Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19.

In patients with severe #COVID19, increased levels of autoantibodies against PAR1 were found. These might serve as allosteric agonists of PAR1 on endothelial cells and platelets, and thus might contribute to the pathogenesis of microthrombosis in COVID-19. https://bit.ly/3pqM9Vv.

Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Immune perturbation is a hallmark of Coronavirus Disease 2019 (COVID-19) with ambiguous roles of various immune cell compartments. Plasma cells, responsible for antibody production, have a two-pronged response while mounting an immune defence with 1) physiological immune response producing neutralizing antibodies against protein structures of SARS-CoV-2 and 2) potentially deleterious autoantibody generation. Growing evidence hints towards broad activation of plasma cells and the presence of pathologic autoantibodies (abs) that mediate immune perturbation in acute COVID-19 [1]. Recently, a systematic screening for abs confirmed induction of diverse functional abs in SARS-CoV-2 infection, targeting several immunomodulatory proteins, including cytokines/chemokines and their respective G-protein coupled receptors (GPCR) [1]. Abs against GPCR act as agonistic and allosteric receptor modulators and are linked to chronic inflammatory diseases [2] and, as we recently demonstrated, disease severity in acute COVID-19 [3].

Do patients with rheumatoid arthritis show a different course of COVID-19 compared to patients with spondyloarthritis?

OBJECTIVES: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the most common inflammatory rheumatic diseases (IRD). The aim of this study was to elucidate differences in the outcome of SARS-CoV-2 infection in RA- and SpA-patients. METHODS: Data from the German COVID-19 registry for IRD patients from 30th March to 16th November 2020 were analysed. 208 RA and SpA patients were included in the study, matched for gender and age. RESULTS: 104 SpA patients (40% patients with ankylosing spondylitis, 54% with psoriatic arthritis and 6% with enteropathic arthritis) were compared to 104 RA patients. For both groups, median age was 56 years. TNF-i treatment was reported in 45% of the SpA and in 19% of RA patients (p=0.001). Glucocorticoids were used in 13% of the SpA and in 40% of the RA patients (p=0.001). In both groups, the majority of the patients (97% SpA, 95% RA) recovered from COVID-19. Hospitalisation was needed in 16% of the SpA and in 30% of the RA patients (p=0.05), and oxygen treatment in 10% and 18% respectively (p=ns). Three versus six (p=ns) fatal courses were reported in the SpA versus the RA group. CONCLUSIONS: The study revealed that the hospitalisation rate during COVID-19 infection, but not the mortality, was significantly higher in RA as compared to SpA patients. This could be explained either by different treatment strategies or by different susceptibilities of the two diseases.

SARS-CoV-2 Infection and COVID-19 Outcomes in Rheumatic Diseases: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: The relative risk of SARS-CoV-2 infection and COVID-19 disease severity among people with rheumatic and musculoskeletal diseases (RMDs) compared to those without RMDs is unclear. This study was undertaken to quantify the risk of SARS-CoV-2 infection in those with RMDs and describe clinical outcomes of COVID-19 in these patients. METHODS: We conducted a systematic literature review using 14 databases from January 1, 2019 to February 13, 2021. We included observational studies and experimental trials in RMD patients that described comparative rates of SARS-CoV-2 infection, hospitalization, oxygen supplementation/intensive care unit (ICU) admission/mechanical ventilation, or death attributed to COVID-19. Methodologic quality was evaluated using the Joanna Briggs Institute critical appraisal tools or the Newcastle-Ottawa scale. Risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated, as applicable for each outcome, using the Mantel-Haenszel formula with random effects models. RESULTS: Of the 5,799 abstracts screened, 100 studies met the criteria for inclusion in the systematic review, and 54 of 100 had a low risk of bias. Among the studies included in the meta-analyses, we identified an increased prevalence of SARS-CoV-2 infection in patients with an RMD (RR 1.53 [95% CI 1.16-2.01]) compared to the general population. The odds of hospitalization, ICU admission, and mechanical ventilation were similar in patients with and those without an RMD, whereas the mortality rate was increased in patients with RMDs (OR 1.74 [95% CI 1.08-2.80]). In a smaller number of studies, the adjusted risk of outcomes related to COVID-19 was assessed, and the results varied; some studies demonstrated an increased risk while other studies showed no difference in risk in patients with an RMD compared to those without an RMD. CONCLUSION: Patients with RMDs have higher rates of SARS-CoV-2 infection and an increased mortality rate.

Humoral protection to SARS-CoV2 declines faster in patients on TNF alpha blocking therapies.

BACKGROUND: The persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID. METHODS: 23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls. RESULTS: While anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected. CONCLUSION: Although the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

TNFi is associated with positive outcome, but JAKi and rituximab are associated with negative outcome of SARS-CoV-2 infection in patients with RMD.

INTRODUCTION: Several risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor. METHODS: Data from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model. RESULTS: 2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome. CONCLUSION: General risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity-even without glucocorticoids-have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.

Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.

BACKGROUND: We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. METHODS: From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. RESULTS: We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. CONCLUSION: Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort.

INTRODUCTION: In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. OBJECTIVE: Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. METHODS: 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. RESULTS: Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. CONCLUSION: We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.

Older age, comorbidity, glucocorticoid use and disease activity are risk factors for COVID-19 hospitalisation in patients with inflammatory rheumatic and musculoskeletal diseases.

INTRODUCTION: Whether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated. Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation. METHODS: Patients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated. Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19. RESULTS: Data from 468 patients with RMD with SARS-CoV-2 infection were reported. Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died. Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation. Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91). CONCLUSION: Age was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs. Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic.

National registry for patients with inflammatory rheumatic diseases (IRD) infected with SARS-CoV-2 in Germany (ReCoVery): a valuable mean to gain rapid and reliable knowledge of the clinical course of SARS-CoV-2 infections in patients with IRD.

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. METHODS: Using an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. RESULTS: Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. CONCLUSIONS: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.