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Background Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancers. The risk factors and pathophysiological mechanisms of venous thromboembolic events (VTEs) of this new therapeutic class are still to be specified. Methods The included patients had to have cancer and should be treated with ICI. Data analyzed included demographic data, biological data, and immune-related adverse events (IRAEs). We studied the prevalence of VTEs and the factors associated with VTEs. Results Of 374 patients on ICI, over a median follow-up period of 15.2 months, the number of VTE was 50 (13.4%). The majority of patients were treated for metastatic melanoma or nonsmall cell lung cancer. There was no difference in prevalence or survival between cancer types. Patients with combined therapy composed of nivolumab and ipilimumab had higher 1-year cumulative VTE occurrence (29.3% [95% confidence interval [CI]: 9.7; 44.6]) than patients with pembrolizumab (14.9%, [95%CI: 2.5; 25.8], p = 0.03) or nivolumab (9.1%, [95% CI: 5.0; 12.9], p Conclusion The prevalence of VTE was 14.2% under ICIs. IRAE and combine treatment of nivolumab and ipilimumab were associated with VTE. The pathophysiological mechanisms are multiple and complex with a possible link to aberrant activation of the immune system.

International audience; Abstract Objective pulmonary arterial hypertension (PAH) is a leading cause of death in mixed connective tissue disease (MCTD). We aimed to describe PAH in well-characterized MCTD patients. Methods MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, systemic lupus erythematous (SLE) patients with PAH, and systemic sclerosis (SSc) patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. Results thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD), and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1 year, 5 years, and 10 years, following PAH diagnosis were 83%, 67%, and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. Conclusion PAH is a rare and severe complication of MCTD, associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia, and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as predictor of mortality in MCTD-PAH.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by skin fibrosis, vasculopathy, and dysimmunity. Data regarding osteitis in SSc are scarce.We performed a nationwide multicenter, retrospective, case-control study including patients with SSc, according to the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification, with a diagnosis of osteitis. The objectives of the study were to describe, to characterize, and to identify associated factors for osteitis in patients with SSc.Forty-eight patients were included. Twenty-six patients (54.1%) had osteitis beneath digital tip ulcers. Physical symptoms included pain (36 of 48, 75%), erythema (35 of 48, 73%), and local warmth (35 of 48, 73%). Thirty-one (65%) patients had median (interquartile range) C-reactive protein levels2 mg/liter of 8 (2.7-44.3) mg/liter. On radiography, computed tomography, or magnetic resonance imaging, osteitis was characterized by swelling or abscess of soft tissues, with acro-osteolysis or lysis in 28 patients (58%). Microbiological sampling was performed in 45 (94%) patients. Most pathogens were Staphylococcus aureus (43.8%), anaerobes and Enterobacteriaceae (29.1%), and Pseudomonas aeruginosa (10.4%). Management comprised antibiotics in 37 (77.1%) patients and/or surgery in 26 (54.2%). Fluoroquinolones were used in 22 (45.8%) patients, and amoxicillin plus β-lactamase inhibitor in 7 (14.6%). Six (12.6%) patients relapsed, 6 (12.6%) patients had osteitis recurrence, 15 (32%) sequelae, and 2 patients had septic shock and died.This study confirmed digital tip ulcers as an associated factor for osteitis and revealed a high rate of functional sequelae. Antimicrobial therapy with oral fluoroquinolone or intravenous amoxicillin and β-lactamase inhibitor are used as first-line antibiotic therapy in SSc patients with osteitis.

