Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Intravenous versus subcutaneous tocilizumab in Takayasu arteritis: multicentre retrospective study.

OBJECTIVES: In this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients. METHODS: We conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019. RESULTS: A total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034). During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR=2.55, 95% CI 1.08 to 6.02; p=0.033). The overall cumulative incidence of relapse at 12 months in TAK patients was at 13.7% (95% CI 7.6% to 21.5%), with 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab. Adverse events occurred in 14 (15%) patients on intravenous route and in 2 (11%) on SC tocilizumab. CONCLUSION: In this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of disease-modifying antirheumatic drugs-refractory TAK patients at 6 months.

JAK inhibitors in difficult-to-treat adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis.

OBJECTIVES: Excessive and inappropriate production of pro-inflammatory cytokines plays a key role in Still's disease. Janus kinase inhibitor (JAKi) agents mainly block pro-inflammatory cytokine pathways, notably IL-6 and IFN. The objective was to assess the efficacy and safety of JAKi agents in difficult-to-treat systemic JIA or adult-onset Still's disease (AOSD). METHODS: This retrospective study was based on a national survey conducted in the departments of rheumatology, paediatric rheumatology and internal medicine of French hospitals regarding systemic JIA and AOSD patients who received JAKi agents. The data were collected with a standardized questionnaire and analysed at different times (treatment initiation, months 1, 3 and 6 and the end of follow-up). RESULTS: Nine patients (seven adults) were included. All patients showed inadequate response to CS or conventional synthetic or biologic DMARDs. Baricitinib was used in five patients, ruxolitinib in two, tofacitinib in two and upadacitinib in one. A JAKi was used combined with CS in all but two patients. A JAKi was associated with anakinra and CS in one patient, and with MTX, anakinra and CS in another. The median (range) follow-up was 16 (1-33) months. Two cases out of nine showed complete remission, 3/9 partial response and 4/9 treatment failure. At the last visit, CS could be decreased but not stopped. Tolerance of the JAKi was acceptable (no severe adverse events). CONCLUSION: JAKi agents may be a therapeutic option for some patients with difficult-to-treat Still's disease, especially those with partial response to medium- or high-dose CS or biologics.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Perioperative Doppler ultrasound assessment of portal vein flow pulsatility in high-risk cardiac surgery patients: a multicentre prospective cohort study.

BACKGROUND: Portal vein Doppler ultrasound pulsatility measured by transoesophageal echocardiography is a marker of the haemodynamic impact of venous congestion in cardiac surgery. We investigated whether the presence of abnormal portal vein flow pulsatility is associated with a longer duration of invasive life support and postoperative complications in high-risk patients. METHODS: In this multicentre cohort study, pulsed-wave Doppler ultrasound assessments of portal vein flow were performed during anaesthesia before initiation of cardiopulmonary bypass (before CPB) and after separation of cardiopulmonary bypass (after CPB). Abnormal pulsatility was defined as portal pulsatility fraction (PPF) ≥50% (PPF50). The primary outcome was the cumulative time in perioperative organ dysfunction (TPOD) requiring invasive life support during 28 days. Secondary outcomes included major postoperative complications. RESULTS: 373 patients, 71 (22.0%) had PPF50 before CPB and 77 (24.9%) after CPB. PPF50 was associated with longer duration of TPOD (median [inter-quartile range]; before CPB: 27 h [11-72] vs 19 h [8.5-42], P=0.02; after CPB: 27 h [11-61] vs 20 h [8-42], P=0.006). After adjusting for confounders, PPF50 before CPB showed significant association with TPOD. PPF50 after CPB was associated with a higher rate of major postoperative complications (36.4% vs 20.3%, P=0.006). CONCLUSIONS: Abnormal portal vein flow pulsatility before cardiopulmonary bypass was associated with longer duration of life support therapy after cardiac surgery in high-risk patients. Abnormal portal vein flow pulsatility after cardiopulmonary bypass separation was associated with a higher risk of major postoperative complications although this association was not independent of other factors. CLINICAL TRIAL REGISTRATION: NCT03656263.

Clinical impact and prognosis of cryoglobulinemia and cryofibrinogenemia in systemic sclerosis.

