Anti-SAE autoantibody in dermatomyositis: original comparative study and review of the literature.

OBJECTIVE: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM. METHODS: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature. RESULTS: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003). CONCLUSION: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.

Tocilizumab in Behçet Disease: A Multicenter Study of 30 Patients.

OBJECTIVE: To evaluate tocilizumab (TCZ) efficacy in patients with refractory Behçet disease (BD). METHODS: This is a multicenter study of 30 patients fulfilling the international criteria for BD and treated with TCZ at different European referral centers. The clinical response was evaluated at 6 months from TCZ initiation. RESULTS: Ninety percent of patients with BD were refractory or intolerant to anti-tumor necrosis factor (anti-TNF) agents. Overall, TCZ was effective in 25 (83%) patients with BD of whom 18 (60%) and 7 (23%) were complete and partial responders, respectively. The complete response was 67%, 60%, and 42% in patients with uveitis (18/30), neurological manifestations (5/30), and mucocutaneous and/or articular (7/30) manifestations, respectively. TCZ had a significant steroid-sparing effect allowing patients to decrease their median daily prednisone dose from 20 (IQR 10-40) mg/day to 9 (IQR 5-13) mg at 6 months (P < 0.001). The number of patients with BD needing concomitant disease-modifying antirheumatic drug therapy fell from 7 (23%) to 4 (13%) at 6 months. Mild to moderate side effects were observed in 6 (20%) patients, and 3 (10%) presented with serious adverse events (pneumonia, intestinal perforation, and septicemia) requiring therapy discontinuation in 2 cases. CONCLUSION: TCZ seems to be an effective alternative to anti-TNF agents in treating BD-related uveitis and neurological manifestations.

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.

Efficacy and safety of TNF-α antagonists and tocilizumab in Takayasu arteritis: multicentre retrospective study of 209 patients.

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.

Correlation between Ultra-Wide-Field Retinal Imaging Findings and Vascular Supra-Aortic Changes in Takayasu Arteritis.

(1) Background: Takayasu arteritis (TA) is a chronic inflammatory large-vessel vasculitis. Ultra-wide-field imaging allows describing the retinal lesions in these patients and correlating them with vascular supra-aortic stenosis. (2) Methods: In total, 54 eyes of 27 patients diagnosed with TA were included, and a complete ophthalmological examination was performed, including UWF color fundus photography (UWF-CFP), fluorescein angiography (UWF-FA), and computed tomography angiography measuring supra-aortic stenosis. Eleven patients underwent Doppler ultrasound imaging assessing the blood flow velocity (BFV) in the central retinal artery (CRA). (3) Results: Microaneurysms were detected in 18.5% of eyes on fundus examination, in 24.4% of eyes on UWF-CFP, and in 94.4% of eyes on UWF-FA. The number of microaneurysms significantly correlated with the presence of an ipsilateral supra-aortic stenosis (p = 0.026), the presence of hypertension (p = 0.0011), and the duration of the disease (p = 0.007). The number of microaneurysms per eye negatively correlated with the BFV in the CRA (r = -0.61; p = 0.003). (4) Conclusions: UWF-FA improved the assessment of TA-associated retinal findings. The significant correlation between the number of microaneurysms and the BFV in the CRA gives new insight to our understanding of Takayasu retinopathy. The total number of microaneurysms could be used as an interesting prognostic factor for TA.

Spectrum and Outcome of Noninfectious Aortitis.

OBJECTIVE: To assess the spectrum and long-term outcome of patients with noninfectious aortitis. METHODS: We 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. RESULTS: We 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. CONCLUSION: Noninfectious aortitis accounts for significant morbidity and mortality. CIA seems to carry the highest rate of vascular complications.

SARS-CoV-2 outbreak in immune-mediated inflammatory diseases: the Euro-COVIMID multicentre cross-sectional study.

