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Summary Background Patients with COVID-19 pneumonia can have increased inflammation and elevated cytokines, including interleukin (IL)-6, which might be deleterious. Thus, sarilumab, a high-affinity anti-IL-6 receptor antibody, might improve the outcome of patients with moderate-to-severe COVID-19 pneumonia. Methods We did a multicentric, open-label, Bayesian randomised, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance and a WHO Clinical Progression Scale [CPS] score of 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomisation list stratified on centre and with blocks randomly selected among 2 and 4, to receive usual care plus 400 mg of sarilumab intravenously on day 1 and on day 3 if clinically indicated (sarilumab group) or usual care alone (usual care group). Primary outcomes were the proportion of patients with WHO-CPS scores greater than 5 on the 10-point scale on day 4 and survival without invasive or non-invasive ventilation at day 14. This completed trial is closed to new participants and is registered with ClinicalTrials.gov , NCT04324073 . Findings 165 patients were recruited from March 27 to April 6, 2020, and 148 patients were randomised (68 patients to the sarilumab group and 80 to the usual care group) and followed up for 90 days. Median age was 61·7 years [IQR 53·0–71·1] in the sarilumab group and 62·8 years [56·0–71·7] in the usual care group. In the sarilumab group 49 (72%) of 68 were men and in the usual care group 59 (78%) of 76 were men. Four patients in the usual care group withdrew consent and were not analysed. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0·2%; 90% credible interval [CrI] −11·7 to 12·2), with a posterior probability of absolute risk difference greater than 0 of 48·9%. At day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died, (median posterior hazard ratio [HR] 1·10; 90% CrI 0·69–1·74) with a posterior probability HR greater than 1 of 37·4%. Serious adverse events occurred in 27 (40%) patients in the sarilumab group and 28 (37%) patients in the usual care group (p=0·73). Interpretation Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival. Funding Assistance publique—Hopitaux de Paris

Objective To assess the effectiveness of corticosteroids among older adults with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen. Methods We used routine care data from 36 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids with at least 0.4 mg/kg/day equivalent prednisone (treatment group) versus standard of care (control group). Participants were adults aged 80 years or older with PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or CT scan images typical of COVID-19 pneumonia, requiring oxygen ≥3 L/min, and with an inflammatory syndrome (C-reactive protein ≥40 mg/L). The primary outcome was overall survival at day 14. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. Results Among the 267 patients included in the analysis, 98 were assigned to the treatment group. Their median age was 86 years (interquartile range 83–90 years) and 95% had a SARS-CoV-2 PCR-confirmed diagnosis. In total, 43/98 (43.9%) patients in the treatment group and 84/166 (50.6%) in the control group died before day 14 (weighted hazard ratio 0.67, 95% CI 0.46–0.99). The treatment and control groups did not differ significantly for the proportion of patients discharged to home/rehabilitation at day 14 (weighted relative risk 1.12, 95% CI 0.68–1.82). Twenty-two (16.7%) patients receiving corticosteroids developed adverse events, but only 11 (6.4%) from the control group. Conclusions Corticosteroids were associated with a significant increase in the overall survival at day 14 of patients aged 80 years and older hospitalized for severe COVID-19.

OBJECTIVE: To assess the effectiveness of corticosteroids on outcomes of patients with COVID-19 pneumonia requiring oxygen without mechanical ventilation. METHODS: We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) versus standard of care (no-CTC group) among adults 18 to 80 years old with confirmed COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death by day 28. In our main analysis, characteristics of patients at baseline (i.e., time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. RESULTS: Among the 891 patients included in the analysis, 203 were assigned to the CTC group. Use of corticosteroids was not significantly associated with risk of intubation or death by day 28 (weighted hazard ratio [wHR] 0.92, 95% CI 0.61 to 1.39) or cumulative death rate (wHR 1.03, 95% CI 0.54 to 1.98). However, use of corticosteroids was associated with reduced risk of intubation or death by day 28 in the prespecified subgroups of patients requiring oxygen ≥ 3 L/min (wHR 0.50, 95% CI 0.30 to 0.85) or C-reactive protein level ≥ 100 mg/L (wHR 0.44, 95%CI 0.23 to 0.85). Number of hyperglycaemia events was higher for patients with than without corticosteroids, but number of infections was similar. CONCLUSIONS: We found no association between the use of corticosteroids and intubation or death in the broad population of patients 18 to 80 years old with COVID-19 hospitalized in non-intensive care unit settings. However, the treatment was associated with reduced risk of intubation or death for patients with ≥ 3 L/min oxygen or C-reactive protein level ≥ 100 mg/L at baseline. Further research need to confirm the right timing of corticosteroids for patients with COVID-19 requiring oxygen only.

ObjectiveImmunoglobulin G4-related disease (IgG4-RD) is a rare orphan disease. Lung, pleura, pericardium, mediastinum, aorta and lymph node involvement has been reported with variable frequency and mostly in Asian studies. The objective of this study was to describe thoracic involvement assessed by high-resolution thoracic computed tomography (CT) in Caucasian patients with IgG4-RD.MethodsThoracic CT scans before treatment were retrospectively collected through the French case registry of IgG4-RD and a single tertiary referral centre. CT scans were reviewed by two experts in thoracic imagery blinded from clinical data.Results48 IgG4-RD patients with thoracic involvement were analysed. All had American College of Rheumatology/European League Against Rheumatism classification scores ≥20 and comprehensive diagnostic criteria for IgG4-RD. CT scan findings showed heterogeneous lesions. Seven patterns were observed: peribronchovascular involvement (56%), lymph node enlargement (31%), nodular disease (25%), interstitial disease (25%), ground-glass opacities (10%), pleural disease (8%) and retromediastinal fibrosis (4%). In 37% of cases two or more patterns were associated. Asthma was significantly associated with peribronchovascular involvement (p=0.04). Among eight patients evaluated by CT scan before and after treatments, only two patients with interstitial disease displayed no improvement.ConclusionThoracic involvement of IgG4-RD is heterogeneous and likely underestimated. The main thoracic CT scan patterns are peribronchovascular thickening and thoracic lymph nodes.

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

Objectives To study the percentage, suppressive function and plasticity of Treg in giant cell arteritis (GCA), and the effects of glucocorticoids and tocilizumab. Methods Blood samples were obtained from 40 controls and 43 GCA patients at baseline and after treatment with glucocorticoids + IV tocilizumab (n = 20) or glucocorticoids (n = 23). Treg percentage and phenotype were assessed by flow cytometry. Suppressive function of Treg was assessed by measuring their ability to inhibit effector T‐cell (Teff) proliferation and polarisation into Th1 and Th17 cells. Results Treg (CD4+CD25highFoxP3+) frequency in total CD4+ T cells was decreased in active GCA patients when compared to controls (2.5% vs. 4.7%, P, In this study, we demonstrated quantitative and functional disruptions in the regulatory immune response of patients with giant cell arteritis, resulting in increased proliferation and Th17 polarization of effector T cells. In addition, our results suggest that, through a specific blockade of the IL‐6 pathway, tocilizumab associated with glucocorticoids restores a better quantitative and qualitative Treg immune response than glucocorticoids alone. GCA, giant cell arteritis. Teff, effector T‐cells; Th17, T helper‐17 cells; Treg, regulatory T‐cells.