INTRODUCTION: An association of systemic sclerosis (SSc) with cryoglobulin and/or cryofibrinogenemia has been described. However, clinical, biological, morphological and prognostic implications are unknown. The objective of this study was to describe the phenotype and evaluate the prognosis of cryoglobulinemia and/or cryofibrinogenemia in the progression of SSc. MATERIALS AND METHODS: Patients were included from the Systemic Scleroderma Toulouse Cohort (SSTC), between June 1, 2005 and May 31, 2018, and underwent a measurement of a cryoglobulin and/or cryofibrinogen in immunology laboratory at the Toulouse University Hospital Center. Patients with and without cryoglobulinemia >50 mg/l and patients with and without cryofibrinogenemia were compared to identified the impact of cryoprcipitate on the phenotype. Mortality based on cryoprecipitate was explored. RESULTS: 166 patients were included in the study. 43.3% and 46.6% had a cryoglobulinemia >50 mg/l and cryofibrinogenemia, respectively. Cryoglobulin >50 mg was not associated with microvascular damage. Cryoglobulin does not influence the phenotype. 5-and 10-years survival were 97.6% and 88.8% respectively in patients with cryoglobulinemia >50 mg/l versus 91.9% and 78.4% in patients without cryoglobulin>50 mg/l. 10-years survival was better for patients with cryoglobulinemia >50 mg/l (log-rank 0.0363). Cryofibrinogenemia was not associated with neoplasia, any clinical (in particular ischemic damage), biological or morphological features. Cryofibrinogenemia had no influence on the mortality of these patients. CONCLUSION: Cryoglobulinemia and cryofibrinogenemia are frequent in SSc. The presence of cryoprecipitate (cryoglobulin or cryofibrinogen) not influence the phenotype and has not associated with a poor survival.

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.

Sine scleroderma, limited cutaneous, and diffused cutaneous systemic sclerosis survival and predictors of mortality.

BACKGROUND: Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature. OBJECTIVE: To determine the mortality and its predictors in a long-term follow-up of a bi-centric cohort of SSc patients. METHODS: A retrospective observational study by systematically analyzing the medical records of patients diagnosed with SSc in Toulouse University Hospital and Ducuing Hospital. Standardized Mortality Ratio (SMR), mortality at 1, 3, 5, 10, and 15 years of disease and causes of death were described. Predictors of mortality using Cox regression were assessed. RESULTS: Three hundred seventy-five patients were included: 63 with diffuse cutaneous SSc, 279 with limited cutaneous SSc, and 33 with sine scleroderma. The SMR ratio was 1.88 (95% CI 1.46-1.97). The overall survival rates were 97.6% at 1 year, 93.4% at 3 years, 87.1% at 5 years, 77.9% at 10 years, and 61.3% at 15 years. Sixty-nine deaths were recorded. 46.4% were SSc related deaths secondary to interstitial lung disease (ILD) (34.4%), pulmonary hypertension (31.2%), and digestive tract involvement (18.8%). 53.6% were non-related to SSc: cardiovascular disorders (37.8%) and various infections (35.1%) largely distanced those from cancer (13.5%). Four significant independent predictive factors were identified: carbon monoxide diffusing capacity (DLCO) < 70% (HR=3.01; p=0.0053), C-reactive protein (CRP) >5 mg/l (HR=2.13; p=0.0174), cardiac involvement (HR=2.86; p=0.0012), and the fact of being male (HR=3.25; p=0.0004). CONCLUSION: Long-term data confirmed high mortality of SSc. Male sex, DLCO <70%, cardiac involvement, and CRP> 5mg/l were identified as independent predictors of mortality.

Presentation and Real-World Management of Giant Cell Arteritis (Artemis Study).

Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.

Daytime Variation of Clinical Outcome in Cardiac Surgery: A Propensity-Matched Cohort Study.

