prise en charge thérapeutique des patients respectant les critères diagnostics ACR/EULAR de la PR et de la ScS dans deux centres universitaires. La réponse aux bDMARD a été évaluée sur le plan articulaire (selon les critères EULAR pour 19 séquences, sur le maintien thérapeutique pour 2 séquences) ainsi que sur l'atteinte pulmonaire (évolution des EFR). Vingt-deux patients ont été identifiés. L'atteinte pulmonaire interstitielle était fréquente (n = 11). Seulement 7 patients ont été traités uniquement par traitement de fond conventionnel. La molécule la plus utilisée était le méthotrexate. Le recours aux bDMARD était fréquent (15/22), significativement plus important chez les patients ayant des facteurs rhumatoïdes (OR 26,7 ; p = 0,004) et avec une tendance chez les patients ayant un plus haut taux d'anti-CCP (160 vs 15 UI ; p = 0,11) ou une pneumopathie interstitielle diffuse (OR 10,6 ; p = 0,063). Le tocilizumab a été le traitement le plus choisi (n = 8) suivi du rituximab (n = 5), de l'abatacept et des anti-TNF (n = 4 respectivement). Les bDMARD à visée anti-lymphocytaire (abatacept, rituximab) permettaient généralement une réponse bonne ou modérée (n = 9/10) avec une diminution significative du DAS28 à 6 mois (−1,75 ; p = 0,016). Les bDMARD à visée anti-cytokinique (tocilizumab, etanercept, infliximab) ont moins fréquemment permis un contrôle de l'atteinte articulaire (réponse bonne ou modérée : n = 3/9) avec une diminution du DAS28 à 6 mois moins importante (−0,79 ; p = 0,36). Deux séquences concernant le tocilizumab ont eu un arrêt précoce pour intolérance ne permettant pas leur évaluation. Un patient a reçu du tofacitinib avec une bonne réponse clinique mais avec un arrêt à 9 mois pour intolérance. Les données EFR n'ont pas évolué significativement sous bDMARD. Le tocilizumab a été fréquemment utilisé, notamment à partir de 2016, date à laquelle une efficacité sur l'atteinte pulmonaire chez les patients atteints de ScS a été évoquée. La forte prévalence de l'atteinte pulmonaire interstitielle dans notre série, notamment chez les patients non contrôlés par traitement de fond conventionnel, a pu influencer le choix thérapeutique. Pour autant le tocilizumab n'a pas permis une bonne réponse sur le plan articulaire dans la majorité des cas. Chez les patients ayant à la fois une PR et une ScS réfractaire aux traitements de fond conventionnels, les bDMARDs à visée anti-lymphocytaire (abatacept, rituximab) ont permis une amélioration plus fréquente et plus marquée de l'atteinte articulaire que les bDMARD anti-cytokiniques.

Diagnosis of lysosomal disorders (LDs) may be hampered by their clinical heterogeneity, phenotypic overlap, and variable age at onset. Conventional biological diagnostic procedures are based on a series of sequential investigations and require multiple sampling. Early diagnosis may allow for timely treatment and prevent clinical complications. In order to improve LDs diagnosis, we developed a capture-based next generation sequencing (NGS) panel allowing the detection of single nucleotide variants (SNVs), small insertions and deletions, and copy number variants (CNVs) in 51 genes related to LDs. The design of the LD panel covered at least coding regions, promoter region, and flanking intronic sequences for 51 genes. The validation of this panel consisted in testing 21 well-characterized samples and evaluating analytical and diagnostic performance metrics. Bioinformatics pipelines have been validated for SNVs, indels and CNVs. The clinical output of this panel was tested in five novel cases. This capture-based NGS panel provides an average coverage depth of 474× which allows the detection of SNVs and CNVs in one comprehensive assay. All the targeted regions were covered above the minimum required depth of 30×. To illustrate the clinical utility, five novel cases have been sequenced using this panel and the identified variants have been confirmed using Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). The application of NGS as first-line approach to analyze suspected LD cases may speed up the identification of alterations in LD-associated genes. NGS approaches combined with bioinformatics analyses, are a useful and cost-effective tool for identifying the causative variations in LDs.

Neoplasms containing glomus cells are uncommon. Glomus cells within an angiomatosis, so called glomangiomatosis, is exceedingly rare with only three previously reported cases. We are describing the fourth case from a 17-year-old boy which involved his left hand, fingers, and distal forearm. We will review the previously reported cases.

