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International audience; Hepatitis C virus (HCV) has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes are specialized in producing immunoglobulins, and within chronic HCV infection they can cause a range that goes from polyclonal hypergammaglobulinemia without clinical repercussions, passing by mixed cryoglobulinemic vasculitis and eventually reaching B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the last steps towards overt malignancy. This has direct implications in treatment strategies, which always include the use of direct-acting antiviral agents sometimes associated with immunosuppressants. The role of direct-acting antiviral agents has been well established in patients with cryoglobulinemia vasculitis. Its positive impact on B cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.

Supplemental Digital Content is available in the text, Infectious aortitis (IA) is a rare and severe disease. The treatment classically associates open surgery with prolonged antibiotic therapy. This study aimed to describe clinical characteristics, medical and surgical supports in a large and current series of IA. We conducted a retrospective multicenter study of native aorta IA, between 2000 and 2019. Inclusion criteria were the presence of a microorganism on blood culture, aortic sample or any other validated technique and structural anomaly in imaging. We included 55 patients (85% men), with a median age of 65. Microbiology data substantially differed from previous studies with 12 Gram-negative rods IA, of which only 3 due to Salmonella spp., 24 Gram-positive cocci IA of which 12 Streptococcus spp., and 18 IA due to intracellular growth and/or fastidious microorganisms, of which 8 Coxiella burnetii, 3 Treponema pallidum, and 5 tuberculosis suspicious cases. Fifteen patients (27%) presented with thoracic IA, 31 (56%) with abdominal IA, and 9 (16%) with thoraco-abdominal IA. Eight patients had no surgery, 41 underwent open surgery, only 4 endovascular aneurysm repair, and 2 a combination of these 2 techniques. Nine patients died before 1-month follow-up. There was no difference in the mortality rate between the different types of germ or localization of IA. The variety of germs involved in IA increases. Positron emission tomography-computed tomography scan is a very useful tool for diagnosis. Surgery is still mainly done in open approach and a prospective multicenter study seems necessary to better determine the place of endovascular aneurysm repair versus open surgery.

Background:Coronavirus disease 2019 (COVID-19), has raised several questions in patients with immune-mediated inflammatory diseases (IMID). Whether the seroprevalence and factors associated with symptomatic COVID-19 are similar in IMID patients and in the general population is still unknown.Objectives:To assess the serological and clinical prevalence of COVID-19 in European IMID patients, along with the factors associated with its risk and the impacts the pandemic had on the IMID management.Methods:Prospective multicentre cross-sectional study among patients with five IMID (i.e. systemic lupus erythematous, Sjögren’s syndrome, rheumatoid arthritis, axial spondylarthritis or giant cell arteritis) from six tertiary-referral centers from France, Germany, Italy, Portugal, Spain and United Kingdom. Demographics, comorbidities, IMID, treatments, flares and COVID-19 details were collected. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests were systematically performed.Results:Between June 7 and December 8, 2020, 3028 patients were included (median age 58 years, 73.9% females). SARS-CoV-2 antibodies were detected in 166 (5.5%) patients. Symptomatic COVID-19 was seen in 122 patients (prevalence: 4.0%, 95% CI 3.4-4.8%); 23 (24.2%) of them were hospitalized and four (3.2%) died. In multivariate logistic regression analysis, symptomatic COVID-19 was more likely to be observed in patients with higher levels of C-reactive protein (OR: 1.18; 95% CI 1.05-1.33; p = 0.006), and increased with the number of IMID flares (OR: 1.27; 95% CI 1.02-1.58; p = 0.03). Conversely, it was less likely to occur in patients treated with biological therapy (OR: 0.51; 95% CI 0.32-0.82; p = 0.006). During the pandemic, at least one self-reported disease flare was seen in 654 (21.6%) patients. Also, 519 (20.6%) patients experienced changes in their treatment, with 125 of these (24.1%) being due to COVID-19.Conclusion:The SARS-CoV-2 prevalence in IMID patients over the study period seems to be similar to that of the general population1. The IMID inflammatory status seems to be independently associated with the development of COVID-19.References:[1]Pollán M, Pérez-Gómez B, Pastor-Barriuso R, Oteo J, Hernán MA, Pérez-Olmeda M, et al. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet Lond Engl. 2020 Aug 22;396(10250):535–44.Disclosure of Interests:None declared.

Background:In this large worldwide TAK registry, we report 209 patients treated with TNF-α antagonists and tocilizumab aiming to compare their safety and efficacy, and determine the predictive factors of treatment response and relapse.Objectives:To assess safety and efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK).Methods:We conducted a retrospective multicenter study in referral centers from France, Italy, Spain, Israel, Japan, Tunisia and Russia about biological-targeted therapies in TAK during the period from January 2017 to September 2019 for the data collection.Results:Two-hundred nine patients with TAK [median age of 29 years [7-62], and 186 (89%) females] were included. They received either TNF-α antagonists [n=132 (63%) with 172 lines; infliximab (n=109), adalimumab (n=45), golimumab (n=8), certolizumab (n=6) and etanercept (n=5)], or tocilizumab [n=77 (37%) with 121 lines; intravenous and subcutaneous in 95 and 26 cases, respectively]. A complete response at 6 months was evidenced in 101/152 (66%) on TNF-α antagonists and 75/107 (70%) on tocilizumab, respectively. Age ≥ 30 years [OR= 2.09 [1.09; 3.99]] was associated with complete response, whereas vascular signs [0.26 [0.1;0.65]], baseline prednisone ≥ 20 mg/day [0.51 [0.28;0.93]] were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvements [HR 2.44 (1.06;5.65) and 3.66 (1.18;11.4), respectively], and systemic signs at baseline [HR 2.01 (1.30;3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNFα antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biological-targeted therapies of whom 37 (21%) and 21 (17%), (p=0.4) on TNF-α antagonists and tocilizumab, respectivelyConclusion:This large multicenter study shows high efficacy of biological-targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.Disclosure of Interests:None declared