Objective To assess prevalence of aortic involvement in relapsing polychondritis (RP) patients; to evaluate clinical features and long-term outcome of RP patients exhibiting aortitis, aortic ectasia and/or aneurysm. Methods One hundred and seventy-two RP patients underwent aortic computed tomography (CT)-scan; they were seen in 3 medical centers. Results Eleven patients (6.4%) had aortic involvement, occurring within a median time of 2 years after RP diagnosis. CT-scan showed isolated aortitis ( n = 2); the 9 other patients exhibited: aortitis and aortic aneurysm ( n = 2) or ectasia ( n = 1), isolated aortic aneurysm ( n = 4) or ectasia ( n = 2); aortic localizations were as follows: thoracic ( n = 6), abdominal ( n = 2), thoracic and abdominal ( n = 4) aorta. Patients exhibited: resolution ( n = 3) improvement ( n = 3), stabilization ( n = 4) or deterioration ( n = 1) of aortic localization. Five patients experienced recurrence of aortic localization; one patient died of aortic abdominal aneurysm rupture. Predictive factors of death related to aortic complications were: aortitis on CT-scan, higher median levels of erythrocyte sedimentation rate. Predictive parameters of aortic relapses were: aortitis on CT-scan and involvement of the abdominal aorta. Conclusions This study underlines that aortic involvement is severe in RP. Furthermore, we suggest that RP patients exhibiting poor prognostic factors, including panaortitis and higher values of ESR, may require more aggressive therapy.

Purpose Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient’s life quality index (LQI). Methods This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. Results Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. Conclusions Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician’s armamentarium which is preferred by some patients and is cost-effective. ClinicalTrials.gov Identifier NCT02180763 Clinical Implications Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. Capsule Summary This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician’s armamentarium.

International audience; [u]PURPOSE:[/u] ULISSE is the only study that prospectively assessed the efficiency of a standardized strategy, compared to an open strategy for the etiologic diagnosis of uveitis. Our aim was to evaluate the diagnostic yield of the tests prescribed in the ULISSE study to clarify their relevance. [u]METHODS:[/u] ULISSE is a non-inferiority, prospective, multicenter and cluster randomized study. The standardized strategy is a two-steps strategy: in the first step, common standard tests were performed, and in the second step, tests were guided by the clinical and anatomic type of uveitis. We reported the relevance of the diagnostic tests used in the standardized strategy, as well as the profitability of the tests that were prescribed to more than twenty patients in each group. Based on diagnostic criteria, either an ophthalmologist, or an internist, established the profitability of a test by considering whether the test lead to a diagnosis or not. [u]RESULTS:[/u] Among the 676 patients included (standardized 303; open 373), a diagnosis was made for 152 (50.4%) in the standardized group and 203 (54.4%) in the open group. The most common entities were HLA-B27 associated uveitis (22%), spondyloarthritis (11%), sarcoidosis (18%), tuberculosis (10.7%) and herpes virus infections (8.5%). Among the first step's systematic tests, tuberculin skin test was the most contributive investigation (17.1%), followed by chest X-ray (8.4%), C reactive protein and ESR (6.6% and 5.1%), complete blood count (2.2%) and VDRL (2.0%). The second step's most often contributive tests were: HLA B27 (56.3%), chest-CT (30.3%) and angiotensin converting enzyme (ACE) (16.5%). HLA B27 and ACE were significantly more contributive in the standardized group than in the open group. Immunological tests were never contributive. Among the free investigations, or among the investigations guided by clinical or paraclinical findings, the most often contributive tests were: Quantiferon(R) (24%), electrophoresis of serum protein (7.8%) and sacroiliac imagery (46.4%). Intracellular serologies (1.7%), serum calcium (2.1%) and hepatic tests (3.3%) were exceptionally contributive. Among the third intention tests, labial salivary gland biopsies were contributive in 17.9% of cases, but the profitability of other invasive investigations (anterior chamber tap, vitrectomy, bronchoscopy and lumbar puncture) or specialized imagery (18F-FDG PET, Brain MRI) could not be determined since these test were rarely performed. [u]CONCLUSION:[/u] Only a few diagnostic tests are useful for the etiological assessment of uveitis. They are often cheap, simple, more often guided by the clinical findings, and lead to an etiological diagnosis in most patients. On the other hand, some tests are never or exceptionally contributive, such as immunological tests or intracellular serologies. Further studies are required to evaluate the profitability of third intention imagery and invasive investigations.

The identification of cardiac sarcoidosis is challenging as there is no gold standard consensually admitted for its diagnosis. The aim of this study was to evaluate the diagnostic value of the assessment of cardiac dynamic 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET/CT) and net influx constant (Ki) in patients suspected of cardiac sarcoidosis. Data obtained from 30 biopsy-proven sarcoidosis patients suspected of cardiac sarcoidosis who underwent a 50-min list-mode cardiac dynamic 18F-FDG PET/CT after a 24 h high-fat and low-carbohydrate diet were analyzed. A normalized coefficient of variation of quantitative glucose influx constant, calculated as the ratio: standard deviation of the segmental Ki (min−1)/global Ki (min−1) was determined using a validated software (Carimas® 2.4, Turku PET Centre). Cardiac sarcoidosis was diagnosed according to the Japanese Ministry of Health and Welfare criteria. Receiving operating curve analysis was performed to determine sensitivity and specificity of cardiac dynamic 18F-FDG PET/CT analysis to diagnose cardiac sarcoidosis. Six out of 30 patients (20%) were diagnosed as having cardiac sarcoidosis. Myocardial glucose metabolism was significantly heterogeneous in patients with cardiac sarcoidosis who showed significantly higher normalized coefficient of variation values compared to patients without cardiac sarcoidosis (0.513 ± 0.175 vs. 0.205 ± 0.081; p = 0.0007). Using ROC curve analysis, we found a cut-off value of 0.38 for the diagnosis of cardiac sarcoidosis with a sensitivity of 100% and a specificity of 91%. Our results suggest that quantitative analysis of cardiac dynamic 18F-FDG PET/CT could be a useful tool for the diagnosis of cardiac sarcoidosis.

Objective.To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD).Methods.We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7).Results.Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission. Canakinumab resulted in complete or partial remission in 3/7 and 4/7 patients, respectively.Conclusion.These data support frequent partial responses, showing a better response with canakinumab. The genotype and therapeutic outcomes correlation should help in the personalization of treatment.