La polychondrite atrophiante (PCA) est une maladie inflammatoire, multi-systémique rare dont les causes sont encore inconnues. Nous ne disposons actuellement d’aucun score de mesure permettant d’évaluer et de surveiller les lésions chez les patients porteurs de cette pathologie. Notre objectif principal était d’élaborer un outil de mesure concernant le damage au cours de la polychondrite atrophiante, le Relapsing Polychondritis Damage Index (RPDAM). Nous avons réalisé une étude internationale multicentrique par méthode Delphi en 4 tours durant laquelle des experts ont été invités à évaluer la pertinence des items liés au damage dans la PCA (141 items ont été obtenus à partir d’une revue de la littérature et 12 ont été proposés par les experts), en utilisant l’échelle de Likert. La sélection des items pour chacun des tours suivants était basée sur la cotation médiane attribuée à chaque item. Vingt-quatre experts de 11 nationalités différentes ont participé au premier tour et 22 aux 3 tours suivants. Parmi les 153 items initiaux liés au damage, 44 ont été sélectionnés durant le tour 1, 30 durant le tour 2 et 16 durant le tour 3. Au cours de la 4e étape, nous avons affiné le score à un total de 17 items concernant les atteintes cartilagineuses auriculaires, nasales, laryngo-trachéo-bronchiques et les manifestations ophtalmologiques, respiratoires, cardiovasculaires et hématologiques ainsi que les effets secondaires liés au traitement. Nous avons développé, par consensus international, un score lésionnel d’évaluer chez les patients souffrant de PCA. Après validation, le score RPDAM contribuera à améliorer la prise en charge des patients souffrant de cette pathologie rare mais également à standardiser le recueil de données pour de prochains essais cliniques.

Objective Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)– and steroid‐resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin‐1 in patients with IVIG‐resistant KD. Methods Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient’s body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C‐reactive protein (CRP) levels. Results Seventy‐five percent of patients in the intention‐to‐treat group and 87.5% in the per‐protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1–99.8%) of physician evaluations and on 100% (95% CI 73.5–100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7–81.3%]) and 6 of 12 patients (50% [95% CI 21.1–78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. Conclusion Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG‐refractory KD.

Objective. Rituximab was proven superior to azathioprine for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The high cost of rituximab might, however, limit its routine use. This study determined the cost-effectiveness of intravenous rituximab (5 x 500 mg until month 18), versus oral azathioprine (2 mg/kg per day, gradually decreased between month 12 and 22), for maintenance treatment of patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited vasculitis, aged 18-75. Methods. We performed a single-trial based economic evaluation. MAIN-RITSAN was a 28-month multicentre, prospective, randomised, controlled open-label trial. We estimated the cost of healthcare resources and quality of life using prospectively collected data. Healthcare costs were estimated from the perspective of the French Social Health Insurance's perspective, using 2016 tariffs for reimbursement. Utilities were derived from Short Form 36 scores. We estimated total average cost, incremental cost per incremental relapse averted and per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to assess uncertainty over relapses, severe adverse events, discount rate, utility weights, time horizon and the cost of rituximab. Costs drivers were tested using a generalised linear model. Results. Total average costs were (sic)13,387 ((sic)11,605-(sic)15,646) and (sic)10,217 ((sic)7,567-12,949) in the rituximab and azathioprine groups respectively. The incremental cost-effectiveness ratio (ICER) was (sic)12,824 per relapse averted and the incremental cost-utility ratio (ICUR) (sic) 37,782 per QALY gained. Besides the unit cost of rituximab, the major cost drivers were relapses and severe adverse events. Conclusion. Maintenance treatment by rituximab could be cost-effective for preventing relapses in patients with AAV.

Introduction. - Olmesartan is an angiotensin II receptor blocker, used to treat arterial hypertension. Severe digestive manifestations have been associated with olmesartan, including sprue-like enteropathy and lymphocytic colitis. Observations. - We report two cases of sprue-like enteropathy associated with olmesartan, leading to malabsorption syndrome related to villous atrophy. After olmesartan discontinuation, patients exhibited resolution of clinical digestive symptoms and disappearance of biochemical abnormalities. Conclusion. - Our case reports underscore that accurate questioning is crucial in diagnostic approach, allowing to make the diagnosis of sprue-like enteropathy related to olmesartan in our patients. Interestingly, particular attention has recently been drawn to the fact that sprue-like disease may be a class effect of angiotensin II receptor blockers; further investigations are warranted to confirm these latter data. (C) 2018 Societe Nationale Francaise de Medecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.

INTRODUCTION:Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by a beta-glucocerebrosidase deficiency and responsible for a lysosomal storage disorder. GD is characterized by haematological, visceral and bone involvements. The aim of this study was to describe the diagnostic journey of type 1 GD patients as well as the role of the internist. METHODS:A retrospective multicentric study involving type 1 GD patients has been conducted in 16 centers, between 2009 and 2011. RESULTS:Fifty-five type 1 GD patients were included, under the care of an internist or an haematologist. They were originally hospitalized in 8 different specialized units. Diagnosis was established by bone-marrow aspiration in 22 patients (40%), by enzymatic assay of glucocerebrosidase activity in 15 patients (27%), and by bone-marrow biopsy in 9 patients (16%). The use of enzymatic assay became more frequent after 1990. The delay between first hospitalization due to GD symptoms and definitive diagnosis was less than one year for 38 patients. Patients with suspected GD were mainly referred to an internist physician. CONCLUSION:GD seems to be better recognized and quickly diagnosed since 1990 in spite of the multiplicity of journeys. The role of the internist seems important.