Background:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential for any autoimmune or inflammatory disease (AIID). We performed a disease-finding “basket trial” (TRANSREGNCT01988506) in patients affected by one of 11 different AIID and reported the outcome of the first 46 patients (Rosenzwajg et al, ARD 2019).Objectives:Here we analyzed and discussed results from deep immunophenotyping, of 78 patients, to comprehensively study the effect of ld-IL2 on the immune system of patients affected by various AIIDMethods:We performed a prospective, open label, phase I-IIa study in 78 patients with a mild to moderate form of one of 13 selected AIID. All patients received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Deep immunophenotyping was performed before and after 5 days of ld-IL2.Results:ld-IL2 significantly expands both memory Tregs as well as naïve Tregs, including recent thymic emigrant Tregs. It also activates Tregs as demonstrated by the significantly increased expression of HLA-DR, CD39, CD73, GITR, CTLA-4. Similar results were observed across the different AIID.Conclusion:ld-IL2 “universally” improves Treg fitness across 13 autoimmune and inflammatory disease.References:[1]Rosenzwajg M#, Lorenzon R#, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.Disclosure of Interests:Michelle Rosenzwajg: None declared, Roberta Lorenzon: None declared, Patrice cacoub: None declared, Fabien Pitoiset: None declared, Selim Aractingi: None declared, Beatrice Banneville Speakers bureau: Lilly, Novartis, Laurent Beaugerie: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Julien Champey: None declared, Olivier Chazouilleres: None declared, Christophe Corpechot: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Arsene Mekinian: None declared, Elodie Regnier: None declared, david Saadoun: None declared, Joe-Elie Salem: None declared, Jérémie SELLAM: None declared, Philippe Seksik: None declared, David Klatzmann Consultant of: ILTOO Pharma

Background:Aortitis is a group of disorders characterized by the inflammation of the aorta. The most common causes of aortitis are the large-vessel vasculitis i.e. giant cell arteritis (GCA) and Takayasu arteritis (TA). However, aortitis may be isolated. Because of the wide variation in the course of aortitis, predicting outcome is challenging. The optimal management strategy of isolated aortitis (IA) is still unclear as IA is poorly defined, with data consisting of small retrospective and case control studies.Objectives:To assess the long-term outcome and prognosis factors for vascular complications in patients with isolated aortitis.Methods:Retrospective multicenter study of 353 patients with non-infectious aortitis including 136 giant cell arteritis (GCA), 96 Takayasu arteritis (TA) and 73 isolated aortitis (IA). Factors associated with event-free survival, vascular event-free survival and revascularization-free survival were assessed. Risk factors for vascular complications were identified in multivariate analysis.Results:After a median follow up of 52 months, vascular complications were observed in 32.3 %, revascularization in 30 % and death in 7.6%. The 5-year cumulative incidence of vascular complications was 58% (41; 71), 20% (13; 29), and 19 % (11; 28) in IA, GCA and TA, respectively. In multivariate analysis, IA [HR, 1.85 (1.19 to 2.88), p=0.017] and male gender [1.77 (1.26 to 2.49), pConclusion:IA has a worse vascular prognosis than GCA and TA. Sixty percent of IA patients will experience a vascular complication within 5 years from diagnosis.Disclosure of Interests:None declared

Objectives:To assess long term efficacy of tocilizumab in treatment-naive patients with Takayasu arteritis (TAK).Methods:In this multicenter, prospective, open-labelled trial, we aim to evaluate the benefit of adding tocilizumab to steroids in treatment-naïve patients with TAK, on discontinuation of steroids after 6 months of tocilizumab treatment, and to assess relapse-free survival following tocilizumab discontinuation.Results:Thirteen patients with TAK were included, with a median age of 32 years [19-45] and 12 (92%) females. Six (54%) patients met the primary end-point. Among 11 (85%) patients which achieved remission at 6 months, 6 (54%) have reached primary endpoint.. Among the 5 remaining patients which continued steroids, 3 had a prednisone-equivalent dosage < 5mg/day. A significant decrease of disease activity was observed after 6 months of tocilizumab therapy: decrease of median NIH scale (3 [3-4] at baseline, versus 1 [0-2] after 6 months; p No severe AEs were considered related to study treatment and none required tocilizumab interruption or dose reduction. No deaths have occurred during the study period.Conclusion:Tocilizumab seems an effective steroid sparing therapy in TAK but its effect appears to be suspensive.Disclosure of Interests:Arsene Mekinian: None declared, david Saadoun: None declared, jerome.connault@chu-nantes.fr jerome.connault@chu-nantes.fr: None declared, i-quere@chu-montpellier.fr i-quere@chu-montpellier.fr: None declared, Patrick Jégo: None declared, nicolas.limal@aphp.fr nicolas.limal@aphp.fr: None declared, wxv wxv: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Mathieu Vautier: None declared, lea.savey@aphp.fr>; lea.savey@aphp.fr>;: None declared, Patrice cacoub: None declared, olivier fain: None declared