Objective In most patients with nonsevere systemic necrotizing vasculitides (SNVs), remission is achieved with glucocorticoids alone, but one-third experience a relapse within 2 years. This study was undertaken to determine whether the addition of azathioprine (AZA) to glucocorticoids could achieve a higher sustained remission rate of newly diagnosed nonsevere eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), microscopic polyangiitis (MPA), or polyarteritis nodosa (PAN). Methods All patients included in this double-blind trial received glucocorticoids, gradually tapered over 12 months, and were randomized to receive AZA or placebo for 12 months, with stratification according to SNV (EGPA or MPA/PAN). The primary end point was the combined rate of remission induction failures and minor or major relapses at month 24. Results Ninety-five patients (51 with EGPA, 25 with MPA, and 19 with PAN) met the inclusion criteria, were randomized, and received at least 1 dose of AZA (n = 46) or placebo (n = 49). At month 24, 47.8% of the patients receiving AZA versus 49% of the patients receiving placebo had remission induction failures or relapses (P = 0.86). Secondary end points were comparable between the AZA and placebo arms. These included initial remission rate (95.7% versus 87.8%), total relapse rate (44.2% versus 40.5%), and glucocorticoid use. Two patients in the placebo arm died; 22 patients in the AZA arm (47.8%) and 23 patients in the placebo arm (46.9%) experienced ≥1 severe adverse event. For EGPA patients, the primary end point (48% in the AZA arm versus 46.2% in the placebo arm) and the percent of patients who experienced asthma/rhinosinusitis exacerbations (24% in the AZA arm versus 19.2% in the placebo arm) were comparable between treatment arms. Conclusion Addition of AZA to glucocorticoids for the induction of remission of nonsevere SNVs does not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.

Methods: Data on clinical characteristics, histologic features, and treatment response from 260 patients with IgAV included in a French multicenter retrospective survey were analyzed. Efficacy data were compared using different statistical models. Results: The mean ± SD age of the patients with IgAV at diagnosis was 50.1 ± 18 years, and 63% of patients were male. Baseline manifestations included purpura (100%), arthralgias/arthritis/myalgia (61%), glomerulonephritis (70%), and/or gastrointestinal involvement (53%). Thirty percent of patients showed renal failure at baseline. In univariate analysis, the response to therapy was 80% (64 of 80) in patients treated with corticosteroids (CS) alone, compared to 77% (23 of 30) in patients treated with CS plus cyclophosphamide (CYC) and 59% (10 of 17) in patients treated with colchicine (P = 0.17). Multivariable analysis showed that treatment with CS or CS plus CYC was more effective than colchicine in achieving a response. Efficacy differences were demonstrated using different statistical models: in the multivariable logistic regression model, odds ratio (OR) 3.68, 95% confidence interval (95% CI) 1.10–12.33 (P = 0.03); in the inverse probability weighting on propensity score model, OR 3.75, 95% CI 1.28–10.99 (P = 0.02). The efficacy of CS plus CYC as compared to CS alone was discordant according to the analytic method used. Analysis with the multivariable logistic regression model did not demonstrate a difference between CS plus CYC and CS alone (OR 0.88, 95% CI 0.29–2.67; P = 0.82). In contrast, inverse probability weighting on propensity score showed that CS plus CYC was more effective than CS alone (OR 1.79, 95% CI 1.00–3.20; P = 0.049). Conclusion: This series constitutes the largest series of adults with IgAV reported in the literature so far. It provides data on clinical and histologic presentation and therapeutic efficacy, suggesting that CS alone appears to be a reasonable first‐line therapy in patients with IgAV, while the benefit of adding CYC to CS remains uncertain.

BACKGROUND AND PURPOSE: 3D-TOF-MRA and DSA are 2 available tools to demonstrate neurovascular involvement in primary central nervous system vasculitis. We aimed to compare the diagnostic concordance of vessel imaging using 3D-TOF-MRA and DSA in patients with primary central nervous system vasculitis. MATERIALS AND METHODS: We retrospectively identified all patients included in the French primary central nervous system vasculitis cohort of 85 patients who underwent, at baseline, both intracranial 3D-TOF-MRA and DSA in an interval of no more than 2 weeks and before treatment initiation. Two neuroradiologists independently reviewed all 3D-TOF-MRA and DSA imaging. Brain vasculature was divided into 25 arterial segments. Concordance between 3D-TOF-MRA and DSA for the identification of arterial stenosis was assessed by the Cohen κ Index. RESULTS: Thirty-one patients met the inclusion criteria, including 20 imaged with a 1.5T MR unit and 11 with a 3T MR unit. Among the 25 patients (81%) with abnormal DSA findings, 24 demonstrated abnormal 3D-TOF-MRA findings, whereas all 6 remaining patients with normal DSA findings had normal 3D-TOF-MRA findings. In the per-segment analysis, concordance between 1.5T 3D-TOF-MRA and DSA was 0.82 (95% CI, 0.75–0.93), and between 3T 3D-TOF-MRA and DSA, it was 0.87 (95% CI, 0.78–0.91). CONCLUSIONS: 3D-TOF-MRA shows a high concordance with DSA in diagnostic performance when analyzing brain vasculature in patients with primary central nervous system vasculitis. In patients with negative 3T 3D-TOF-MRA findings, the added diagnostic value of DSA is limited.

Objective We aimed to analyse the effect of maintenance therapy after induction on the outcomes of adult patients with primary angiitis of the CNS (PACNS). Methods We analysed long-term outcomes (relapse, survival and functional status) of patients enrolled in the French multicentre PACNS cohort who achieved remission after induction treatment and with ⩾12 months' follow-up, according to whether or not they received maintenance therapy. Good outcome was defined as relapse-free survival and good functional status (modified Rankin scale ⩽ 2) at last follow-up. Results Ninety-seven patients [46 (47%) female, median age: 46 (18-78) years at diagnosis] were followed up for a median of 55 (5-198) months. Induction treatment consisted of glucocorticoids in 95 (98%) patients, combined with an immunosuppressant in 80 (83%) patients, mostly CYC. Maintenance therapy was prescribed in 48 (49%) patients, following CYC in 42 of them. Maintenance therapy was started 4 (3-18) months after glucocorticoid initiation. At last follow-up, good outcomes were observed in 32 (67%) patients who had received maintenance therapy vs 10 (20%) who had not (P < 0.0001). Thirty-two (33%) patients experienced relapse [10 (22%) had received maintenance therapy while 22 (45%) had not, P = 0.01]; four subsequently died from relapse. In the multivariate analysis, maintenance therapy was the only independent predictor of good outcome [odds ratio (OR) = 7.8 (95% CI: 3.21, 20.36), P < 0.0001]. Conclusion The results of this long-term follow-up study suggest that maintenance therapy in adults with PACNS is associated with better functional outcomes and lower relapse rates. Further studies are needed to confirm these findings.

Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

Background Tocilizumab (TCZ) is a recombinant humanized anti-interleukin-6 receptor monoclonal antibody. There is increasing evidence of TCZ efficacy in refractory auto-immune diseases. Objectives To describe off-label use, efficacy and tolerance of TCZ use in Internal Medicine Departments. Methods This is a retrospective, descriptive and multicenter study from 9 departments of Internal Medicine. Data were reported using a standardized case report file in January 2019. Results Fifty one patients were included (19 men, 32 women). Mean age was 55.6 ± 17 years (range 23 - 80). TCZ was used in: - 12 connective tissue diseases (23.5%): relapsing polychondritis (n=6), systemic sclerosis (n=3), anti-synthetase syndrome (n=1), and unclassified connective tissue disease (n=3). - 10 vasculitis (19%): Takayasu arteritis (n=7), Cogan disease (n=1), panarteritis nodosa (n=1), unclassified vasculitis (n=1). - 10 ophthalmologic conditions (19%): non infectious posterior uveitis (n=8), sympathetic ophtalmia (n=1), Basedow orbitopathy (n=1). - 8 adult-onset Still’s diseases (16%). - 5 cases of polymyalgia rheumatica (10%) - 3 miscellaneous diseases (6%): idiopathic AA amyloidosis, multicentric non HHV8 Castelmann disease, Erdheim Chester disease (1 case each). Mean disease duration was 7.5 ± 6.4 years. In 44 cases (86%) TCZ was administered for refractory disease to corticosteroids and immunosuppressive drugs. Previous therapies included corticosteroids (83%), methotrexate (66%), TNF inhibitor drug (44%), azathioprine (20.8%), mycophenolate (12%), cyclophosphamide (8%), rituximab (10%), hydroxychloroquine (6%), anakinra in 2 patients and interferon, dapsone, etoposide, leflunomide, abatacept, salazopyrin or intra-venous immunoglobulin in 1 patient each. TCZ was initiated as first-ligne therapy (15.5%), second-line therapy (17.5%), third-line therapy (31%), fourth-line therapy (19%), fifth-line therapy (14%), sixth-line therapy (12%) or as seventh line therapy in one case. TCZ was associated with methotrexate in 3 cases (6%). Treatment route was intravenous (96%). At the end of the follow up, 41 patients (80%) were still using TCZ, with a mean follow up period of 22 ± 23 months (range 1-90). In these patients, daily corticosteroid use significantly decrease from 16.5 ± 18 mg to 5.7 ± 13.7 mg (p TCZ was interrupted in 10 patients (19%), because of treatment failure (n=2), loss of efficacy (n=2) or side effect (=6). Side effects were infection (2 pneumonias, zona, sinus infection), pruritus (n=1), urticaria (n=1), dyslipidemia (n=1), high blood pressure (n=2), infusion-related reaction (n=1), bullous dermatitis (n=1), acute renal failure (n=1), angioedema (n=1), mouth ulcers (n=1). Conclusion TCZ is used in various autoimmune diseases. TCZ allowed a significant corticosteroids reduction and short term efficacy was 93% in patients using TCZ for more than 6 months. Nevertheless TCZ was interrupted in 19% of the patients. TCZ use will probably be more common in the future to treat refractory autoimmune diseases. Disclosure of Interests None declared

Background Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis. Methods A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors. Results A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68–6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03–3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival. Conclusions Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease. Electronic supplementary material The online version of this article (10.1186/s13075-019-1867-1) contains supplementary material, which is available to authorized users.

International audience; The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3].Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16].Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency.Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial.This trial consists in two parts: a retrospective and a prospective study.The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

Objective.Deficiency in alpha-1 antitrypsin (AAT) is a possible pathogenic cofactor in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the clinical effect of AAT deficiency remains poorly established in this setting. This study aimed to describe the clinical phenotypes and outcomes of AAV according to AAT phenotypes.Methods.This study was conducted retrospectively at Caen University Hospital and included all consecutive granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with positive proteinase 3-ANCA or myeloperoxidase-ANCA, from January 2000 or September 2011, respectively, to June 2016. AAT dosage (nephelometry) and phenotyping (isoelectric focusing in agarose gel) were performed.Results.Among the 142 patients with AAV, including 88 GPA and 54 MPA, 102 (72%) had the MM phenotype, 5 (4%) had a nonpolymerogenic M-variant phenotype, 18 (13%) had the deficient allele MZ, 12 (8%) had MS, 2 (1%) had ZZ, 2 (1%) had SZ, and 1 (1%) had SS. M, Z, and S allele frequencies were 84%, 8%, and 6%, respectively. No association was observed between AAT deficiency and ANCA subtype or AAV phenotype, except for intraalveolar hemorrhage (IAH), which was more frequent in patients harboring at least 1 of the deficient Z or S alleles than in those without any deficient alleles (p < 0.01). Global, renal, or relapse-free survival rates were similar for all subgroups.Conclusion.This study shows that AAT deficiency confers, independently of ANCA subtype, a higher risk of IAH. Prospective studies are required to refine these data and to assess the need for replacement therapy in AAT-deficient patients with AAV.

Background The risk of early death is particularly high in patients over the age of 65 presenting with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We hypothesized that by combining disease severity markers, a comorbidity index and serious adverse event reports, we would be able to identify early predictors of one-year mortality in this population. Methods We performed a multicentre, retrospective study in the nephrology and internal medicine departments of six tertiary hospitals in northern France. A total of 149 patients (median [interquartile range (IQR)] age: 72.7 [68.5–76.8] years) presenting with ANCA-associated vasculitis and renal involvement were included between January 2002 and June 2015. The primary endpoint was the one-year mortality rate. Results Renal function was severely impaired at presentation (median [IQR] peak serum creatinine (SCr): 337 [211–522] μmol/l), and 45 patients required dialysis. The Five-Factor Score (FFS, scored as + 1 point for each poor prognostic factor (age > 65 years, cardiac symptoms, gastrointestinal involvement, SCr ≥150 μmol/L, and the absence of ear, nose, and throat involvement)) was ≥3 in 120 cases. The one-year mortality rate was 19.5%. Most of the deaths occurred before month 6, and most of these were related to severe infections. In a univariate analysis, age, a high comorbidity index, a performance status of 3 or 4, a lack of co-trimoxazole prophylaxis, early severe infection, and disease activity parameters (such as the albumin level, haemoglobin level, peak SCr level, dialysis status, and high FFS) were significantly associated with one-year mortality. In a multivariable analysis, the best predictors were a high FFS (relative risk (RR) [95% confidence interval (CI)] = 2.57 [1.30–5.09]; p = 0.006) and the occurrence of a severe infection during the first month (RR [95%CI] = 2.74 [1.27–5.92]; p = 0.01). Conclusions When considering various disease severity markers in over-65 patients with ANCA-associated renal vasculitis, we found that an early, severe infection (which occurred in about a quarter of the patients) is a strong predictor of one-year mortality. A reduction in immunosuppression, the early detection of infections, and co-trimoxazole prophylaxis might help to reduce mortality in this population. Electronic supplementary material The online version of this article (10.1186/s12882-018-1102-3) contains supplementary material, which is available to authorized users.