Explore trial participants’ and research team members’ perceptions of the impact of the videoconference-based, supportive care program (SPIN-CHAT Program) during early COVID-19 for individuals with systemic sclerosis (SSc). Data were collected cross-sectionally. A social constructivist paradigm was adopted, and one-on-one videoconference-based, semi-structured interviews were conducted with SPIN-CHAT Trial participants and research team members. A hybrid inductive-deductive approach and reflexive thematic analysis were used. Of the 40 SPIN-CHAT Trial participants and 28 research team members approached, 30 trial participants (Mean age = 54.9; SD = 13.0 years) and 22 research team members agreed to participate. Those who took part in interviews had similar characteristics to those who declined. Five themes were identified: (1) The SPIN-CHAT Program conferred a range of positive psychological health outcomes, (2) People who don’t have SSc don’t get it: The importance of SSc-specific programming, (3) The group-based format of the SPIN-CHAT Program created a safe space to connect and meet similar others, (4) The structure and schedule of the SPIN-CHAT Program reduced feelings of boredom and contributed to enhanced psychological health, (5) The necessity of knowledge, skills, and tools to self-manage SSc and navigate COVID-19. Participants’ and research team members’ perspectives elucidated SPIN-CHAT Program benefits and how these benefits may have been realized. Results underscore the importance of social support from similar others, structure, and self-management to enhance psychological health during COVID-19. clinicaltrials.gov (NCT04335279)IMPLICATIONS FOR REHABILITATIONThe videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis.SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health.Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted. The videoconference-based, supportive care SPIN-CHAT Program enhanced psychological health amongst individuals affected by systemic sclerosis. SPIN-CHAT Program participants and research team members shared that being around similar others, program structure, and self-management support were important and may have contributed to enhanced psychological health. Further efforts are required to explore experiences within supportive care programs to better understand if and how psychological health is impacted.

Resume Introduction L’hypertension arterielle pulmonaire (HTAP) est une complication grave des connectivites. Les donnees d’utilisation des prostanoides dans cette population sont peu nombreuses. L’objectif de cette etude etait de decrire les caracteristiques des patients traites par prostanoides dans cette indication, et de rapporter les donnees d’efficacite et de tolerance. Methodes Il s’agit d’une etude retrospective multicentrique. Les patients traites depuis 2006 ont ete identifies dans 5 centres hospitaliers. Les donnees concernant l’HTAP et la connectivite sous-jacente ont ete recueillies avant introduction des prostanoides et sous traitement. Resultats Vingt-et-un patients ont ete inclus, dont 20 (95 %) avaient une sclerodermie systemique cutanee limitee. Dix-neuf patients etaient traites par mono- ou bitherapie orale avant adjonction du prostanoide. Le treprostinil etait la molecule la plus utilisee (57 % des patients). A l’introduction du prostanoide, 19 patients (90 %) etaient consideres a haut risque de mortalite. Parmi les patients ayant eu un catheterisme cardiaque droit de reevaluation, il n’y avait pas de difference significative des parametres hemodynamiques par rapport a l’evaluation avant prostanoide. Aucune aggravation extrarespiratoire de la connectivite n’a ete constatee sous traitement. La survie a 1 an de l’introduction de prostanoide etait de 62 %. En analyse univariee, la classe fonctionnelle NYHA etait correlee a la survie sous traitement. Conclusion Cette etude presente des donnees originales d’utilisation des prostanoides dans une cohorte composee majoritairement de patients avec une sclerodermie systemique sous-jacente. Elle souligne la difficulte d’effectuer un suivi standardise sous traitement, chez des patients fragiles. La tolerance des prostanoides est superposable a celle rapportee dans l’HTAP idiopathique.

Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.govNCT04246528. Registered on 27 January 2020

Objective The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. Methods We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. Results Forty-three cases were included. IBD [mainly Crohn’s disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4–15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19–56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). Conclusions This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