Background:Takayasu arteritis (TA) is a chronic inflammatory large-vessel vasculitis, predominantly affecting the aorta and its main branchesObjectives:To assess safety and efficacy of biologics (i.e. TNF-α antagonists and tocilizumab) in patients with Takayasu arteritis (TA).Methods:We conducted a retrospective multicenter study in referral centers from Europe and several countries in the world about biological-targeted therapies in Takayasu arteritis during the period from January 2017 to September 2019.Results:Retrospective multicenter study of characteristics and outcome of 49 TA patients [80% of females; median age 42 [20-55] years] treated by TNF-α antagonists (80%) or tocilizumab (20%)] and fulfilling ACR and/or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of TA patients were inadequately controlled with, or intolerant to, conventional immunosuppressive therapy [median number of 3 (1-5)]. Overall response (i.e. complete and partial) to biological-targeted treatments at 6 and 12 months was of 75% and 83%, respectively. There were a significantly lower C-reactive protein levels at initiation of biological-targeted treatments [22 [10-46] mg/l vs 58 [26-76] mg/l, (p=0.006)] and a trend toward lower immunosuppressants drugs used prior biologics (p=0.054) in responders (i.e. complete and/or partial responders) relative to non-responders to biological-targeted treatments. C-reactive protein levels and daily prednisone dosage significantly decreased after 12 months of biological-targeted treatments [30 vs 6 mg/l, pConclusion:This nationwide study shows high efficacy of biological-targeted treatments in refractory TA patients with an acceptable safety profile.Acknowledgments:NODisclosure of Interests:Arsene Mekinian: None declared, Mathieu Vautier: None declared, Matthieu resche-rigon: None declared, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOBI, Savino Sciascia: None declared, olivier.espitia@chu-nantes.fr olivier.espitia@chu-nantes.fr: None declared, Patrice cacoub: None declared, olivier fain: None declared, david Saadoun: None declared

Background:Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main forms of large vessels vasculitis (LVV). Vessel inflammation leads to aneurysms, wall thickening, stenosis, and, in some cases, complete occlusion of the artery. Due to the wide variation in the course of LVV, predicting outcome is challenging. To our knowledge, data regarding prognosis factors of LVI in LVV patients and comparison of outcome of LVI in GCA and TAK are lacking. An early identification of patients with higher mortality could help to prevent deaths and vascular complications.Objectives:To assess prognosis factors and outcome of large vessel involvement (LVI) in large vessels vasculitis (LVV) patients.Methods:Retrospective multicenter study of characteristics and outcomes of 417 patients with LVI including 299 Takayasu arteritis (TAK) and 118 Giant cell arteritis (GCA-LVI) were analyzed. Logistic regression analysis assessed prognosis factors in LVV patients. Outcome of LVI among TAK and GCA-LVI patients (ischemic complications, aneurysms complications, relapses and revascularization) were assessed.Results:In multivariable analysis, stroke/transient ischemic attack [HR: 3.63 (1.46 - 9.04), p=0.006] was independently associated with vascular complications in LVV. The 10-years aneurysm free survival was significantly lower [67% (48 – 93) vs 89% (84 – 95), p=0.02] in GCA-LVI compare to TAK patients. The 5-years relapse free survival was significantly lower [47% (37 – 60) vs 69% (63 – 75), pConclusion:This large nationwide cohort of LVI provided prognosis factors of vascular complications in LVV patients. TAK and GCA-LVI have different long-term outcome in term of aneurysm development, relapse and revascularization.Disclosure of Interests:None declared

Background Buerger’s disease or thromboangiitis obliterans (TAO) is a non-atherosclerotic arteritis of distal extremities. Data regarding long term outcome of patients with Buerger’s disease or thromboangiitis obliterans (TAO) are lacking and most series come from Middle-East and Far-East. Objectives We aim report clinical presentation and assess long-term outcome and prognosis factors in a large cohort of TAO. Methods Retrospective multicenter study of characteristics and outcomes of 224 TAO patients fulfilling Papa’s and/or 5 Shinoya’s criterias were analysed. Factors associated with vascular event free survival and amputation free survival were identified. Results The median age at diagnosis was 38.532–46 years, 51 (28.5%) patients were female and 81.5% were Caucasians. All but 3 were smokers with a median of 22 pack-year and 22.8% were also addict to cannabis. At diagnosis, 53% had claudication, 73% trophic disorders and 8.8% an infection. Lower extremities and upper extremities were affected in 54% and 28% respectively. Superficial vein thrombosis, Raynaud’s phenomen and arthralgia occurred in 18%, 41% and 8%, respectively. Ethnic group (non-Caucasian) and ischaemic ulcers or necrosis were independent factors of vascular events HR=7.67 [3.1–19.2] p=0.005 and 2.28 [1.3–4] p Conclusions This nationwide study shows that 34% of TAO patients will experience an amputation within 15 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications. Disclosure of Interest None declared