Background The development of more potent therapeutic approaches of KD is an urgent need because intravenous immunoglobulin (IVIg) treatment is not effective in 20% of patients, increasing the risk of coronary dilatations/aneurysms. The combination of genetic and transcriptomic data revealed the key role of interleukin-1 (IL-1) signaling in KD vasculitis and mouse model of KD has shown that anakinra (IL1RA: IL-1R1receptor antagonist) could prevent the development of vascular aneurysms. Objectives To assess as primary objective, the efficacy of anakinra in patients with KD who fail to respond to at least one infusion of 2g/kg of IVIg. To assess its safety and tolerability and its effect on disease activity, systemic inflammation and coronary lesions. Methods A 45-day, phase IIa proof of concept study open labeled with anakinra dose escalation, with a target of at least 12 patients completing the study Eligible patients had KD according to the AHA criteria, duration of fever ≤ 14 days, and were ≥ 3 months and 5 Kg. They had persistent (or relapsing) fever (≥38°C) within 48h of the last IVIG infusion, had not received other alternative treatment including steroids, and had no others exclusion criteria. After informed consent, they received a starting dose of 2mg/kg (patients <10kg and/or <8 months: 4mg/kg) of anakinra, which could be increased every 24h of 2mg/kg until a maximum of 6mg/kg (patients <10kg and/or <8 months: 8mg/kg), in case of persistent fever. Anakinra treatment duration was 15 days. Outcome measures were fever, KD symptoms, blood inflammation and cardiac echography. Total study duration was 45 days. Clinical trials: NCT02390596. The study is supported by a grant from the French ministry of health, APHP, national PHRC 2014. IRB approval was obtained and all patients (parents) gave informed consent. Results 18 patients were screened and 16 were included and 13 have completed the study. Anakinra was started in 16 patients (14 boys, 2 girls) at a median age 2 years (3 months to 6 years) and at a median of 9.5 days after the onset of fever. 4 patients escaped early for SAE, and 1 had sJIA final diagnosis. The maximum dose of anakinra was 6mg/kg in 6 patients, 4mg/kg in 6, and 2mg/kg in 4. Mean PGA decreased from 7.80 (4-10) to 1.2 (0-3) at D14. Median temperature was 37.6°C (36.7-39.7) at day 3 and 37.2°C at D7 (36.7- 37.9)). Median CRP was 135mg/L at screening and decreased to 9.5 mg/L at D7. 8/14 evaluated patients had coronary dilatation (Z score max ≥2.5mm) at inclusion, 5/14 at D14 and 3/14 at D45. 3/14 patients who increased Z score at D14 decreased it at J45. We observed 3 severe adverse events (SAE) where treatment was discontinued: anakinra overdose, MAS in a patient evolving to sJIA and increase of coronary dilatation. Others AE included cytolytic hepatitis (2 patients), hypereosinophilia (1), injection site reaction (1) and pancreatitis (1) without treatment discontinuation. Conclusion We have realized the first experimental study assessing IL-1 blockade in severe refractory KD. 15 days-duration of anakinra treatment, given early in the course of IVIG-resistant KD, was rapidly effective on KD symptoms, biologic inflammation and coronary dilatations in almost all patients, with a good tolerability. This study calls for further investigation of IL1 blockade in KD Disclosure of Interests Isabelle Koné-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, stephanie tellier: None declared, virginie Lambert: None declared, Corinne Guitton: None declared, alexandre belot: None declared, Perrine Dusser: None declared, Linda Rossi-Semerano Grant/research support from: Roche, Isabelle Marie: None declared, gregory allain: None declared, helene agostini: None declared, celine piedvache: None declared

Background: Gaucher disease is a rare inborn error of lysosomal metabolism, characterized by lysosomal storage of the beta-glucosylceramide. Bleedings observed in type-1 Gaucher disease (GD1) are commonly attributed to a low platelet count, but they can also occur when the platelet count is normal or slightly low. Abnormal platelet function has been described and deficiencies in coagulation factors too, such as factors II, V, VII, VIII, IX, X, XI, XII, and von Willebrand factor. However, studies are few in number, involving few patients and having varying conclusions. The aim of this study was to analyze clotting factor deficiencies in a larger cohort of French patients with GD1. Methods: This is an observational national study. The coagulation parameters were collected during routine GD1 monitoring and described retrospectively. Results: We highlighted low levels of various coagulation factors in 46% of the patients with GD1. The most frequent coagulation abnormalities encountered were factor V, X, XI, and XII deficiencies. Deficits were usually mild and coagulation abnormalities tended to be more frequent in non-splenectomized patients. Conclusions: In conclusion, frequent and varied coagulation abnormalities were found in a high proportion of GD1 patients.