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Background: The definition of Takayasu arteritis (TAK) remission and disease activity is still unclear. Vascular imaging is an essential tool for following-up patients. Herein, we aimed to compare the evolution of vascular lesions (ie vessel wall thickening and stenosis) under conventional disease-modifying anti-rheumatic drugs (cDMARDs) relatively to biological DMARDs (bDMARDs) in TAK patients followed with the same CT angiography modalities., Method: We compared 75 lines of therapy in TAK patients who received cDMARDs (n = 40 lines) and bDMARDs (n = 35 lines) using CT angiography. We established 1-3 main target vessels with vessel wall thickening and/or stenosis. Every targeted vessel had its thickness and its lumen diameter measured at the initiation of immunosuppressive treatment and at 12 months., Results: We observed an overall reduction of arterial wall thickness in 73% of cases and 31% had >25% of wall thickness relative decrease. Using a linear mixed effects model, first line immunosuppressive therapy (p= 0.012) and bDMARDs relatively to cDMARDs (p= 0.026) were independently associated with vessel wall thickness reduction in TAK. Thirty-eight percent of the stenotic vessels had a > 25% relative increase in lumen diameter under immunosuppressive therapy. The relative increase >25% in lumen diameter was noted in 56% vs 17% with bDMARDs compared with cDMARDs., Conclusion: Immunosuppressive treatments can reduce arterial wall thickness and widen lumen diameter in TAK. bDMARDs seems to be more effective than cDMARDs to improve arterial lesions in TAK., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Summary: PICAFlow is a R-written integrative workflow dedicated to flow/mass cytometry data handling, from pre-processing to deep and comprehensive analysis. It is designed as a powerful all-in-one tool which contains all the necessary functions and packages presented in a user-friendly and ease-to-use fashion. PICAFlow also includes important features that are very frequently lacking in other close software, such as interactive R Shiny applications for real-time data transformation and compensation as well as normalization methods aiming to remove batch effects and unwanted inter- and intra-group heterogeneity. It also allows to perform dimensionality reduction, cell clustering (using different available approaches), as well as complementary statistical analyses and export different support for data interpretation and visualization., Availability: PICAFlow is available as a R-written package hosted at the following GitHub repository: https://github.com/PaulRegnier/PICAFlow and is complemented by a fully detailed tutorial available at the following URL: https://paul-regnier.fr/tutoriel-picaflow/., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Objectives: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach., Methods: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy., Results: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively., Conclusions: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK)., Methods: A total of 209 patients with TAK [median age 29 years (interquartile range 7-62)], 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; i.v. and s.c. in 95 and 26 cases, respectively]., Results: A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years [odds ratio 2.09 (95% CI 1.09, 3.99)] was associated with complete response, whereas vascular signs [OR 0.26 (95% CI 0.1, 0.65)], baseline prednisone ≥20 mg/day [OR 0.51 (95% CI 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 involvement [HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively] and systemic signs at baseline [HR 2.01 (95% CI 1.30, 3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies [37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively]., Conclusion: This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance., Methods: T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated., Results: Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells., Conclusion: There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the efficacy and safety of treatment modalities for major organ involvement of Behçet's syndrome (BS), in order to inform the update of the EULAR recommendations for the management of BS., Methods: A systematic literature review of all randomized controlled trials, controlled clinical trials, or open label trials assessing eye, vascular, nervous system or gastrointestinal system involvement of BS was performed. If controlled trials were not available for answering a specific research question, uncontrolled studies or case series were also included., Results: We reviewed the titles and abstracts of 3927 references and 161 studies met our inclusion criteria. There were only nine randomized controlled trials. Observational studies with IFN-α and monoclonal anti-TNF antibodies showed beneficial results for refractory uveitis. Meta-analysis of case-control studies showed that immunosuppressives decreased the recurrence rate of deep vein thrombosis significantly whereas anticoagulants did not. CYC and high dose glucocorticoids decreased mortality in pulmonary arterial aneurysms and postoperative complications in peripheral artery aneurysms. Beneficial results for gastrointestinal involvement were obtained with 5-ASA derivatives and AZA as first line treatment and with thalidomide and/or monoclonal anti-TNF antibodies in refractory cases. Observational studies for nervous system involvement showed improved outcome with immunosuppressives and glucocorticoids. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A., Conclusion: The majority of studies related to major organ involvement that informed the updated EULAR recommendations for the management of BS were observational studies.