OBJECTIVE: The purpose of the present study was to investigate the hypothesis of a nychthemeral variation in the tolerance to ischemia and reperfusion injury in adult cardiac surgeries. DESIGN: Retrospective cohort study. SETTING: A single academic center. PARTICIPANTS: All patients undergoing nonemergent aortic valve replacement (AVR) ± coronary artery bypass graft between January 2012 and May 2018 were included. They were divided into two groups (morning and afternoon) according to the time of the day at the beginning of surgery. Propensity score matching estimated by multivariate logistic regression with a 1:1 matching ratio was performed to ensure that the two groups were comparable. This allowed obtaining 269 pairs, for a total of 538 patients. INTERVENTION: The objective of the study was to assess whether there were differences in perioperative and postoperative outcomes between the morning and the afternoon groups. RESULTS: There was no between-group difference in the primary composite endpoints, namely the occurrence of death, myocardial infarction, low cardiac output, and stroke during the 30 days following the surgery. Regarding cardiac biomarkers, there were no between-group differences for both postoperative evolution of troponin T plasma levels and the maximum postoperative troponin T plasma level. CONCLUSION: These results did not support the hypothesis that the timing of the surgery could influence the tolerance to ischemia and reperfusion injury, at least in patients undergoing nonemergent AVR or a combined AVR with coronary artery bypass graft.

Acute and Chronic Sarcoid Arthropathies: Characteristics and Treatments From a Retrospective Nationwide French Study.

Introduction: We aimed to analyze patients with acute and chronic joint involvements in sarcoidosis. Methods: This is a retrospective multicenter analysis of patients with proven sarcoidosis, as defined by clinical, radiological, and histological criteria, with at least one clinical and/or ultrasonographic synovitis. Results: Thirty-nine patients with sarcoid arthropathy were included, and among them 19 had acute sarcoidosis (Lofgren's syndrome). Joint involvement and DAS44-CRP were not significantly different in acute and chronic sarcoid arthropathies. Acute forms were more frequent than chronic sarcoid arthropathy in Caucasians, without any difference of sex or age between these 2 forms. Joint involvement was frequently more symmetrical in acute than chronic forms (100 vs. 70%; p < 0.05), with a more frequent involvement in wrists and ankles in acute forms, whereas the tender and swollen joint counts and the DAS44-CRP were similar between the 2 groups. Skin lesions were significantly more frequent in patients with acute forms [17 (89%) vs. 5 (25%); p < 0.05] and were erythema nodosum in all patients with Löfgren's syndrome and sarcoid skin lesions in those with chronic sarcoidosis. Among 20 patients with chronic sarcoidosis, treatment was used in 17 (85%) cases, and consisted in NSAIDs alone (n = 5; 25%), steroids alone (n = 5; 25%), hydroxychloroquine (n = 2; 20%), methotrexate (n = 3; 15%), and TNF inhibitors (n = 2; 10%). A complete/partial joint response was noted in 14 (70%) cases with a DAS44-CRP reduction of 2.07 [1.85-2.44] (from 3.13 [2.76-3.42] to 1.06 [0.9-1.17]; p < 0.05). Conclusion: Sarcoid arthropathies have different clinical phenotypes in acute and chronic forms and various treatment regimens such as hydroxychloroquine and methotrexate could be used in chronic forms.

When and How to Diagnose Fabry Disease in Clinical Pratice.

Fabry disease is a frequent lysosomal storage disorder secondary to the deficiency of alpha-galactosidase A enzyme. This X-linked genetic disease realizes progressive and systemic manifestations that affect both male and female. Fabry disease may present as "classical", as "late-onset" or "non-classical" forms. Symptoms and organ involvements of classical Fabry disease are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Other common symptoms are often poorly recognized, such as gastrointestinal or ear involvements. In classical Fabry disease, symptoms first appear during childhood or during teenage years in males, but later in females. Patients with non-classical or late-onset Fabry disease have delayed manifestations or a single-organ involvement. Diagnosis is therefore difficult when classical organ involvements are missing, in paucisymptomatic patients or in late-onset forms. Recognition of Fabry disease is important because effective treatments are available. They have to be prescribed early. In male, diagnosis is made with alpha-galactosidase A enzyme activity dosage in leukocyte, that is very low or null in classical forms and under 30 percent in late-onset forms. Diagnosis is more challenging in females who may express normal residual enzyme activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide are interesting, especially in females. In this review, we aimed to summarize main clinical manifestations of Fabry disease to know when to evoke Fabry disease and propose a practical diagnosis algorithm to know how to diagnose.