Impact of conventional and biological disease-modifying anti-rheumatic drugs on arterial lesions in Takayasu arteritis.

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.

Eosinophilic granulomatosis polyangiitis (EGPA) complicated with periaortitis, precipitating role of dupilumab? A case report a review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis that affects small size vessels. Only four cases of periaortitis associated with EGPA have been reported in the literature. We report the case of a 67-year-old woman with EGPA who developed periaortitis 11 months after the initiation of dupilumab for uncontrolled asthma with hypereosinophilia. Complete remission of the periaortitis, and of EGPA, was obtained after switching from dupilumab to mepolizumab combined with oral prednisone therapy. Dupilumab has been associated with hypereosinophilia, that is usually asymptomatic and transitory, but symptomatic cases including EGPA were exceptionally reported. Although causality has not yet been established, caution is advisable when prescribing dupilumab for uncontrolled asthma with features that might suggest EGPA.

Screening for Lung Cancer by Chest Computed Tomography During Thromboangiitis Obliterans.

Buerger's disease or thromboangiitis obliterans (TAO) is a non-atherosclerotic inflammatory arteritis strongly associated with smoking exposure. This tobacco use would expose patients to lung cancer. The French-speaking thoracic cancer intergroup recommends screening for lung cancer with a chest computed tomography (CT). Our study aims to evaluate lung cancer screening using chest CT during TAO. Ninety-seven TAO patients were included. The mean age of onset of TAO symptoms was 36.5 ± 10 years, and 73 (75%) were male. The mean follow-up was 8.5 ± 14 years. Overall, at least one chest CT was performed during follow-up in 32 (33%) patients. Twenty-three of the thirty-four (68%) patients who were over 50 at follow-up did not have a CT. An abnormality was found in 15 of the 32 (47%) patients who had a CT: lung nodules 6/15, lung mass 1/15, emphysema 6/15, and others 2. Two cases of lung adenocarcinoma were diagnosed. None died during 2 years follow-up. In conclusion, two-third of the TAO patients over 50 years of age did not receive the routine screening recommended in the general smoking population. Two cases of lung cancer have been diagnosed. Improving screening practices for lung cancer in this high-risk population is crucial.

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.

Behçet's Disease Uveitis.

Uveitis in Behçet's disease (BD) is frequent (40% of cases) and is a major cause of morbidity. The age of onset of uveitis is between 20 and 30 years. Ocular involvement includes anterior, posterior, or panuveitis. Uveitis may be the first sign of the disease in 20% of cases or it may appear 2 or 3 years after the first symptoms. Panuveitis is the most common presentation and is more commonly found in men. Bilateralization usually occurs on average 2 years after the first symptoms. The estimated risk of blindness at 5 years is 10-15%. BD uveitis has several ophthalmological features that distinguish it from other uveitis. The main goals in the management of patients are the rapid resolution of intraocular inflammation, the prevention of recurrent attacks, the achievement of complete remission, and the preservation of vision. Biologic therapies have changed the management of intraocular inflammation. The aim of this review is to provide an update to a previous article by our team on pathogenesis, diagnostic approaches, and the therapeutic strategy of BD uveitis.

Prognosis and long-term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients.

Type I cryoglobulinemia (CG) accounts for 10%-15% of all cryoglobulinemias and are exclusively seen in clonal proliferative hematologic conditions. In this multicenter nationwide cohort study, we analyzed the prognosis and long-term outcomes of 168 patients with type I CG (93 (55.4%) IgM and 75 [44.6%] IgG). Five- and 10-year event-free survivals (EFS) were 26.5% (95% CI 18.2%-38.4%) and 20.8% (95% CI 13.1%-33.1%), respectively. In multivariable analysis, factors associated with poorer EFS were renal involvement (HR: 2.42, 95% CI 1.41-4.17, p = .001) and IgG type I CG (HR: 1.96, 95% CI 1.13-3.33, p = 0.016), regardless of underlying hematological disorders. IgG type I CG patients had higher cumulative incidence of relapse (94.6% [95% CI 57.8%-99.4%] vs. 56.6% [95% CI 36.6%-72.4%], p = .0002) and death at 10 years (35.8% [19.8%-64.6%] vs. 71.3% [54.0%-94.2%], p = .01) as compared to IgM CG, respectively. Overall, complete response of type I CG at 6 months was 38.7%, with no significant difference between Igs isotypes. In conclusion, renal involvement and IgG CG were identified as independent poor prognostic factors of type I CG.