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Objective The aim of the study was to describe clinical and biological characteristics and thrombotic relapses of patients diagnosed with antiphospholipid syndrome (APS) after the age of 65 years, in comparison with patients diagnosed with APS before 65. Methods This retrospective multicenter study was performed to 2005 from 2017 and included patients diagnosed with APS after the age of 65 years, in accordance with Sydney criteria. We compared these patients with APS patients diagnosed before the age of 65 years, and with control thrombotic patients older than 65 years. Results Fifty-eight APS patients over the age of 65 years were compared to 127 APS patients aged less than 65 and to 58 controls. In elderly APS versus younger APS, there was a male predominance (58.6% vs 36.2% p = .001); myocardial infarction and lower limb deep vein thrombosis (LLDVT) were more frequent in elderly, respectively, 12.1% versus 1.6% ( p = .005), and 44.8% versus 29.9% ( p = .048). Anticardiolipin antibody (aCL) IgM was more frequently found in old patients compared to younger patients (33.9% vs 18.1%, p = .02), contrary to lupus anticoagulant (LAC) (52.8% vs 66.9%, p = .02). Older patients were more often diagnosed with single positive APS (82.8% vs 59.8% p = .002). The thrombotic relapse free survival was lower in elderly APS patients ( p = .044) compared to younger APS. Elderly APS patients had more recurrent arterial and venous thrombosis ( p = .03) and had poorer overall survival ( p = .004) than elderly controls. Conclusion In this study, APS was different in patients aged more than 65 years, with a male predominance and more myocardial infarctions and LLDVT at diagnosis. Single antiphopholipid positivity and aCL IgM were more frequent in older patients. Older patient with APS had more thrombotic recurrence during follow-up. Compared to elderly controls, elderly APS patients had more thrombosis recurrences and poorer survival.

ObjectiveWhile myocardial impairment is a predictor of poor prognosis in antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), little is known about valvular involvement. This study aims at describing the clinical presentation, management, and outcome of endocarditis associated with AAV.MethodsWe conducted a multicenter retrospective study in centers affiliated with the French Vasculitis Study Group. We included patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or eosinophilic GPA with endocardial impairment. A systematic review was then performed through PubMed, Embase, and Cochrane Library from inception up to September 2020.ResultsThe retrospective cohort included 9 patients (82%) with GPA, 1 (9%) with MPA, and 1 (9%) with unclassified AAV. Clinical presentation included acute valvular insufficiency (n = 7, 64%), cardiac failure (n = 3, 27%), dyspnea (n = 3, 27%), and no symptoms (n = 2, 18%). The aortic valve was the most frequently affected (n = 8/10, 80%), and vegetations were noted in 4 of 10 patients (40%). Six patients (55%) underwent surgical valvular replacement. No death from endocarditis was reported. The systematic review retrieved 42 patients from 40 references: 30 (71%) had GPA, 21 (50%) presented with vegetations, the aortic valve (n = 26, 62%) was the most frequently involved. Valvular replacement was required in 20 cases (48%) and 5 patients (13%) died from the endocarditic impairment.ConclusionEndocarditis is a rare and potentially life-threatening manifestation of AAV. Acute valvular insufficiency may lead to urgent surgery. Implementing transthoracic echocardiography in standard assessment at baseline and follow-up of AAV might reduce the delay to diagnosis and allow earlier immunosuppressive treatment before surgery is needed.

Objectives GCA is a large vessel vasculitis for which triggering factors remain unknown. Clonal haematopoiesis (CH) was associated with atherosclerosis through the induction of inflammation in myeloid cells, and data suggest that CH expansion and inflammation may support each other to induce a pro-inflammatory loop. Our objective was to describe the impact of JAK2p.V617F-mutated myeloproliferative neoplasms (MPNs) on GCA and to screen MPN-free patients for CH mutations. Methods We performed a retrospective case–control study comparing the characteristics of 21 GCA patients with MPN and 42 age- and gender-matched GCA patients without MPN. Also, 18 GCA patients were screened for CH through next-generation sequencing (NGS). Results The most frequent associated MPN was essential thrombocythaemia (ET; n = 11). Compared with controls, GCA patients with MPN had less-frequent cephalic symptoms (71.4 vs 97.6%; P = 0.004) and higher platelet counts at baseline [485 × 109/l (interquartile range 346–586) vs 346 (296–418); P = 0.02]. There was no difference between groups for other clinical features. Overall survival was significantly shorter in patients with MPN compared with controls [hazard ratio 8.2 (95% CI 1.2, 56.6); P = 0.03]. Finally, screening for CH using NGS in 15 GCA patients without MPN revealed CH in 33%. Conclusion GCA patients with MPN display higher platelet counts and shorter overall survival than controls. This association is not fortuitous, given the possible pathophysiological relationship between the two diseases. CH was found in one-third of GCA patients, which may be higher than the expected prevalence for a similar age, and should be confirmed in a larger cohort.