Objective To describe the efficacy and safety of omalizumab, an anti-IgE monoclonal antibody, in patients with refractory and/or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). Methods We conducted a nationwide retrospective study including EGPA patients who received omalizumab. Response was defined as the absence of asthma and/or sinonasal exacerbations with a prednisone dosage of ≤7.5 mg/day (complete response) or >7.5 mg/day (partial response). Results Seventeen patients (median age 45 years) received omalizumab for severe steroid-dependent asthma (88%) and/or sinonasal involvement (18%). After a median follow-up of 22 months, 6 patients (35%) achieved a complete response, 5 patients (30%) achieved a partial response, and 6 patients (35%) had no improvement. The median Birmingham Vasculitis Activity Score decreased from 2.5 at baseline to 0.5 at 12 months. The median number of exacerbations per month decreased from 1 at baseline to 0 at 12 months, and the median forced expiratory volume in 1 second increased from 63% of the percent predicted at baseline to 85% of the percent predicted at 12 months. The median prednisone dosage decreased from 16 mg/day at baseline to 11 mg/day at 6 months and 9 mg/day at 12 months. Omalizumab was discontinued in 8 patients (47%) during follow-up, because of remission (12.5%), adverse event despite disease remission (12.5%), refractory disease (25%), or relapse (50%). Relapses included retrobulbar optic neuritis attributable to EGPA in 2 patients and severe asthma flare in 2 others. Conclusion The results of this study suggest that omalizumab may have a corticosteroid-sparing effect in EGPA patients with asthmatic and/or sinonasal manifestations, but reducing the corticosteroid dose may also increase the risk of severe EGPA flares, which raises the question of the safety of omalizumab in patients with EGPA.

OBJECTIVES: To analyze the factors associated with response to anti-TNFα and to compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in patients with refractory non infectious uveitis. METHODS: Observational multicenter study including 160 patients [median age of 31 [21-42] years with 39% of men] with refractory uveitis treated with anti-TNFα [IFX 5mg/kg at weeks 0, 2, 6 and every 5-6 weeks (n=98) and ADA 40mg/14days (n=62)]. Factors associated to complete response were assessed in multivariate analysis. Comparison between efficacy and safety of IFX and ADA was performed using a propensity score approach accounting for baseline characteristics. RESULTS: Main etiologies of uveitis included Behcet's disease (36%), juvenile idiopathic arthritis (22%), spondylarthropathies (10%) and sarcoidosis (6%). The overall response rate at 6 and 12 months was of 87% (26% of complete response) and 93% (28% of complete response), respectively. The median time to complete response was 2 (0-12) months. In multivariate analysis, Behcet's disease (SHR= 2.52 [1.35-7.71], p=0.004) and a number of uveitis flares before anti-TNFα greater than 5 (HR=1.97 [1.02-3.84], p=0.045) were associated with complete response to anti-TNFα. Side effects were reported in 28% of patients, including 12% of serious adverse events. IFX and ADA did not differ significantly in terms of occurrence of complete response (SHR=0.65 [0.25;1.71], p=0.39), serious side effects (SHR= 0.22 [0.04-1.25], p=0.089) or event free survival (SHR=0.55 [0.28;1.08], p=0.083). CONCLUSIONS: Anti-TNFα are highly effective in refractory inflammatory uveitis. Behcet's disease is associated with increase odds of response. IFX and ADA seem equivalent in terms of efficacy. This article is protected by copyright. All rights reserved

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

Cardiac neonatal lupus syndrome is due to anti-SSA or SSB antibodies and mainly includes congenital heart block (CHB) and dilated cardiomyopathy (DCM). Its optimal management is still debated. We report a large series of autoimmune high degree CHB.Inclusion criteria in this retrospective study were fetuses or neonates with high-degree CHB associated with maternal anti-SSA/SSB antibodies.214 CHB were included: 202 detected in utero at a median term of 23 weeks' gestation (WG) [range 16 to 39 WG] and 12 neonatal cases diagnosed at a median age of 0 days [range birth to 8 days]. The 214 cases of CHB included 202 (94.4%) third-degree CHB, 8 (3.7%) second-degree CHB, and 4 (1.9%) intermittent CHB. In multivariate analysis, the factors associated with feto-neonatal deaths (15.7%) were hydrops (p0.001; hazard ratio [HR] 12.4 [95% confidence interval (95%CI) 4.7-32.7]) and prematurity (p=0.002; HR 17.1 [95%CI 2.8-103.1]). During a median follow-up of 7 years [birth to 36 years], 148 of 187 children born alive (79.1%) had a pacemaker, 35 (18.8%, one missing data) had DCM, and 22 (11.8%) died. In multivariate analysis, factors associated with child death were in utero DCM (p=0.0157; HR 6.37 [95%CI: 1.25-32.44]), postnatal DCM (p0.0001; HR 227.58[95%CI: 24.33-2128.46]) and pacemaker implantation (p=0.0035; HR 0.11[95%CI: 0.02-0.51]). The use of fluorinated steroids was neither associated with survival nor with regression of 2nd degree CHB.In this second largest series of CHB, we confirm some of the previous results. We were unable to find data supporting the routine use of in utero fluorinated steroids.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 9 novembre 2016

Primary immunodeficiency (PID) in adults is rare and mostly revealed by infections. Adults without predisposing factors who were admitted to an intensive care unit (ICU) for infection were screened for PID. Six PID cases were diagnosed, mostly revealed by encapsulated bacterial infections. Investigation of PID after ICU discharge should be considered to improve early detection.

International audience; ObjectivesLarge-vessel involvement (LVI) can occur in giant-cell arteritis (GCA) and may represent a distinct disease subgroup with a higher risk for aortic dilation. This study aimed to better characterize the presentation and evolution of LVI in patients with GCA.Patients and methodsA retrospective multicenter study enrolled 248 GCA patients with LVI and 301 GCA patients without LVI on imaging. Factors associated with aortic dilation were identified in a multivariable model.ResultsThe patients with LVI were younger (p < 0.0001), more likely to be women (p = 0.01), and showed fewer cephalic symptoms (p < 0.0001) and polymyalgia rheumatica (p = 0.001) but more extracranial vascular symptoms (p = 0.05) than the patients without LVI. Glucocorticoids (GC) management did not differ between the two groups, but the GC discontinuation rate was lower in the patients with LVI (p = 0.0003). Repeated aortic imaging procedures were performed at 19 months [range: 5–162 months] and 17 months [range: 6–168 months] after diagnosis in 154 patients with LVI and 123 patients without LVI, respectively, of whom 21% and 7%, respectively, presented new aortic dilations (p = 0.0008). In the patients with LVI, aortic dilation occurred on an aorta segment shown to be inflammatory on previous imaging in 94% of patients. In the multivariate analysis, LVI was the strongest predictor of aortic dilation (hazard ratio: 3.16 [range: 1.34–7.48], p = 0.009).ConclusionsLVI represents a distinct disease pattern of GCA with an increased risk of aortic dilation. Control of the aortic morphology during follow-up is required.