BACKGROUND: The COVID-19 pandemic has raised numerous questions among patients with immune-mediated inflammatory diseases regarding potential reciprocal effects of COVID-19 and their underlying disease, and potential effects of immunomodulatory therapy on outcomes related to COVID-19. The seroprevalence of SARS-CoV-2 and factors associated with symptomatic COVID-19 in patients with immune-mediated inflammatory diseases are still unclear. The Euro-COVIMID study aimed to determine the serological and clinical prevalence of COVID-19 among patients with immune-mediated inflammatory diseases, as well as factors associated with COVID-19 occurrence and the impact of the pandemic in its management. METHODS: In this multicentre cross-sectional study, patients aged 18 years or older with a clinical diagnosis of rheumatoid arthritis, axial spondyloarthritis, systemic lupus erythematosus, Sjögren's syndrome, or giant cell arteritis were recruited from six tertiary referral centres in France, Germany, Italy, Portugal, Spain, and the UK. Demographics, comorbidities, treatments, and recent disease flares, as well as information on COVID-19 symptoms, were collected through a questionnaire completed by participants. SARS-CoV-2 serology was systematically tested. The main outcome was the serological and clinical prevalence of COVID-19. Factors associated with symptomatic COVID-19 were assessed by multivariable logistic regression, and incidence of recent disease flares, changes in treatments for underlying disease, and the reasons for treatment changes were also assessed. This study is registered with ClinicalTrials.gov, NCT04397237. FINDINGS: Between June 7 and Dec 8, 2020, 3136 patients with an immune-mediated inflammatory disease answered the questionnaire. 3028 patients (median age 58 years [IQR 46-67]; 2239 [73·9%] women and 789 [26·1%] men) with symptomatic COVID-19, serological data, or both were included in analyses. SARS-CoV-2 antibodies were detected in 166 (5·5% [95% CI 4·7-6·4]) of 3018 patients who had serology tests. Symptomatic COVID-19 occurred in 122 (4·0% [95% CI 3·4-4·8]) of 3028 patients, of whom 24 (19·7%) were admitted to hospital and four (3·3%) died. Factors associated with symptomatic COVID-19 were higher concentrations of C-reactive protein (odds ratio 1·18, 95% CI 1·05-1·33; p=0·0063), and higher numbers of recent disease flares (1·27, 1·02-1·58; p=0·030), whereas use of biological therapy was associated with reduced risk (0·51, 0·32-0·82; p=0·0057). At least one disease flare occurred in 654 (21·6%) of 3028 patients. Over the study period, 519 (20·6%) of 2514 patients had treatment changes, of which 125 (24·1%) were due to the pandemic. INTERPRETATION: This study provides key insights into the epidemiology and risk factors of COVID-19 among patients with immune-mediated inflammatory diseases. Overall, immunosuppressants do not seem to be deleterious in this scenario, and the control of inflammatory activity seems to be key when facing the pandemic. FUNDING: Pfizer, Sanofi, Amgen, Galapagos, and Lilly.

Medium- and Large-Vessel Vasculitis.

Systemic vasculitides are multisystem blood vessel disorders, which are defined by the size of the vessel predominantly affected, namely small, medium, or large vessels. The term "large vessel" relates to the aorta and its major branches; "medium vessel" refers to the main visceral arteries and veins and their initial branches. The most common causes of large-vessel vasculitis are giant cell arteritis and Takayasu arteritis, and those of medium-vessel arteritis are polyarteritis nodosa and Kawasaki disease. However, there is some overlap, and arteries of any size can potentially be involved in any of the 3 main categories of dominant vessel involvement. In addition to multisystem vasculitides, other forms of vasculitis have been defined, including single-organ vasculitis (eg, isolated aortitis). Prompt identification of vasculitides is important because they are associated with an increased risk of mortality. Left undiagnosed or mismanaged, these conditions may result in serious adverse outcomes that might otherwise have been avoided or minimized. The ethnic and regional differences in the incidence, prevalence, and clinical characteristics of patients with vasculitis should be recognized. Because the clinical presentation of vasculitis is highly variable, the cardiovascular clinician must have a high index of suspicion to establish a reliable and prompt diagnosis. This article reviews the pathophysiology, epidemiology, diagnostic strategies, and management of vasculitis.

Rituximab plus belimumab in non-infectious refractory cryoglobulinemia vasculitis: A pilot study.

OBJECTIVE: To report the efficacy of rituximab plus belimumab in patients with refractory cryoglobulinemia vasculitis (CV). METHODS: Belimumab was administered intravenously at a dose of 10 mg/kg on days 0, 14, 28 and then every month in association with rituximab in 4 patients with refractory CV. Demographic, clinical and laboratory characteristics, treatment modalities and outcomes were recorded. RESULTS: All patients had type II IgM Kappa cryoglobulinemia, which was associated with primary Sjögren syndrome (n = 1), hepatitis C virus infection (n = 1), and essential (n = 2). Main manifestations of CV included purpura (n = 4), arthralgia and peripheral neuropathy (n = 3), and glomerulonephritis and skin ulcers (n = 1). In all cases, CV was refractory and/or relapse following rituximab. Intravenous belimumab infusion along with rituximab resulted in rapid clinical response in the four patients. Osteitis and recurrent urinary tract infections occurred in two patients. CONCLUSION: Belimumab along with rituximab showed promising results in refractory patients with CV.

Performance of serum apolipoprotein-A1 as a sentinel of Covid-19.

BACKGROUND: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19. METHODS: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population. RESULTS: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04). CONCLUSION: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.