Background Studies on bone involvement of sarcoidosis (BS) are scarse. Objectives To analyse in depth main features, treatments and follow up of patients presenting a BS. Methods Among 926 patients with a proved sarcoidosis from four tertiary hospitals in Paris (France) seen between 2000 and 2015, all cases of BS were retrospectively analysed for demography, clinical features, biological tests and imaging results. Inclusion criteria were a) a bone biopsy with epithelioid granuloma and no casein necrosis, or b) radiological evidence of BS, after exclusion of other diagnoses. Results 27 out 926 (2.9%) sarcoidosis patients fullfilled inclusion criteria for BS. Most patients were caucasian (56%), M/F sex ratio 1.5, 30% were active smokers, mean age at sarcoidosis diagnosis was 39±12 years and at BS diagnosis 43±11 years. Extra-osseous involvement of sarcoidosis was found in lymph nodes (93%), lungs (78%), skin (52%), CNS (33%), ENT (33%), and heart (19%). BS was symptomatic in 15/27 (56%) patients i.e. bone pain (15/15), local inflammation (5/15), bone deformation (3/15), arthritis (4/15), and myalgia (5/15). BS was never the revealing symptom of sarcoidosis. BS was more frequently symptomatic when it was a Perthes-Jungling osteitis and an appendicular skeletton involvement. On imaging exams, BS lesions were found at the spine skeletton alone (14/27, 52%), appendicular skeletton alone (10/27, 37%) or both (3/27, 11%). BS lesions had an aspect of pseudo-metastasis (59%), micro-cysts (Perthes-Jungling, 37%) or Paget disease (4%). Bone lesion was unique in 22% and 26% of patients had more than 10 lesions. When a bone biopsy was done it always confirmed the diagnosis (n=9); in all other cases extra-osseous biopsies confirmed the diagnosis of sarcoidosis. Nine patients received a treatment for BS, i.e. prednisone (n=8, 0.25–1 mg/kg/day), hydroxychloroquine (n=8), and methotrexate (n=5). Response to treatment was complete (n=3), partial (n=4) or nul (n=2). Of note, 21 out of 27 patients received an immunosuppressant for a severe form of systemic sarcoidosis (n=11) or for a steroid-sparing effect (n=10). A relapse of BS was noted in 13 patients, with a mean number of relapse of 2.1–24 After a mean follow up of 49 months, BS was in complete remission (8/27, 30%), partial remission (16/27, 59%) or remained active (3/27, 11%). Conclusions Bone involvement remains a rare manifestation of sarcoidosis. It was symptomatic in 56% of patients, mainly when Perthes-Jungling osteitis and appendicular skeletton involvement were present. Extra-osseous involvement of sarcoidosis were always present at the time of BS diagnosis. Treatment remains difficult with frequent relapses. Disclosure of Interest None declared

Background Takayasu arteritis (TA) is a rare large vessel vasculitis of unknown origin. Main epidemiological data come from Asia. TA significantly increases morbidity and mortality and there is an unmet need to identify patients with higher complications and mortality risks. Objectives To report the long term mortality in Takayasu arteritis (TA) and to identify risk factors associated with mortality. Methods We analysed epidemiological data according to gender and ethnic origins, the causes of death, and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 3625–47 years and 276 (86%) patients were women] fulfilling American College of Rheumatology and Ishikawa criteria of TA. Overall survival and factors associated with death and vascular complications were identified. A prognostic score for death and vascular complications was elaborated based on a multivariate model. Results In a cohort of 318 patients, men tended to be more frequently smokers (42% vs. 26%, p=0.07), had more frequently cardiac insufficiency (14% vs. 9%, p=0.034), but less frequently aneurysmal lesion (51% vs. 76%, p=0.005). Ethnic origins were Caucasian/White (n=87, 37%), North-Africa (n=73, 31%), Black (n=56, 18%), and other (n=17, 5%). White patients were more frequently smokers and diagnosis was more frequently made after 35 years. Black patients had less frequently a supra-aortic vessels involvement and more frequently a vessel wall thickening at diagnosis (78% vs. 62%, p=0.033). Among 318 TA patients, 16 (5%) died after a median follow-up of 6.1 years. The mean (±SD) age at death was 3825–47 years with 88% of women. Main causes of death included mesenteric ischemia (n=4, 25%), aortic aneurysm rupture (n=4, 25%), sudden death (n=3, 19%), septic shock (n=3, 19%), pulmonary embolism (n=1, 6%), and cardiogenic shock (n=1, 6%). One, five, and ten years’ overall survival were 98.9% [97.8–100], 98.1% [96.4–99.8], and 96.1% [93.4–98.9%], respectively. Factors associated with mortality were ethnic origin (White 9.5% vs. North Africa 7.1% vs. Black 0%, p=0.049), and tobacco smokers (10.8% vs. 4.2%, p=0.002). We define high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy) elaborated based on the multivariate model. The probability of death and complication free survival at five years was 78.4% (69.4–88.6) and 51.5% (38.3–69.2) (p=0.001) in the low risk and high risk group, respectively. Conclusions The overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. Caucasian and tobacco smokers were associated with mortality in TA. We developed a simple and useful prognosis score to identify patients at risk for vascular complication and death. Disclosure of Interest None declared