International audience; Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.

Background The aim of this study was to evaluate tocilizumab (TCZ) as an add-on therapy to glucocorticoids (GC) during the first 3 months of treatment of giant cell arteritis (GCA). Methods GCA patients, as defined by ≥3/5 ACR criteria and positive temporal artery biopsy (TAB) or angio-CT-scan or PET-scan-proven aortitis, were included in this prospective open-label study. Prednisone was started at 0.7 mg/kg/day and then tapered according to a standardized protocol. All patients received four infusions of TCZ (8 mg/kg/4 weeks) after inclusion. The primary endpoint was the percentage of patients in remission with ≤0.1 mg/kg/day of prednisone at week 26 (W26). Patients were followed for 52 weeks and data prospectively recorded. Results Twenty patients with a median (IQR) age of 72 (69–78) years were included. TAB were positive in 17/19 (90%) patients and 7/16 (44%) had aortitis. Remission was obtained in all cases. At W26, 15 (75%) patients met the primary endpoint. Ten patients experienced relapse during follow-up, mainly patients with aortitis (P = 0.048), or CRP >70 mg/L (P = 0.036) or hemoglobin ≤10 g/dL (P = 0.015) at diagnosis. Among 64 adverse events (AE) reported in 18 patients, three were severe and 30, mostly non-severe infections (n = 15) and hypercholesterolemia (n = 8), were imputable to the study. Conclusion This study shows that an alternative strategy using a short-term treatment with TCZ can be proposed to spare GC for the treatment of GCA. However, 50% of patients experienced relapse during the 9 months following TCZ discontinuation, especially patients with aortitis, or CRP > 70 mg/L or Hb ≤ 10 g/dL at diagnosis. Trial registration: ClinicalTrials.gov (NCT01910038).

Objective 18F-FDG PET/CT can detect large-vessel involvement in giant-cell arteritis (GCA) with a good sensitivity. In patients with clinically and biologically controlled disease, we aimed to assess how vascular uptakes evolve on repetitive FDG-PET/CT. Patients and methods All included patients had to satisfy the 4 following criteria: 1) diagnosis of GCA was retained according to the criteria of the American College of Rheumatology or based on the satisfaction of 2 criteria associated with the demonstration of large-vessel involvement on FDG-PET/CT; 2) all patients had a positive PET/CT that was performed at diagnosis before treatment or within the first 10 days of treatment; 3) another FDG-PET/CT was performed after at least 3 months of controlled disease without any relapse; 4) patients were followed-up at least for 12 months. Results Twenty-five patients (17 [68%] women, median age: 69 [65–78]) with large-vessel inflammation on a baseline FDG-PET/CT and with repetitive imaging during the period with controlled disease were included and followed-up for 62 [25–95] months. Four repeated procedures revealed total extinction of vascular uptakes at 11.5 [8–12] months after the first FDG-PET/CT. Eight PET/CT revealed decreased numbers of vascular uptakes, and 10 procedures revealed no changes. The 3 remaining procedures indicated worsening of the numbers of vascular uptakes in the absence of relapse. Conclusions Our study revealed long-term persistent vascular uptake on repeated FDG-PET/CT in > 80% of our GCA patients with large-vessel inflammation and clinical-biological controlled disease. Prospective studies are required to confirm these findings.

Background Long-term anticoagulation is recommended in antiphospholipid syndrome with thrombosis in order to prevent recurrences. While the current mainstay relies on vitamin K antagonists, their long-term maintenance may remain challenging. Objectives To report on the safety and the efficacy of oral direct inhibitors of thrombin and factor Xa (ODIs) in antiphospholipid syndrome (APS). Methods We performed a descriptive analysis of patients with APS enrolled in a French multicentre observational cohort between January 2012 and March 2014 and receiving ODIs. The main outcomes were the occurrence of a thrombotic recurrence or bleeding events. Results Twenty-six patients with APS (primary in 12) received ODIs. Twenty patients had been previously treated with VKA (n = 19), or fondaparinux (n = 1) for a median duration of 3 years. ODIs were introduced as second-line therapy because of INR lability/therapeutic simplification (n = 17), recurrent thrombosis (n = 1), VKA's associated bleeding event (n = 1), and atrial fibrillation (n = 1). Six patients received ODIs as first-line therapy. After a median [IQR] follow-up of 19 [8–29] months, one relapse of arterial thrombosis, two bleeding events (hypermenorrhea and rectal bleeding under rivaroxaban) and one recurrent migraine were reported, leading to discontinuation of therapy in these 4 patients. Conclusion ODIs might be an alternative therapeutic option in APS. Prospective studies are warranted to evaluate their safety in this condition.

Multicentric reticulohistyocytosis (MRH) is a rare multisystemic non-Langerhans histiocytosis characterized by cutaneous nodules and severe destructive polyarthritis, sometimes associated with constitutional symptoms and various organ involvements. Its treatment remains empirical and challenging. We first report herein, the successful treatment of a multicentric reticulohistiocytosis patient with anakinra based on cutaneous biopsy immunostaining and serum cytokines features. A first-line treatment associating methotrexate, cortisone and hydoxychloroquine showed none improvement. Therefore, while further tests were performed to rule out an associated malignancy, auto-immune disease or mycobacterial infection, a treatment with anakinra was chosen instead of anti-TNF-alpha drugs. As soon as the 5th day, anakinra allowed control of fever, then rapid improvement of constitutional symptoms, arthritis, cutaneous lesions, and normalization of C-reactive protein, IL-6, and especially IL-1β levels. Then methotrexate was added, while anakinra was removed at the 12th month, with persistent and complete remission over the two-year follow up. Further assessment of IL-1 pathogenic role and blockade on larger cohorts of patient could open new therapeutic perspectives for refractory/relapsing MRH, considering the good tolerance profile of specific targeting drugs.

To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegnener's] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg-Strauss] [EGPA]).

Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58–73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6–34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05–8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05–7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41–99) and 94% (95% CI, 86–100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14–88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome.

To the Editor,The severe prognosis of Erdheim-Chester disease (ECD) is essentially based on central nervous system involvement and probably on cardiac injuries [1,2]. Recently, treatments blocking ...