Resume Introduction Le choix d’un traitement medicamenteux pour la sclerodermie systemique est oriente par des recommandations nationales et internationales. Le but principal de l’etude etait de decrire et d’analyser ces traitements chez nos patients. Nous avons egalement souhaite evaluer leur observance medicamenteuse. Methode Il s’agit d’une etude observationnelle monocentrique sur deux cohortes de patients atteints de sclerodermie systemique ; une cohorte principale comprenant des patients ambulatoires, inclus prospectivement, avec un recueil exhaustif des traitements ; et une cohorte secondaire avec recueil des donnees d’observance par autoquestionnaire. Resultats La cohorte principale a inclus 157 patients dont 31 cas de sclerodermie systemique diffuse. Un medicament vasodilatateur pour le phenomene de Raynaud etait prescrit chez 75 patients (47,9 %) et un traitement specifique de l’hypertension arterielle pulmonaire chez 10 patients (6,4 %). Les « immunomodulateurs/immunosuppresseurs » concernaient 62 patients (39,5 %), qui recevaient de la prednisone (n = 37, 23,6 %), du mycophenolate mofetil (n = 14, 8,9 %), de l’hydroxychloroquine (n = 12, 7,6 %) et de la colchicine (n = 22, 14 %). Un traitement pour l’atteinte digestive etait prescrit pour 106 patients (67,5 %) et un traitement d’une crise renale sclerodermique par inhibiteur de l’enzyme de conversion pour 6 patients (3,8 %). Parmi les 42 patients de la cohorte secondaire, 21,4 % rapportaient une bonne observance, notamment les plus âges (p = 0,045) ou ceux n’ayant pas experimente d’effets indesirables (p = 0,009). Conclusion Notre etude apporte des donnees originales de vraie vie qui illustre l’heterogeneite des habitudes de prescription dans la sclerodermie systemique. Comme cela a deja ete rapporte, l’observance medicamenteuse n’est pas satisfaisante.

Objective To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS). Methods A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments. Results Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p r = 0.47, p p Conclusions Rheumatic manifestations are very prevalent in SchS. However, bone pain can be misleading and contribute to misdiagnosis. Bone scan abnormalities are very prevalent and correlate with disease activity and treatments. IL1-Ra has a dramatic and durable efficacy but may not be required in every patient early on.

Objectives To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN). Methods A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease. Results Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8–50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases. Conclusion These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.

Objective Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort. Methods We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy. Results Sixty-three patients [27 women, median age 60 years (18–83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1–296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation. Conclusion Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.

Objectives This study aimed to examine the sensitivity of muscle biopsy (MB) in ANCA-associated vasculitis (AAV), identify factors predicting MB positivity and assess the prognostic value of a positive MB. Methods We conducted a single-centre retrospective study of AAV with an MB performed at diagnosis. AAV classification [granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA)] followed the European Medicines Agency algorithm. A logistic regression model was used to identify the factors associated with MB positivity. Survival curves were generated using the Kaplan–Meier method. Results Among 276 AAV patients (1995–2018), 101 had an MB. Seventy-eight patients were included: 33 with GPA, 25 with MPA and 20 with EGPA. MB samples were positive in 45 cases (58%): 17 GPA, 16 MPA and 12 EGPA. Univariate analysis focussed on GPA and MPA, revealed that the MB yield was higher in females [22/31 (71%) vs 11/27 (41%); P = 0.02] and in anti-MPO patients [25/37 (68%) vs 6/19 (32%) for anti-PR3; P = 0.01]. By multivariate analysis, three factors predicted MB positivity: anti-MPO ANCA [odds ratio (OR) 10.67 (CI 2.09, 81.68)], female sex [OR 5.3 (CI 1.16, 32.35)] and neutrophil count [OR 1.33 (CI 1.07, 1.8)]. MB positivity had no impact on relapse, death or end-stage renal disease–free survival. Conclusions MB is a safe and efficient diagnostic tool for AAV. Predictors of MB yield include ANCA type, sex and neutrophil count. MB cannot substitute for kidney biopsy when indicated, but should be considered in other cases.