Background Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders, but the mechanisms responsible for HCV-associated autoimmunity are not well understood. Results Here we show that TLR9 stimulation of atypical memory (AtM) B cells from patients with HCV-associated cryoglobulinemia vasculitis induce the secretion of IFNγ, TNFα but not IL17A by CD4 + CD25 - effector T cells and stimulate their proliferation. Conversely, they reduce the proliferative capacity of CD4 + CD25 hi CD127 -/low FoxP3 + regulatory T cells. TLR9-stimulated AtM secrete TNFα and IgMs with rheumatoid factor activity. We identify a transcriptional signature specific of TLR9-stimulated AtM, centred on TNFα overexpression. AtM B-cell expansions display intraclonal diversity of mutated IgM with features of antigen-driven maturation. AtM-derived antibodies possess rheumatoid factor activity, with each antibody clone targeting a unique epitope on the human IgG Fc region. AtM antibodies are neither polyreactive nor reactive to ubiquitous autoantigens and importantly, not cross-reactive against HCV antigens including NS3 and E2 proteins. Conclusions These data strongly suggest a central role for AtM in defective tolerance of HCV-CV patients through TLR9 reactivation of anergic AtM and production of IgM antibodies with rheumatoid factor activity. Disclosure of Interest None declared

Background In small-size and short term studies of hepatitis C virus (HCV)-cryoglobulinemia vasculitis (CryoVas), direct antiviral agents (DAAs) showed a better response rate and tolerance than interferon containing regimens. Objectives To evaluate the effectiveness and tolerance of all oral interferon-free DAA in a large CryoVas cohort with long-term follow-up. Methods This prospective international multicenter cohort study included 148 symptomatic HCV-CryoVas patients (53.7% with cirrhosis and 49.3% antiviral-naive). They all received DAA, i.e. sofosbuvir (SOF) plus daclatasvir (n=53), SOF plus ribavirin (n=51), SOF plus ledipasvir (n=23), or SOF plus simeprevir (n=18), for 12 or 24 weeks. The primary endpoint was the clinical response of CryoVas symptoms at week 12 after stopping DAAs. Results 106 (72.6%) patients showed a complete response, 33 (22.6%) a partial response and 7 (4.8%) no response of CryoVas symptoms. Cryoglobulinemia was no longer found in 53.1%. A sustained virological response was obtained in 97.2%. Premature DAA withdrawal was noted in 4.1%. Two factors were associated with a poor response: a severe form of CryoVas [OR 0.33, 95% CI: 0.12 to 0.91; p=0.03] and peripheral neuropathy [OR 0.31, 95% CI: 0.11 to 0.84; p=0.02]. After a median follow-up of 15.3 months, 4 (2.8%) patients died. The final clearance rates of CryoVas manifestations were as follows: purpura (97.2%), renal involvement (91.5%), arthralgia (85.7%), neuropathy (77.1%) and cryoglobulinemia (53.8%). Only SOF plus ledipasvir regimen showed significant superiority [OR 4.09, 95% CI: 1.19 to 19.00; p=0.04]. Conclusions The different DAA combinations showed high response rates of HCV-CryoVas symptoms. The tolerance was good, and the mortality rate was very low. We identified prognosis factors of response to DAA. Disclosure of Interest P. Cacoub Consultant for: Janssen, BMS, Abbvie, GSK, Astra zeneka, Gilead, Merck, Roche, Servier, Vifor, S. N. Si ahmed Consultant for: BMS, Abbvie, Gilead, Roche, Janssen, Y. ferfar: None declared, S. Pol Consultant for: Sanofi, Novartis, Vertex, Boehringer, Janssen, BMS, Abbvie, GSK, Astra zeneka, Gilead, Merck, Roche, Servier, Vifor, D. Thabut: None declared, C. Hezode Consultant for: BMS, Merck, Abbvie, Gilead, Roche, Janssen, L. Alric Consultant for: BMS, Abbvie, Gilead, Janssen, Merck, C. Comarmond: None declared, G. Ragab: None declared, L. Quatuccio: None declared, M. Hegazy: None declared, T. Poynard: None declared, M. Resche Rigon: None declared, D. Saadoun Consultant for: medimmune, BMS, Abbvie, GSK, Astra zeneka, Gilead, Merck, Roche, Servier

Background Objectives We report the long term outcome of 46 TA patients treated with tocilizumab, describe the factors of response and compare the vascular event free survival to DMARDs. Methods retrospective nationwide french study Results We observed a decrease in the NIH scale; in C-reactive protein levels and in daily prednisone dose at 3 and 6 months, respectively; p Conclusions This nationwide study shows that tocilizumab may reduce the incidence of vascular complications in TA. Disclosure of Interest None declared