Objectives: To assess the efficacy and safety of rituximab (RTX) in patients with Takayasu arteritis (TAK)., Methods: We conducted a retrospective study on seven TAK patients treated with RTX. Six of the seven patients had a disease refractory to high dose glucocorticoids and conventional immunosuppressive and/or biologic agents. One newly diagnosed, treatment-naïve TAK patient refused glucocorticoids and received RTX alone. Clinical evaluation, laboratory tests and imaging modalities (CT or MR-angiography, and 18F-fluorodeoxyglucose PET/CT) were performed at first RTX administration and every 6 months thereafter. Disease activity was assessed using the Kerr index. We also performed a literature review using PubMed, Ovid MEDLINE and Cochrane library., Results: Seven patients (6 females) were included in the study. Mean (s.d.) age was 32.4 (17.3) years. At first RTX administration, all patients had active disease according to the Kerr index (⩾2), and had also evidence of active disease at PET/CT. Despite RTX treatment, four of the seven patients had evidence of persistent disease activity and/or radiographic disease progression during follow-up. Three out of seven patients in whom RTX was employed as rescue therapy achieved complete remission. In the literature review, we identified five papers describing nine patients treated with RTX with good results in eight cases, but short follow-up., Conclusion: Our data do not support a role for RTX as first line biologic therapy in TAK patients, but it may have a role in some patients as second or third line biologic therapy., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease caused by the onset of rapidly progressive and widespread small-vessel thromboses in the presence of aPLs. The aim of this study was to examine pregnancy-related CAPS., Methods: Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the follow-up. RESULTS; Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10), aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3). No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up of 4.8 years (range 2-8 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre-eclampsia or eclampsia that occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was observed. Two mothers suddenly died 2.5 and 6 years after CAPS., Conclusion: The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum. Subsequent pregnancies are at very high risk.

Objective: Chronic HCV infection is associated with extra-hepatic manifestations. Recent studies have suggested an immunomodulatory role for vitamin D during HCV infection. We investigated the association between serum vitamin D status and the presence of HCV extra-hepatic manifestations., Methods: 25(OH)D serum levels were assessed in 94 HCV(+)RNA(+) patients [including 48 patients with mixed cryoglobulinaemia (MC) vasculitis]. Correlations between serum 25(OH)D levels and the presence of extra-hepatic manifestations of HCV infection were analysed., Results: Overall, 84 of 94 patients (89%) had hypovitaminosis D (≤30 ng/ml). Patients with vitamin D deficiency vs insufficiency vs sufficiency more frequently had systemic vasculitis (P = 0.02), in particular purpura (P = 0.006), detectable MC (P = 0.008) and low C4 serum levels (P = 0.006). Serum levels of 25(OH)D were also correlated with cryoglobulin and C4 levels and with marginal zone B cells and regulatory T cells. In multivariate analysis, the presence of MC and systemic vasculitis remained independently associated with low 25(OH)D levels., Conclusion: In chronic HCV infection, low 25(OH)D levels correlate with the presence of mixed cryoglobulinaemia and systemic vasculitis in chronic HCV infection. These findings suggest the potential multifaceted benefits of vitamin D supplementation in HCV-infected patients with extra-hepatic manifestations, but interventional studies are needed to confirm these data.

Objective: To describe the pseudotumoural presentation of neuro-Behçet's disease (NBD)., Methods: We report here the main characteristics, treatment and outcome of 23 patients (5 personal cases and 18 patients from the literature) with a pseudotumoural presentation of NBD. Pseudotumoural NBD patients were compared with 69 consecutive patients, with a classical form of NBD., Results: The median age was 39 (range 27-48 years) years, with a male predominance (65.2%). Clinical features of the pseudotumoural NBD included hemi- or tetra-pyramidal symptoms (n = 20), headache (n = 17), cerebellar syndrome (n = 3), sphincter impotence (n = 3) and pseudobulbar signs (n = 2). CNS imaging showed pseudotumoural lesions mainly in the capsulo-thalamic area (69.6 vs 11.6% for classical NBD; P < 0.01). Histological analysis revealed necrotic lesions with perivascular inflammatory infiltrate without signs of tumoural or infectious lesions. Patients with pseudotumoural NBD had more severe initial disability status (Rankin's score ≥3 in 65.2 vs 24.7%; P < 0.01) and had a 3 years' longer duration between neurological signs and BD diagnosis (P = 0.01) compared with patients with classical NBD. Treatment consisted of CSs (n = 21, 95.5%) and immunosuppressive agents (n = 10, 35.7%) that led to complete clinical and imaging remission in 60.9% of patients. Two (8.7%) of the 23 patients with pseudotumoural NBD died of bedridden state complications., Conclusion: The pseudotumoural form of NBD is a rare and life-threatening condition.

Background: Cryofibrinogenaemia (CryoFg) is an under-recognized cryoprotein that can be life-threatening when untreated. Symptoms are mainly thrombotic cutaneous manifestations, but other thrombotic localizations may occur. In patients with end-stage renal disease, thromboses are common. However, the implication of CryoFg was never assessed. The aim of this study is to describe the prevalence and the significance of CryoFg in patients with renal disorders., Methods: One hundred and one consecutive patients admitted in a nephrology department for the management of renal disorders were tested for the presence of serum cryoprotein, i.e. cryoglobulinaemia and CryoFg. We analysed clinical and biological factors associated with the presence of CryoFg., Results: Among the 101 patients, 11 patients had positive CryoFg without detectable cryoglobulin (11%). Median CryoFg level was 0.07 g/L (0.05-1.16). Main epidemiological features and causes of nephropathy, in particular vascular nephropathies, were similar between CryoFg- and CryoFg+ patients. No biological difference (haematuria, proteinuria, creatinine level and glomerular filtration rate using Modification of Diet in Renal Disease) was found between CryoFg- and CryoFg+ patients. In contrast, CryoFg+ compared to CryoFg- patients had more frequent severe thrombotic events (36 versus 0%, P < 0.0001). Severe thrombotic events included renal artery thrombosis in two patients, recurrent arteriovenous fistula thrombosis in one and recurrent dialysis catheter thrombosis with superior vena cava obstruction in one. The presence of CryoFg was not associated with other manifestations, in particular cutaneous manifestations., Conclusion: Cryofibrinogenaemia is detected in up to 11% of patients with renal disorders. In such patients, the presence of CryoFg is associated with thrombotic events.