Relationship between change in physical activity and in clinical status in patients with idiopathic inflammatory myopathy: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the relationship between changes in clinical status on daily life physical activity (PA) in patients with idiopathic inflammatory myopathy (IIM). METHODS: Patients with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) or overlap myositis (OM) who presented either a new-onset or relapsing IIM, stable disease on maintenance therapy or were undergoing immunosuppressant tapering were included. Patients were evaluated at inclusion (V0), and at two follow-up visits (V1, 94±12 days from V0; V2, 96±17 days from V1). The American College of Rheumatology/European League against Rheumatism (ACR/EULAR) response criteria was recorded. PA assessed using 14-days raw accelerometry data gathered using a wrist-worn accelerometer after each visit (mean daily Euclidean norm minus 1 g (ENMO) was computed). RESULTS: Fifty-five patients (16 OM, 27 IMNM and 12 DM) were included. At baseline, 67% of patients had an ENMO Z-score less than 1. At inclusion, ENMO mainly correlated with health assessment questionnaire score (HAQ, ρ=-0.51, p<0.01), manual muscle testing 8 (MMT8, ρ=0.42, p<0.01), creatinine level (ρ=0.41, p<0.01), and SF-36 physical functioning score (ρ=0.38, p<0.002). At follow-up, ENMO changes mainly correlated with changes in MMT8, HAQ, SF-36 fatigue, and depression score (all ρ>0.43, all p<0.001). Level of agreement between ACR/EULAR response criteria and changes in PA was 15, 45, and 90% for minimal (n = 13), moderate (n = 20), and major (n = 10) improvements, respectively. CONCLUSION: Baseline PA levels and change in PA correlated with muscle strength and function, yet changes in PA were also influenced by psychological status. Only patients with major improvements on the ACR/EULAR criteria had significant increase in PA. Accelerometer may serve as an objective tool to define a clinically relevant real-life outcome.

Risk Factors and Prevention of Pneumocystis jirovecii Pneumonia in Patients With Autoimmune and Inflammatory Diseases.

Patients with autoimmune and/or inflammatory diseases (AIIDs) are prone to serious infectious complications such as Pneumocystis jirovecii pneumonia (PJP). In non-HIV patients, the prognosis is poorer, and diagnostic tests are of lower sensitivity. Given the low incidence of PJP in AIIDs, with the exception of granulomatosis with polyangiitis, and the non-negligible side effects of chemoprophylaxis, routine prescription of primary prophylaxis is still debated. Absolute peripheral lymphopenia, high doses of corticosteroids, combination with other immunosuppressive agents, and concomitant lung disease are strong predictors for the development of PJP and thus should warrant primary prophylaxis. Trimethoprim-sulfamethoxazole is considered first-line therapy and is the most extensively used drug for PJP prophylaxis. Nevertheless, it may expose patients to side effects. Effective alternative drugs such as atovaquone or aerosolized pentamidine could be used when trimethoprim-sulfamethoxazole is not tolerated or contraindicated. No standard guidelines are available to guide PJP prophylaxis in patients with AIIDs. This review covers the epidemiology, risk factors, and prevention of pneumocystis in the context of AIIDs.

Severe diffuse alveolar hemorrhage related to autoimmune disease: a multicenter study.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) occurs during the course of autoimmune disease and may be life threatening. The objective was to assess characteristics and prognosis factors of DAH who required intensive care unit (ICU) admission in patients with autoimmune diseases. METHODS: French multicenter retrospective study including patients presenting DAH related to autoimmune diseases requiring ICU admission from 2000 to 2016. RESULTS: One hundred four patients (54% of men) with median age of 56 [32-68] years were included with 79 (76%) systemic vasculitis and 25 (24%) connective tissue disorders. All patients received steroids, and 72 (69%), 12 (11.5%), and 57 (55%) patients had cyclophosphamide, rituximab, and plasma exchanges, respectively. During ICU stay, 52 (50%), 36 (35%), and 55 (53%) patients required mechanical ventilation, vasopressor use, and renal replacement therapy, respectively. Factors associated with mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96-0.99] per 10 years, p < 0.0001), vasculitis-related DAH (0.52 [0.27-0.98], p = 0.04), and time from dyspnea onset to ICU admission (0.99 [0.99-1] per day, p = 0.03). ICU mortality was 15%. Factors associated with alive status at ICU discharge were chronic cardiac failure (HR [95%CI] 0.37 [0.15-0.94], p = 0.04), antiphospholipid syndrome-related DAH (3.17 [1.89-5.32], p < 0.0001), SAPS II (0.98 [0.97-0.99], p = 0.007), and oxygen flow at ICU admission (0.95 [0.91-0.99] per liter/min, p = 0.04). CONCLUSION: DAH in autoimmune diseases is a life-threatening complication which requires mechanical ventilation in half of the cases admitted to ICU.