RésuméLes biothérapies utilisées dans le traitement des uvéites non infectieuses incluent l’interféron (IFN), les immunoglobulines intraveineuses (IgIV), ainsi que les anticorps monoclonaux et les protéines de fusion (anti-TNFα, anakinra, tocilizumab, rituximab). L’IFN permet d’induire une rémission prolongée, se maintenant après l’arrêt du traitement, chez 20 à 40 % des patients. Les effets secondaires (syndrome pseudo-grippal, effets psychiatriques) limitent son utilisation. Les anti-TNFα (infliximab, adalimumab) représentent une alternative thérapeutique attractive dans les uvéites sévères résistantes aux immunosuppresseurs, en particulier dans la maladie de Behçet. Ils sont efficaces la plupart du temps (>90 % des cas), et rapidement ; mais leur action est souvent suspensive. Les anti-TNFα sont utilisées de façon prolongée ou dans l’attente de l’efficacité d’un autre immunosuppresseur, une fois l’inflammation oculaire contrôlée. Les IgIV sont utilisées dans la maladie de Birdshot. Leur tolérance est bonne mais leur efficacité est transitoire. Le rituximab a montré son efficacité dans quelques observations d’inflammations oculaires variées (uvéites, sclérites et pseudo-tumeurs inflammatoires associées à la granulomatose avec polyangéite) ainsi que dans la pemphigoïde cicatricielle. Le risque d’infection limite son utilisation dans les maladies résistantes aux traitements conventionnels. L’anakinra (anti-IL1R) a montré des résultats intéressants en termes d’efficacité dans une petite étude ouverte sur la maladie de Behçet. Sa sécurité d’utilisation est bonne et son court délai d’action peut être intéressant pour le traitement des uvéites sévères.AbstractBiotherapies used in clinical practice for the treatment of uveitis include monoclonal antibodies and fusion proteins (anti-TNFα, anakinra, tocilizumab and rituximab), interferons (IFN) and intravenous immunoglobulins (IVIg). IFN is capable of inducing prolonged remission and continued after his discontinuation, in 20–40% of patients. Side effects (flu-like, psychological effects) limit its use in practice. Anti-TNFα (infliximab and adalimumab) represents an attractive alternative therapeutic in severe uveitis refractory to immunosuppressants, especially in Behçet's disease. They are generally (>90% of cases) and rapidly effective but their action is often suspensive. Anti-TNFα requires an extended prescription or takes over from another immunosuppressant once ocular inflammation has been controlled. IVIg are used for the treatment of Birdshot's disease. Tolerance of IVIg is good but their efficacy is transient. Rituximab showed an efficacy in few observations of various inflammatory eye diseases (uveitis, scleritis and idiopathic inflammatory pseudo-tumors or associated with granulomatosis with polyangiitis) and cicatricial pemphigoid. The risk of infection limits its use in refractory diseases to conventional therapy. Anakinra (a soluble antagonist of IL-1r) showed interesting results in terms of efficiency in one small open study in Behçet's disease. Its safety profile is good and with a quick action that could be interesting for the treatment of severe uveitis.

Cryoglobulinaemia refers to the serum presence of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures

Objectives To assess long term outcome and to elaborate a prognostic score for vascular complications in patients with Takayasu arteritis (TA). Methods Retrospective multicenter study of characteristics and outcome of 318 TA patients [86% of females; median age 36 [25–47] years; median follow-up of 6.1 years] fulfilling ACR and/or Ishikawa criteria. Factors associated with the event free survival (EFS), relapse free survival (RFS) and incidence of vascular complications were assessed. A prognostic score for vascular complications was elaborated based on a multivariate model. Results The 5- and 10-years event free survival (EFS), relapse free survival (RFS) and complication free survival were 48.2% (42.2;54.9) and 36.4% (30.3;43.9), 58.6% (52.7;65.1) and 47.7% (41.2;55.1), and 69.9% (64.3;76) and 53.7% (46.8;61.7), respectively. Progressive disease course (p=0.018) and carotidodynia (p=0.036) were independently associated with EFS. Male gender (p=0.048), elevated C reactive protein level (p=0.013), and carotidodynia (p=0.003) were associated with RFS. Progressive disease course (p=0.017), thoracic aorta involvement (p=0.009), and retinopathy (p=0.002) were associated with complication free survival. We define high risk patients for vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). The probability of complication free survival at five years was 78.4% (69.4;88.6) and 51.5% (38.3;69.2) in the low risk and high risk group, respectively. Conclusions This nationwide study shows that 50% of TA patients will relapse and experience a vascular complication at 10 years. We could define high risk TA patients for vascular complications. Disclosure of Interest None declared

Objectives Interferon-free direct-acting antiviral (DAA)-based therapy has proven to be very effective in patients with hepatitis C virus-cryoglobulinemia vasculitis (HCV-CV). However, their mechanisms of action and their effects on cellular immunity remain poorly defined. Methods 27 HCV-CV patients treated with DAA therapy, 12 healthy donors (HD) and 12 HCV were included. We investigated the effects of DAA-based therapy on cellular and cytokine abnormalities in HCV-CV patients by flow cytometry, cytokine Multiplex and enzyme-linked immunosorbent assay. Results Compared with HD and HCV, pre-DAA abnormalities in HCV-CV patients included a decreased percentage of CD4+CD25hiFoxP3+ regulatory T cells (P Conclusions Our results indicate that DAA-based therapy effectively normalizes many of the disturbances in peripheral B and T lymphocyte homeostasis of HCV-CV patients. Disclosure of Interest None declared