Objectives Comprehensive analyses of cause-specific death patterns in GCA are sparse. We studied the patterns and time trends in GCA-related mortality using a large death certificate database. Methods We obtained multiple-cause-of-death data from the French national death certificate database for 1980-2011. GCA-associated deaths were defined as decedents ⩾55 years old with GCA listed as an underlying or non-underlying cause of death. Time trends of death rates were analysed and the mean age at death with GCA and in the general population ⩾55 years old were calculated. Standardized mortality odds ratios (SMORs) were calculated for 17 selected causes of death (based on 2000-11 data). Results The analyses pertained to approximately 15 000 death certificates listing GCA (including approximately 6300 for 2000-11). Annual standardized death rates for GCA increased to a peak in 1997 and then decreased (Spearman's correlation test, both P < 0.0001). Mean age at death was higher for GCA than for general population decedents (Student's t-test, P < 0.0001). GCA deaths were frequently or strongly associated with aortic aneurysm and dissection (1.85% of death certificates, SMOR: 3.09, 95% CI: 2.48, 3.82), hypertensive disease (20.78%, SMOR: 2.22, 95% CI: 1.97, 2.50), diabetes mellitus (11.27%, SMOR: 1.96, 95% CI: 1.72, 2.23), certain infectious and parasitic diseases (12.12%, SMOR: 1.76, 95% CI: 1.55, 2.00) and ischaemic heart disease (16.54%, SMOR: 1.45, 95% CI: 1.35, 1.64). Conclusion GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities. These findings help provide better insights into the outcomes of GCA.

IF 2.969; International audience; Anti-Mi2 are dermatomyositis-specific autoantibodies (Aabs) that have been associated, in small cohorts, with a good prognosis possibly related to a lower malignancy risk. Our objective was to describe the phenotype of anti-Mi-2 dermatomyositis (DM) in a larger cohort. A national multicenter retrospective cohort study was performed including all patients with a clinical phenotype suggestive of DM (cutaneous manifestations and/or muscle involvement) and a positive anti-Mi2 Aabs. Medical records were retrospectively reviewed to assess clinical and histological features, and presence of cancer occurring ± 3 years of diagnosing myositis (CAM).

Marlène Pasquet,1 Isabelle Pellier,2 Nathalie Aladjidi,3 Anne Auvrignon,4 Patrick Cherin,5 Pierre Clerson,6 Gregoire Jacques Noël Cozon,7 Roland Jaussaud,8 Boris Bienvenu,9 Cyrille Hoarau10 1Pediatric Hematology and Oncology Department, University Hospital Centre of Toulouse, Toulouse, 2University Hospital of Angers, Angers, 3Paediatric Hematology Unit, CEREVANCE, CIC 1401, Inserm CICP, Hospital Pellegrin, 4Trousseau Hospital, 5Internal Medicine Department, Paris, 6Soladis Clinical Studies, Roubaix, 7Clinical Immunology, Edouard Herriot Hospital, Lyon, 8Internal Medicine and Clinical Immunology Department, University Hospital Centre of Nancy, Nancy, 9Internal Medicine Department, University Hospital Centre of Caen, Caen, 10Renal Transplantation and Clinical immunology Department, University Hospital Centre of Tours, Tours, France Objective: To assess quality of life and satisfaction regarding immunoglobulin-replacement therapy (IgRT) treatment according to the route (intravenous Ig [IVIg] or subcutaneous Ig [SCIg]) and place of administration (home-based IgRT or hospital-based IgRT).Subjects and methods: Children 5–15 years old treated for primary immunodeficiency disease (PIDD) with IgRT for ≥3 months were included in a prospective, noninterventional cohort study and followed over 12 months. Quality of life was assessed with the Child Health Questionnaire – parent form (CHQ-PF)-50 questionnaire. Satisfaction with IgRT was measured with a three-dimensional scale (Life Quality Index [LQI] with three components: factor I [FI], treatment interference; FII, therapy-related problems; FIII, therapy settings).Results: A total of 44 children (9.7±3.2 years old) receiving IgRT for a mean of 5.6±4.5 years (median 4.1 years) entered the study: 18 (40.9%) were receiving hospital-based IVIg, two (4.6%) were receiving home-based IVIg, and 24 (54.6%) were treated by home-based SCIg. LQI FIII was higher for home-based SCIg than for hospital-based IVIg (P=0.0003), but there was no difference for LQI FI or LQI FII. LQI FIII significantly improved in five patients who switched from IVIg to SCIg during the follow-up when compared to patients who pursued the same regimen (either IVIg or SCIg). No difference was found on CHQ-PF50 subscales, LQI FI, or LQI FII.Conclusion: Home-based SCIg gave higher satisfaction regarding therapy settings than hospital-based IVIg. No difference was found on other subscales of the LQI or CHQ-PF50 between hospital-based IVIG and home-based SCIG. Keywords: primary immunodeficiency, pediatric, immunotherapy, immunoglobulins, satisfaction, preference

International audience; Elhers-Danlos syndrome (EDS) is the clinical manifestation of connective tissue disorders, and comprises several clinical forms with no specific symptoms and selective medical examinations which result in a delay in diagnosis of about 10 years. The EDS hypermobility type (hEDS) is characterized by generalized joint hypermobility, variable skin hyperextensibility and impaired proprioception. Since somatosensory processing and multisensory integration are crucial for both perception and action, we put forth the hypothesis that somatosensory deficits in hEDS patients may lead, among other clinical symptoms, to misperception of verticality and postural instability. Therefore, the purpose of this study was twofold: (i) to assess the impact of somatosensory deficit on subjective visual vertical (SVV) and postural stability; and (ii) to quantify the effect of wearing somatosensory orthoses (i.e., compressive garments and insoles) on postural stability. Six hEDS patients and six age- and gender-matched controls underwent a SVV (sitting, standing, lying on the right side) evaluation and a postural control evaluation on a force platform (Synapsys), with or without visual information (eyes open (EO)/eyes closed (EC)). These two latter conditions performed either without orthoses, or with compression garments (CG), or insoles, or both. Results showed that patients did not exhibit a substantial perceived tilt of the visual vertical in the direction of the body tilt (Aubert effect) as did the control subjects. Interestingly, such differential effects were only apparent when the rod was initially positioned to the left of the vertical axis (opposite the longitudinal body axis). In addition, patients showed greater postural instability (sway area) than the controls. The removal of vision exacerbated this instability, especially in the mediolateral (ML) direction. The wearing of orthoses improved postural stability, especially in the eyes-closed condition, with a particularly marked effect in the anteroposterior (AP) direction. Hence, this study suggests that hEDS is associated with changes in the relative contributions of somatosensory and vestibular inputs to verticality perception. Moreover, postural control impairment was offset, at least partially, by wearing somatosensory orthoses.