Background Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Objective To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen. Design Randomized controlled trial. (ClinicalTrials.gov: NCT02433522). Setting 39 clinical centers in France. Patients 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy. Intervention Rituximab or placebo infusion every 6 months for 18 months (4 infusions). Measurements The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0. Results From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group. Limitation Potential selection bias based on previous rituximab response and tolerance. Conclusion Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy. Primary funding source French Ministry of Health and Hoffmann-La Roche.

ObjectiveThe randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter’s titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12.MethodsMAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV.ResultsAt M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV.ConclusionsWe were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.

International audience; Background: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. Objective: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. Methods: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy–associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. Results: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W– group). Cumulative probabilities of 10-year survival in W+ versus W– groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W– groups were 72% versus 58% (P = 0.3) and 2.5 (0.3–4) versus 1 (0–2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. Conclusions: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.

Aortic wall 18F-fluorodeoxyglucose (FDG)-uptake does not allow differentiation of aortitis from atheroma, which is problematic in clinical practice for diagnosing large vessel vasculitis giant-cell arteritis (GCA) in elderly patients. The purpose of this study was to compare the FDG uptake characteristics of GCA aortitis and aortic atheroma using positron emission tomography/FDG computed tomography (FDG-PET/CT). This study compared FDG aortic uptake between patients with GCA aortitis and patients with aortic atheroma; previously defined by contrast enhanced CT. Visual grading according to standardized FDG-PET/CT interpretation criteria and semi-quantitative analyses (maximum standardized uptake value (SUVmax), delta SUV (∆SUV), target to background ratios (TBR)) of FDG aortic uptake were conducted. The aorta was divided into 5 segments for analysis. 29 GCA aortitis and 66 aortic atheroma patients were included. A grade 3 FDG uptake of the aortic wall was identified for 23 (79.3%) GCA aortitis patients and none in the atheroma patient group (p max, ∆SUV and TBRs) were significantly higher in the aortitis group. ∆SUV was the feature with the largest differential between aortitis and aortic atheroma. In this study, GCA aortitis could be distinguished from an aortic atheroma by the presence of an aortic wall FDG uptake grade 3, an FDG uptake of the 5 aortic segments, and FDG uptake of the peripheral arteries.