Neutrophil, NETs and Behçet's disease: A review.

Behçet's disease (BD) is a chronic systemic vasculitis characterized by recurrent oral and genital ulcers, skin lesions, articular, neurological, vascular and sight-threatening ocular inflammation. BD is thought to share both autoimmune and autoinflammatory disease features. BD is triggered by environmental factors such as infectious agents in genetically predisposed subjects. Neutrophils seem to play an instrumental role in BD and recent works regarding the role of neutrophils extracellular traps (NETs) provides new insight in the pathophysiology of BD and the mechanisms involved in immune thrombosis. This review provides a recent overview on the role of neutrophils and NETs in the pathogenesis of BD.

Reduction of Neutrophil Activation by Phosphodiesterase 4 Blockade in Behçet's Disease.

OBJECTIVE: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small-molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD. METHODS: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition. RESULTS: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up-regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis. CONCLUSION: We highlight key biologic effects of apremilast on neutrophils in BD.

Vascular Behçet's disease: a comparative study from Turkey and France.

OBJECTIVES: Vascular Behçet's disease (VBD) is a systemic vasculitis involving both arterial and venous vessels of all sizes and occurring in up to 40% of patients with BD. VBD is the main cause of mortality in BD. Although commonly seen around the Mediterranean region, comparative studies in VBD are lacking. We aimed to compare the course and therapeutic approaches of VBD in two large cohorts from Turkey and France. METHODS: We included 291 VBD patients (female/male:63/228, mean age: 41.2±11.3 years) who were followed up in the Department of Internal Medicine and Clinical Immunology at Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France (n=131) and Rheumatology Division of Marmara University School of Medicine, Istanbul, Turkey (n=160). All clinical and demographical data were acquired from patient charts retrospectively. RESULTS: Smoking, family history for BD, HLA-B*51 presence and pathergy positivity were significantly higher in Turkish patients (TR), while neurologic involvement was more prominent in the French (FR) group. After a median follow-up of 77 months, 562 vascular events occurred including 440 venous events, 115 arterial events and 7 cardiac thrombi. In 79 (29%) patients, first vascular event developed before BD diagnosis and for 77 (28%) of them, vascular involvement was the presenting sign of the disease. First relapse developed in 130 (44.7%) patients after median 24.5 (1-276) months of follow-up (TR: 46.3% (n=74), FR: 42.7% (n=56), p=0.56). Survival graph revealed that FR cohort has 1.64 times increased recurrent event risk compared to TR cohort (HR=1.64 (1.1-2.44), p=.014) and although did not reach to statistical significance, IS treatment after the first vascular event decreased further vascular events (HR= 0.66 (0.43-1.01, p=.057). CONCLUSIONS: Almost half of patients relapsed of VBD within 2 years after the first vascular event. Immunosuppressants decrease VBD relapses.

Interferon signature in giant cell arteritis aortitis.

OBJECTIVES: Molecular mechanisms underlying large-vessel involvement in giant cell arteritis (LV-GCA) are largely unknown. Herein, we explore the critical involvement of pro-inflammatory signaling pathways in both aorta and T cells from patients with LV-GCA. METHODS: We analyzed transcriptome and interferon gene signature in inflamed aortas from LV-GCA patients and compared them to non-inflammatory control aorta. Differential transcriptomic analyses of circulating CD4+ and CD8+ T cells were also performed between patients with active GCA (not under any immunosuppressants or corticosteroid doses higher than 10 mg/day by the time of blood collection) and healthy donors. Interferon-alpha serum levels were measured using ultra-sensitive technique (HD-X Simoa Planar Technology) in GCA patients according to disease activity status. RESULTS: Transcriptomic analyses revealed 1042, 1479 and 2075 significantly dysregulated genes for aortas, CD4+ and CD8+ cells from LV-GCA patients, respectively, as compared to controls. A great enrichment for pathways linked to interferons (type I, II and III), JAK/STAT signaling, cytokines and chemokines was seen across aortas and circulating T cells. A type I interferon signature was identified as significantly upregulated in the aorta of patients with LV-GCA, notably regarding EPSTI1 and IFI44L genes. STAT3 was significantly upregulated in both aorta and T cells and appeared as central in related gene networks from LV-GCA patients. Interferon-alpha serum levels were higher in patients with active GCA when compared to those in remission (0.024 vs. 0.011 pg/mL; p = 0.028). CONCLUSION: LV-GCA presents a clear type I interferon signature in aortas, which paves the way for tailored therapeutical targeting.