Background Giant cell arteritis (GCA) is a large-vessel vasculitis affecting elderly people, and most frequently women (sex-ratio of 2.3). Some studies suggest an increased risk of malignancies in GCA. Objectives We aimed to describe the clinical, paraclinical characteristics and outcomes of GCA patients with concomitant malignancy and compare them to a control group without malignancy. Methods Patients with a diagnosis of GCA and of solid neoplasm or malignant blood disease, within one year before or after the diagnosis of vasculitis, were included. A random group of age-matched (3:1) control patients from our monocentric inception cohort of GCA patients from Caen University Hospital was constituted. Results Twenty-four observations were collected (median age 75.5 years). All fulfilled ≥3/5 ACR criteria. Temporal artery biopsy was positive in 17 cases (70.8%). There were 1 active (4.2%) and 9 former (37.5%) smokers. Only 1 patient had a previous prostate cancer. Malignancies were 10 malignant blood diseases (41.7%, 3 chronic lymphoid leukemias, 3 essential thrombocythemias, 1 myeloma, 1 chronic myelomonocytic leukemia, 1 MALT lymphoma, 1 Waldenstrom9s macroglobulinemia) and 14 solid neoplasms (58.3%, 3 lung, 3 breast, 2 prostate, 1 thyroid, 1 colon, 1 pleural cancers, 1 melanoma, 1 Kaposi9s sarcoma and 1 Merkel cell carcinoma). Malignancy was diagnosed at a median of 1 month after GCA diagnosis in 21 patients and before in the other 3. Diagnosis of malignancy was made in consultation in 5 patients (3 skin cancers and 2 breast cancers), on lab tests in 13 (thrombocytosis, anemia or increased prostate specific antigen) and on imaging in 6. Treatments of malignancy included chemotherapy alone in 8 patients (33.3%), simple monitoring in 6 patients (25%), surgery alone in 4 patients (16.7%), surgery and radiotherapy and/or chemotherapy in 4 patients (16.7%), decrease of corticosteroids in 1 patient, and 1 patient was lost to follow-up. Two patients (8.3%) died from infectious complications, 8 patients (33.3%) had a GCA relapse, including one with concomitant malignancy relapse. After a median follow-up of 16 months [0–134], 5 patients (20.8%) were weaned from steroids, all considered in malignancy remission. Seven patients (29.1%) were still under chemotherapy, 9 patients (37.5%) were considered to be in malignancy remission. There were more males in patients with concomitant malignancy, compared to the control group (respectively 15/24 and 21/72, p Conclusions Our study shows an over-representation of male gender in GCA with concomitant malignancy. Vasculitis outcomes were not influenced by the malignancy treatment. The diversity of malignancies encountered in this study raises the issue of an incidental association. Initial clinical and paraclinical follow-up dictated by vasculitis may have led to an early identification of associated malignancy, and thus represent a lead time bias. Disclosure of Interest None declared

Background Deficiency in α-1-antitrypsin (AAT), which is the main proteinase 3 (PR3) inhibitor, is now recognized as a pathogenic factor in some cases of anti-PR3 anti-neutrophil cytoplasmic antibodies (ANCA) related granulomatosis with polyangiitis (GPA). However, the clinical impact of AAT deficiency remains poorly established in this setting. Objectives The purpose of our study was to describe the clinical phenotypes and outcomes of anti-PR3 GPA patients according to their AAT status. Methods A retrospective monocentric study carried out in Caen University Hospital led to identify anti-PR3 GPA patients, from 09/21/2011 to 06/10/2016. AAT dosage and phenotype (isoelectric focusing in agarose gel) were performed for all patients. Categorical variables were reported as percentages and compared using Chi2 or Fisher9s tests according to expected frequencies. Continuous variables were expressed as means and analysed using Student9s t-test. Associations between survival, renal survival or relapse-free survival, and AAT phenotype were evaluated by the log-rank test. A p-value Results Among the 72 identified anti-PR3 GPA patients, 40 (56%) were male. Median age at diagnosis was 60.5 years old. Patients mainly had constitutional symptoms (51, 71%), pulmonary (52, 72%), ear, nose or throat (ENT) (49, 68%), rheumatologic (45, 63%), and renal (44, 61%) involvements. Median initial BVAS score was 38 (maximum score: 63). Twelve (17%) deaths and 33 (46%) relapsing patients were noted (median follow-up: 55 months). Forty-eight (67%) patients had MM phenotype, 10 (14%) MZ phenotype, 8 (11%) MS phenotype, 3 (4%) M-variant phenotype, 2 (3%) ZZ phenotype and 1 (1%) ZS phenotype. Allele frequencies of M, Z and S allele were 81, 10 and 6%, respectively. The whole patient cohort had the same immunosuppressant drug regimen. Only intra-alveolar hemorrhage (IAH), that was more frequent in Z or S deficient allele patients, and ENT involvement, that was more frequent in those with Z allele, were significantly associated with AAT deficiency. Among the 13 patients carrying Z allele, 9 had normal AAT level, including 6 without any biologic inflammatory parameter at the time of AAT dosage. Global survival, renal survival or relapse-free survival were identical between Z carriers compared to non-Z carriers (respectively 0.77, 0.75 and 1), and between Z or S carriers compared to those without (respectively 0.91, 0.44 and 0.32). Conclusions This study confirms the epidemiological association of anti-PR3 GPA with AAT deficiency, and find an interesting higher risk of IAH in this setting. The identical prognosis of both subgroups should be related to other therapeutic added in IAH, including plasma exchanges. Prospective studies are required to specify these data and to assess the need for replacement therapy in AAT deficient patients. Disclosure of Interest None declared

Background Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. Patients and methods This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. Results We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24 months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥ 1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36 months, 11 patients died including 5 from intracerebral hemorrhages. Conclusion EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.

Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0–1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P

Purpose We aimed to describe the initial treatment that was used in a common hospital-based practice in patients with giant-cell arteritis with and without large-vessel involvement at diagnosis as well as the outcomes in both groups. Methods This retrospective multi-center cohort included patients with giant-cell arteritis diagnosed between 2005 and 2015, all of whom had fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (FDG-PET/CT) performed at giant-cell arteritis diagnosis and were followed up for ≥12 months. We compared the features, treatment, and outcomes of patients with large-vessel involvement demonstrated on FDG-PET/CT with those of patients with a negative PET/CT. Results Eighty patients (50 women, median age: 71 [53-87] years) were included, 40 of whom had large-vessel involvement demonstrated on FDG-PET/CT and 40 who did not. After a median 56-month follow-up time, 42 (53%) patients had discontinued glucocorticoid (GC) treatment. Patients with and without large-vessel involvement were indistinguishable in the initial median dose of prednisone (0.74 mg/kg vs 0.75 mg/kg, P = .56), overall GC duration ( P = .77), GC discontinuation rate ( P = .65), relapse rate ( P = .50), frequency of GC-dependent disease requiring GC-sparing treatments ( P = .62), and fatality rate ( P = .06). Conclusion In the setting of tertiary hospital recruitment, large-vessel involvement at giant-cell arteritis diagnosis using a PET/CT study had no influence on the choice of initial GC dose and had no impact on outcomes. Prospective studies are required to confirm these findings.

International audience; PURPOSE:The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell arteritis (GCA).METHODS:We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per-patient and a per-segment analysis, using Cohen's kappa concordance index.RESULTS:We included 28 patients (21/7 women/men, median age 67 [56-82]). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 [1-7] and 3 [1-6] vascular territories were involved on positive PET/CT and CTA, respectively (p = 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 [0.64-1]. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 [0.54-0.75]. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively.CONCLUSIONS:CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta's branches.

Summary Background To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined. Aims To determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities. Methods Videocapsule endoscopy was performed on 50 patients with SSc. Results Prevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P