Background: Giant cell arteritis (GCA) is the most common systemic vasculitis. Relapses are frequent. The aim of this study was to identify relapse risk factors in patients with GCA with complete large-vessel imaging at diagnosis. Methods: Patients with GCA followed in our institution between April 1998 and April 2018 were included retrospectively. We included only patients who had undergone large vascular imaging investigations at diagnosis by computed tomography (CT)-scan and/or positron emission tomography (PET)-scan and/or angio-magnetic resonance imaging (MRI). Clinical, biological, and radiological data were collected. Relapse was defined as the reappearance of GCA symptoms, with concomitant increase in inflammatory markers, requiring treatment adjustment. Relapsing patients (R) and non-relapsing patients (NR) were compared. Relapse and multiple relapses (>2) risk factors were identified in multivariable Cox analyses. Results: This study included 254 patients (73.2% women), with a median age of 72 years at diagnosis and a median follow up of 32.5 months. At diagnosis, 160 patients (63%) had an inflammatory large-vessel involvement on imaging, 46.1% (117 patients) relapsed at least once, and 21.3% (54 patients) had multiple relapses. The median delay of first relapse after diagnosis was 9 months. The second relapse delay was 21.5 months. NR patients had more stroke at diagnosis than R ( p = 0.03) and the brachiocephalic trunk was involved more frequently on CT-scan ( p = 0.046), as carotids ( p = 0.02) in R patients. Multivariate Cox model identified male gender [hazard ratio (HR): 0.51, confidence interval (CI) (0.27–0.96), p = 0.04] as a relapse protective factor, and peripheral musculoskeletal manifestations [HR: 1.74 (1.03–2.94), p = 0.004] as a relapse risk factor. Peripheral musculoskeletal manifestations [HR: 2.78 (1.23–6.28), p = 0.014], negative temporal artery biopsy [HR: 2.29 (1.18–4.45), p = 0.015], large-vessel involvement like upper limb ischemia [HR: 8.84 (2.48–31.56), p = 0.001] and inflammation of arm arteries on CT-scan [HR: 2.39 (1.02–5.58), p = 0.04] at diagnosis were risk factors of multiple relapses. Conclusion: Male gender was a protective factor for GCA relapse and peripheral musculoskeletal manifestations appeared as a relapsing risk factor. Moreover, this study identified a particular clinical phenotype of multi-relapsing patients with GCA, characterized by peripheral musculoskeletal manifestations, negative temporal artery biopsy, and large-vessel involvement with upper limb ischemia or inflammation of arm arteries. Plain language Summary At giant cell arteritis diagnosis, large-vessel inflammatory involvement is predictive of multiple relapses 46.1% of patients with GCA relapse, and 21.3% undergo multiple relapses; Male gender appears as a protective factor for relapsing in GCA; Peripheral musculoskeletal manifestations are a relapse and multiple relapses risk factor; A negative temporal artery biopsy is predictive of multiple relapses; Large-vessel involvement is predictive of multiple relapses.

Points essentiels Une aortite, definie par un epaississement parietal de l’aorte, est observee chez environ 50 % des patients ayant une arterite a cellules geantes (ACG). Des lesions structurales de l’aorte, ectasie ou anevrisme, peuvent survenir, avec ou sans aspect inflammatoire de l’aorte, parfois des le diagnostic d’ACG, mais le plus souvent au cours du suivi. La mise en evidence de l’atteinte aortique, a rechercher chez tout patient des le diagnostic d’ACG, repose sur une imagerie de l’aorte, angio-TDM, angio-IRM, ou TEP-TDM. Le pronostic de l’aortite et de ses complications reste mal connu, mais la mortalite liee aux evenements graves, rupture d’anevrisme ou dissection de l’aorte, pourrait potentiellement etre reduite par un diagnostic plus precoce et une surveillance reguliere. Le traitement de l’aortite de l’ACG repose sur la corticotherapie a forte dose, avec une dose d’attaque de prednisone de 0,7 mg/kg/j selon les recommandations du Groupe d’etude francais de l’arterite a cellules geantes (GEFA). Les ectasies et anevrismes de l’aorte sont a surveiller afin de poser l’indication d’une chirurgie aortique dans les meilleures conditions possibles.

Many factors can contribute to the risk of venous thrombosis observed in hemolytic diseases. Some mechanisms are related to hemolysis by itself, while others seem more specific to each disease. Despite recent advances in the quantification of this risk and in understanding its physiopathology, the association of hemolysis with venous thrombosis is often unknown. The purpose of this general review is to clarify the main pro-thrombotic mechanisms during hemolysis and to synthesize the clinical data currently available. We will focus on the main types of hemolytic pathologies encountered in current practice, namely paroxysmal nocturnal hemoglobinuria, hemoglobinopathies, auto-immune hemolytic anemia and thrombotic microangiopathies.