To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome.This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy.One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications.TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

Intravascular lymphoma (IVL) is a rare and usually fatal disease that belongs to the class of high-grade malignant lymphomas and which is characterized by proliferation of neoplastic lymphoid cells exclusively within the lumina of small blood vessels. Its polymorphic and nonspecific clinical manifestations make antemortem diagnosis very difficult. We report herein a case of IVL revealed by fatal, precapillary, pulmonary arterial hypertension and associated with long-lasting fever. Extensive investigation of the usual causes of pulmonary arterial hypertension was negative. The diagnosis of intravascular lymphoma was made on postmortem analysis, revealing diffuse and sometimes complete obliterations of the lumina of small blood vessels by large B-cell lymphoma, including pulmonary capillaries. Thus, we propose that IVL must be added to the spectrum of etiologies of subacute pulmonary arterial hypertension, notably in the context of associated fever, both entities requiring emergency diagnosis. For this purpose, blood collected via pulmonary capillary-wedge aspiration for cytologic examination may be associated with right-sided heart catheterization when this latter procedure is suitable.

Takayasu arteritis (TAK) is a large-vessel vasculitis that induces damage to the aorta and its branches. Glucocorticoids remain the gold standard of therapy for TAK. The nature of the T cells driving vascular inflammation and the effects of glucocorticoids on the systemic components of TAK are not understood. The aim of this study was to analyze T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta in patients with TAK.T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta were analyzed using Luminex analysis, flow cytometry, and immunohistochemical analysis. The study included 41 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK (17 patients with active TAK and 24 patients with disease in remission), 30 patients with giant cell arteritis and 39 patients with Behçet's disease (disease controls), and 20 age- and sex-matched healthy control subjects.We observed a marked increase in the expression of Th1 and Th17 cells, which correlated with TAK disease activity. The addition of serum from patients with active TAK to sorted CD4+ T cells from healthy donors in culture medium induced significant production of interferon-γ (IFNγ) and interleukin-17A (IL-17A). We demonstrated the presence of IFNγ-, IL-6-, and IL-17A-producing T cells in vascular inflammatory infiltrates in patients with TAK. Corticosteroid therapy was associated with decreased levels of circulating Th1 cytokines in corticosteroid-treated patients with TAK compared with steroid-free patients with TAK (for IL-2, mean ± SD 5,079 ± 5,300 versus 7,359 ± 3,197 pg/ml; for IFNγ, 2,592 ± 3,072 versus 8,393 ± 3,392 pg/ml; for tumor necrosis factor α, 847 ± 724 versus 1,491 ± 392 pg/ml). However, glucocorticoids had essentially no effect on the frequency of Th17 cytokines (IL-1 receptor, IL-17, and IL-23).The Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK. Glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK.

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public–private partnership funded within the European Commission’s Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.

Introduction : les series de sarcoidoses osseuses (SO) sont rares. Dans cette etude multicentrique, les caracteristiques cliniques, paracliniques, therapeutiques de la SO ont ete analysees. Materiel et Methodes : au sein d’une cohorte de 926 patients repondant aux criteres internationaux de sarcoidose, une atteinte osseuse a ete retenue dans 27 cas (2.9%), soit en presence de granulomes epithelioides sans necrose caseeuse lors de la biopsie osseuse, soit devant une imagerie osseuse concordant avec le diagnostic, apres elimination des diagnostics differentiels. Resultats : notre population est plutot masculine (59%) et caucasienne (56%). L’âge moyen au diagnostic de SO est de 42,8 ans. L’atteinte osseuse, au premier plan dans 56% des cas, n’est jamais isolee. Les localisations extra-osseuses predominantes sont les adenopathies mediastinales (93%), l’atteinte pulmonaire (78%), les adenopathies peripheriques (59%) et l’atteinte cutanee (52%). Le nombre moyen d’organes atteints est de 5,2. L’IRM est toujours pathologique (14/14). L’atteinte est unique dans 22% des cas et exclusivement axiale dans 52% des cas. Un tiers des patients a une biopsie osseuse positive. 9 patients ont recu un traitement pour raison osseuse, 8 une corticotherapie et tous au moins un immunomodulateur. La remission totale de la SO est notee seulement chez 30% de nos cas. L’osteite de Perthes-Jungling est significativement plus symptomatique (p

Hepatitis C virus (HCV) has been associated with the development of B-cell non-Hodgkin lymphomas. We recently reported the regression of splenic lymphoma with villous lymphocytes (SLVL) in patients with HCV after antiviral treatment, demonstrating a direct role of HCV in lymphomagenesis. This study expands our previous results in 18 patients with chronic HCV and SLVL. Mixed cryoglobulinemia (MC) was present in all cases and was symptomatic in 13 (72%). All patients were treated with interferon alone or in association with ribavirin. Hematologic and virologic responses were correlated. Fourteen (78%) patients achieved a sustained complete hematologic response after clearance of HCV RNA. Two patients had a virologic partial response and achieved a complete hematologic response. Two virologic nonresponders achieved partial hematologic response. Regardless of the response, monoclonal immunoglobulin gene rearrangement persisted after treatment. This study underscores the role of HCV in the lymphomagenesis and the benefit of antiviral treatment for patients presenting with HCV-driven lymphoproliferations.