Hepatitis C virus (HCV) infection is the second most cocmmon chronic viral infection in the world with a global prevalence of about 2%. Chronic HCV infection is commonly associated with a number of extrahepatic complications. Circulating mixed cryoglobulins (MCs) are detected in 40-60% of HCV-infected patients whereas overt cryoglobulinaemia vasculitis develops in only 5-10% of the cases. MC reflects the expansion of B cells producing a pathogenic IgM with rheumatoid factor (RF) activity. Because cryoglobulin-producing B cells in HCV are mostly monoclonal, HCV-associated MC can be viewed as a benign B cell lymphoproliferative condition. The disease expression of MC vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). The overall risk of non-Hodgkin's lymphoma in patients with HCV-MC is estimated to be 35 times higher than that in the general population. This review will focus on recent advances in our understanding of the clinical course, complications, pathophysiology and treatment of those immune-mediated disorders.

Objective: B lymphocyte stimulator (BLyS) is known to support B-cell proliferation (BCP) in B-cell haemopathies and autoimmune diseases. We assume that BLyS may play a role in the initiation and expression of hepatitis C virus (HCV)-associated BCP. We assessed BLyS serum levels in HCV-infected patients and in various forms of HCV-associated BCP [i.e. mixed cryoglobulin (MC), rheumatoid factor (RF) and systemic vasculitis]., Methods: A total of 76 HCV-infected patients (HCV RNA+) were compared with 13 healthy volunteers. Epidemiological, clinical, immunochemical and virological data were prospectively collected. BLyS serum levels were assessed by an ELISA sandwich method., Results: Of the 76 patients, 38 females, 38 males, mean age 53 +/- 15 yrs; 47 (62%) patients had type II (27 patients) or type III MC (20 patients); 27 (35.5%) patients had HCV-systemic vasculitis. BLyS serum levels tended to be higher in HCV-infected patients than in healthy controls (1.8 +/- 0.9 vs 1.5 +/- 0.2 ng/ml), were higher in patients with MC than without (2.03 +/- 1.02 vs 1.5 +/- 0.5 ng/ml; P = 0.008), and even higher in type II than type III MC (2.3 +/- 1.2 vs 1.7 +/- 0.6 ng/ml; P = 0.03). There was a correlation between BLyS and MC serum levels (R = 0.4; P = 0.004). BLyS serum levels were higher in patients with a positive RF than in those without (2.06 +/- 1.09 vs 1.6 +/- 0.56 ng/ml, P = 0.035), and with systemic vasculitis than in those without (2.24 +/- 1.16 vs 1.6 +/- 0.6 ng/ml; P = 0.006)., Conclusion: BLyS serum levels are significantly correlated with B-cell proliferation during chronic HCV infection. These results strongly suggest a role for BLyS in the induction and expression of HCV-BCP.

Autoantibodies against C1q have been described in many immune-complex diseases including hypocomplementaemic urticarial vasculitis and systemic lupus erythematosus (SLE). No study has focused on the role of anti-C1q antibodies in hepatitis C virus (HCV) infection. The aim of this study was (i) to evaluate the prevalence of anti-C1q antibodies in HCV infection; and (ii) to analyse the association of anti-C1q antibodies with clinical and biological features of HCV-mixed cryoglobulinaemia (MC) vasculitis. We searched for anti-C1q antibodies using an enzyme-linked immunosorbent assay (ELISA) test in 111 HCV patients (75 had cryoglobulin and 23 systemic vasculitis), 60 SLE patients and 109 blood donors. Anti-C1q antibodies were detected in 26% of HCV patients compared to 10% of healthy donors (P < 0.01), and 38% in patients with SLE. Although there was a higher prevalence of anti-C1q antibodies among HCV patients with type III cryoglobulin (50%, P < 0.01), the overall prevalence of anti-C1q antibodies was similar in HCV patients being cryoglobulin-positive or cryoglobulin-negative (26%versus 25%, P = 0.98). A significant association was found between anti-C1q antibodies and low C4 fraction of complement (P < 0.05). No association was found between anti-C1q antibodies and HCV genotype, severity of liver disease or with specific clinical signs of HCV-MC vasculitis. This study shows an increased prevalence of anti-C1q antibodies in HCV-infected patients. Anti-C1q antibodies were associated with low C4 levels. No association was found between anti-C1q antibodies and HCV-MC vasculitis, nor between anti-C1q antibodies and cryoglobulinaemia.