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

Background Thoracic multidetector computed tomography (MDCT) is essential for the detection of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). Thoracic MDCT assessment can reveal the presence of thoracic lymphadenopathies (LAP) whose signification remains uncertain. The purpose of the study was to describe the characteristics and to assess the significance of thoracic LAP in patients with diffuse SSc. Methods We conducted a monocentric observational study on adult patients with diffuse SSc, and collected general patient and first thoracic MDCT characteristics, PET-CT and outcome data. Comparisons were made between patients with and without thoracic LAP. Results Forty-eight patients were included. There were 30 patients (62.5%) with an ILD and 23 (48%) with at least one thoracic LAP on the first MDCT assessment. Median number per patient of thoracic LAP was 3 [1–8], with a mean size of 11.7 ± 1.7 mm, mainly located in right para-tracheal area (22.8% of the total number of LAP), right hilar area (20.3%), left hilar area (6.5%), and sub-carinal area (15.2%). PET-CT showed lymph node hypermetabolism in 11/15 patients (73.3%) with mean SUVmax at 4 ± 1.3. There were significantly more males (p = 0.002) and more patients exposed to silica (p = 0.001) in patients with thoracic LAP. ILD was significantly more extended according to Goh score (p = 0.03), and using semi-quantitative score for mixed ground-glass reticulation (p = 0.01) and global abnormalities (p = 0.03) in patients with thoracic LAP and ILD. Thirteen patients (27.1%) died during follow-up without significant difference according to the presence or not of thoracic LAP (p = 0.15). There was also no significant difference concerning immunosuppressive treatment initiation (p = 0.17). Conclusions Thoracic LAP are common in diffuse SSc and are generally multiple, not bulky, moderately hypermetabolic, and located at the base of the mediastinum lymph node chains. Their presence correlates with the extent of ILD. In absence of ILD, thoracic LAP presence seems to be often explained by silica exposure. Trial Registration: NA.

Summary Background Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjogren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclerodermie Quebec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

ObjectiveTo assess the spectrum and long-term outcome of patients with noninfectious aortitis.MethodsWe performed a retrospective multicenter study of 353 patients (median age at diagnosis was 62 [IQR 46–71] yrs and 242 [68.6%] patients were women) with noninfectious aortitis. Factors associated with vascular complications were assessed in multivariate analysis.ResultsWe included 136 patients with giant cell arteritis (GCA), 96 with Takayasu arteritis (TA), 73 with clinically isolated aortitis (CIA), and 48 with aortitis secondary to inflammatory diseases (including Behçet disease, relapsing polychondritis, IgG4-related disease, Cogan syndrome, ankylosing spondylitis). After a median follow-up of 52 months, vascular complications were observed in 32.3%, revascularizations in 30% of patients, and death in 7.6%. The 5-year cumulative incidence of vascular complications was 58% (95% CI 41–71), 20% (95% CI 13–29), and 19% (95% CI 11–28) in CIA, GCA, and TA, respectively. In multivariate analysis, male sex (HR 2.10, 95% CI 1.45–3.05, P < 0.0001) and CIA (HR 1.76, 95% CI 1.11–2.81, P = 0.02) were independently associated with vascular complications.ConclusionNoninfectious aortitis accounts for significant morbidity and mortality. CIA seems to carry the highest rate of vascular complications.

Background Systemic sclerosis (SSc) is a severe and highly heterogeneous disease. The modified Rodnan skin score (mRSS) is a widely used tool for the assessment of the extent and degree of skin thickness. This study aimed to identify the classes of patients with early similar skin thickening trajectories without any a priori assumptions and study their associations with organ involvement and survival. Methods From the French SSc national cohort, patients with a disease duration of less than 2 years at inclusion and with at least 2 mRSS available within the first 4 years of follow-up were enrolled. Classes of patients with similar mRSS trajectories were identified based on a latent class mixed model. The clinical characteristics and survival rate were compared between the obtained classes. Results A total of 198 patients fulfilled the inclusion criteria, with a total of 641 mRSS available. The median disease duration and follow-up were 0.8 (interquartile range 0.4; 1.2) and 6.3 (3.8; 8.9) years, respectively. Individual trajectories of mRSS were highly heterogeneous between patients. Models with 1–6 latent classes of trajectories were sequentially assessed, and the 5-class model represented the best fit to data. Each class was characterized by a unique global trajectory of mRSS. The median disease duration did not differ significantly between classes. Baseline organ involvement was more frequent in classes with significant change over time (classes 2–5) than in class 1 (low baseline mRSS without significant change over time). Using Cox regression, we observed a progressively increasing risk of death from classes 1 to 5. Conclusions Early identification of clinical phenotype based on skin thickening trajectories could predict morbi-mortality in SSc. This study suggested that mRSS trajectories characterization might be pivotal for clinical practice and future trial designs.