Primary Sjögren's syndrome (SS) is an autoimmune disease associated with a high risk of developing non-Hodgkin's lymphoma. This study was undertaken to determine the nature of B cells driving lymphoproliferation in primary SS.B cell subsets and function were analyzed in peripheral blood from 66 adult patients with primary SS (including 14 patients with B cell lymphoproliferative disease [LPD]) and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. The reactivity of recombinant antibodies isolated from single B cells from patients with primary SS and LPD was tested using an enzyme-linked immunosorbent assay.We observed an expansion of an unusual CD21-/low B cell population that correlated with lymphoproliferation in patients with primary SS. A majority of CD21-/low B cells from patients with primary SS expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment, since their Ig genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21-/low B cells from patients with primary SS remained responsive to Toll-like receptor (TLR) stimulation. Molecules specifically expressed in CD21-/low B cells that are likely to induce their unresponsive stage were detected in gene array analyses.Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible to developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

Objective To investigate the efficacy and tolerance of azathioprine in severe uveitis related to Behcet's disease (BD). Methods We reported 157 consecutive patients with severe uveitis (active posterior uveitis or panuveitis) fulfilling the international criteria for BD and treated with corticosteroids (0.5–1 mg/kg/day) and azathioprine (2.5 mg/kg/day). Long-term outcome and factors associated with complete remission were assessed. Results Mean ± SD age at diagnosis was 29.9 ± 10.1 years, with 71.3% men. At baseline, 59 patients (37.6%) had loss of useful vision, 54 (34.4%) had retinal vasculitis, 66 (42.0%) had panuveitis, and 132 (84.1%) had bilateral uveitis. Following azathioprine therapy, 81 patients (51.6%) were complete responders, 65 (41.4%) were partial responders, and 11 (7%) were nonresponders. The visual acuity significantly improved (P < 0.001), and a significant decrease in the mean oral prednisone dosage (55.3 to 10.5 mg/day; P < 0.001) was observed after therapy. Patients with retinal vasculitis (odds ratio [OR] 0.45 [95% confidence interval (95% CI) 0.2–0.9], P = 0.02) and severe visual loss (OR 0.28 [95% CI 0.2–0.7], P < 0.0001) at diagnosis were less likely to be complete responders. Azathioprine was well tolerated, with only 3 withdrawals due to hepatotoxic effects (n = 2) and bacterial septicemia (n = 1). Conclusion Azathioprine represents an effective and safe therapy in patients with severe uveitis of BD.

Objective To analyze the main characteristics and outcome of polyarteritis nodosa (PAN)–type vasculitis associated with hepatitis C virus (HCV). Methods We reported the characteristics and outcome of 31 patients chronically infected with HCV who satisfied the American College of Rheumatology and Chapel Hill criteria for PAN, seen between 1990 and 2009 in a university center. Results Among a cohort of 161 patients with HCV-related vasculitis, 31 (19.3%) were diagnosed as having PAN. The median age was 64.5 years (interquartile range 49.5–70.5 years), with 54.8% women. Compared with HCV-associated mixed cryoglobulinemia (HCV-MC) vasculitis, HCV-PAN displayed a more severe and acute clinical presentation with more frequent fever and weight loss (P < 0.0001), severe hypertension (P = 0.0006), gastrointestinal tract involvement (P < 0.0001), severe acute sensory-motor multifocal mononeuropathy (P < 0.0001), kidney and liver microaneurysms (P = 0.002), and increased C-reactive protein level (P < 0.0001). Complete clinical remission of vasculitis was achieved in 79.3% of HCV-PAN patients compared to 57.5% of HCV-MC patients (P = 0.05). In multivariate analysis, skin involvement (odds ratio [OR] 2.81, 95% confidence interval [95% CI] 1.27–6.33) and PAN-type vasculitis (OR 3.01, 95% CI 1.16–8.96) were independently associated with a complete clinical response of HCV vasculitis. A glomerular filtration rate

Objectives Inflammatory idiopathic myopathies (IIM) are a heterogeneous group of disorders, ranging from a muscle-specific autoimmune disease to a systemic one that are difficult to assess. Recent insights into IIM pathogenesis highlighted the role of interferon (IFN) in the pathophysiology. The aim of this study was to test if IFN serum levels can a use as a biomarker of disease activity in IIM. Methods IFN type I and II were measured using an ultrasensitive detection technology and assess the potential of IFN. Results One hundred and fifty-two patients (dermatomyositis (DM); n=50, anti-synthetase syndrome (ASyS); n=46, immune-mediated necrotizing myopathy (IMNM); n=32, inclusion body myositis (IBM); n=24) and 33 age-matched healthy donors were included. IFN-α levels were higher only in DM (0.07 pg/ml [0.03-0.23], p