Brain Biopsy for Neurological Diseases of Unknown Etiology in Critically Ill Patients: Feasibility, Safety, and Diagnostic Yield.

OBJECTIVES: Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A French tertiary center. PATIENTS: All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04). CONCLUSIONS: Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.

Mast cells drive pathologic vascular lesions in Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response. OBJECTIVES: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK. METHODS: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis. RESULTS: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and α-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD. CONCLUSIONS: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis.

[Differences of characteristics and outcomes between cancer patients and patients with no active cancer hospitalised for a SARS-CoV-2 infection]. / Comparaison des caractéristiques et des pronostics des patients avec et sans cancer actif hospitalisés pour une infection à SARS-CoV-2.

BACKGROUND: Patients with solid cancer or haematologic malignancies have been considered to be more susceptible to SARS-CoV-2 infection and to more often develop severe complications. We aimed to compare the differences in clinical features and outcomes of COVID-19 patients with and without cancer. METHODS: This was a prospective observational cohort study of consecutive adult patients hospitalised in a COVID-19 unit at Pitié-Salpêtrière Hospital, Paris, France (NCT04320017). RESULTS: Among the 262 patients hospitalised in a medical ward during the pandemics with a confirmed COVID-19 diagnosis, 62 patients had cancer. Clinical presentation, comorbidities, and outcomes were similar between cancer and non-cancer patients. However, cancer patients were more likely to have been contaminated while being hospitalised. CONCLUSIONS: Oncologic and non-oncologic patients hospitalised for COVID-19 shared similar outcomes in terms of death, admission in intensive care, or thrombosis/bleeding. They should benefit from the same therapeutic strategy as the general population during the COVID-19 pandemic.

Women and Pregnancy in Thromboangiitis Obliterans.

Data regarding women and thromboangiitis obliterans (TAO) are conflicted, and a few cases of pregnancy have been described. We aimed to describe the interplay between TAO and pregnancies. Among 224 TAO patients, 22.8% were women. Demographic data, clinical manifestations, and outcomes were similar between men and women. Twenty-one (41.2%) women had 48 pregnancies. Thirty-six (75%) pregnancies with on term and complication free delivery occurred. None of the patients experienced a disease flare of TAO during pregnancy. TAO does not seem to affect pregnancy complications, and pregnancy does not seem to interfere with the course of TAO.

Alcohol consumption among French physicians: A cross-sectional study.

BACKGROUND: Data regarding French physicians' alcohol behaviours are scarce and most studies address this issue within the population of either medical students or residents. We aim to describe and assess the prevalence of hazardous alcohol consumption among French physicians. METHODS: A regional, cross-sectional, survey was conducted in 2018 using an online questionnaire among Parisian general practitioners and hospital doctors. Hazardous alcohol consumption was defined by an Alcohol Use Disorders Identification Test (AUDIT) score ≥ 8. Data were analysed in 2020. RESULTS: Five hundred fifteen physicians completed the survey: 108 general practitioners and 407 hospital physicians. The median age was 40 years [32-55] and 59 % were women. They considered their physical and mental health as average or bad in 10 % and 8% of cases, respectively. The prevalence of hazardous alcohol consumption was 12.6 %. Among the 65 physicians with hazardous alcohol consumption, 27 (41.5 %) did not considered it as risky and four (6.2 %) mentioned a potentially negative impact on patients' care. Factors independently associated with hazardous alcohol consumption were illegal drugs consumption (OR 4.62 [2.05-10.37]) and fixed term contract for hospital doctors (OR 2.69 [1.14-6.36]). CONCLUSIONS: The prevalence of hazardous alcohol consumption among French physicians was 12.6 %. Illegal substance users and fix-termed contract hospital doctors were more likely to have risky alcohol consumption. A large-scale national study would confirm the factors associated with hazardous alcohol consumption and could explore the efficacy of preventive measures to insure the safety and health of physicians and their patients.