Introduction La tomodensitometrie (TDM) thoracique est un examen essentiel pour la detection d’une pneumopathie interstitielle diffuse (PID) dans le cadre de la sclerodermie systemique (ScS). Cependant, cet examen peut reveler des adenopathies mediastinales dont la signification reste incertaine dans cette maladie. Le but de cette etude etait de decrire les adenopathies mediastinales au cours de la ScS diffuse, et d’evaluer leurs determinants et impacts pronostiques. Patients et methodes Nous avons mene une etude retrospective observationnelle monocentrique sur des patients atteints de ScS de forme cutanee diffuse ayant eu au moins une TDM thoracique au cours de leur suivi. Nous avons recueilli les caracteristiques generales des patients et de la premiere TDM thoracique disponible, ainsi que les donnees de TEP-TDM et d’histologie d’adenopathie mediastinale lorsqu’elles etaient realisees. Nous avons egalement analyse la derniere TDM thoracique disponible et recueilli le devenir des patients (deces et/ou introduction d’un immunosuppresseur). Enfin, des analyses comparatives ont ete realisees entre les patients avec ou sans adenopathies mediastinales. Resultats Parmi les 48 patients inclus, 30 (62,5 %) presentaient une PID et 23 (48 %) avaient au moins une adenopathie mediastinale. Le nombre median d’adenopathies mediastinales par patient etait de 3 [1-8], avec une taille moyenne de 11,7 ± 1,7 mm, principalement situee dans la zone para-tracheale droite (22,8 % du nombre total d’adenopathies), la zone hilaire droite (20,3 %), et la zone sous-carinaire (15,2 %). La TEP-TDM montrait un hypermetabolisme des adenopathies mediastinales chez 11/15 patients (73,3 %) avec une SUVmax moyenne de 4 ± 1,3. L’analyse histologique disponible chez 5 patients n’a jamais decrit de granulome ni de cellules tumorales. Il y avait davantage d’hommes (p = 0,002) et d’exposition a la silice (p = 0,001) chez les patients ayant au moins une adenopathie mediastinale. La PID etait significativement plus etendue selon le score de Goh (p = 0,03), et en utilisant un score semi-quantitatif pour le mixte verre depoli-reticulations (p = 0,01) et les anomalies globales (p = 0,03) chez les patients ayant au moins une adenopathie mediastinale. Il n’y avait pas de difference concernant le nombre et la taille maximale des adenopathies mediastinales, ainsi que le score d’extension globale des PID entre la premiere et la derniere TDM thoracique. Dix patients (20,3 %) sont decedes et 37 patients (77,1 %) ont eu au moins un immunosuppresseur debute au cours du suivi, sans difference significative entre les patients avec ou sans adenopathies mediastinales. Conclusion Les adenopathies mediastinales sont frequentes dans la ScS diffuse et sont generalement multiples, non volumineuses, moderement hypermetaboliques, et situees a la base des chaines de ganglions lymphatiques mediastinaux. Aucun diagnostic de neoplasie ou de granulomatose n’a ete pose au cours du suivi. Bien que correlee a l’etendue de la PID, leur presence ne semble pas avoir de consequence en termes de devenir chez ces patients. En l’absence de PID, la presence d’adenopathies mediastinales semble souvent s’expliquer par l’exposition a la silice.