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International audience; Objective. To evaluate the impact of telemedicine use during the coronavirus disease 2019 (COVID-19) pandemic on rheumatology trainees. Methods. A voluntary, anonymous, web-based survey was administered in English, Spanish, or French from August 19 to October 5, 2020. Adult and pediatric rheumatology trainees were invited to participate via social media and email. Using multiple-choice questions and Likert scales, the survey assessed prior and current telemedicine use, impact on training, and supervision after COVID-19 prompted rapid telemedicine implementation. Results. Surveys were received from 302 trainees from 33 countries, with 83% in adult rheumatology training programs. Reported telemedicine use increased from 13% before the pandemic to 82% during the pandemic. United States trainees predominantly used video visits, whereas outside the United States telemedicine was predominantly audio only. Most (65%) evaluated new patients using telemedicine. More respondents were comfortable using telemedicine for follow-up patients (69%) than for new patients (25%). Only 39% of respondents reported receiving telemedicine-focused training, including instruction on software, clinical skills, and billing, whereas more than half of United States trainees (59%) had training. Postconsultation verbal discussion was the most frequent form of supervision; 24% reported no supervision. Trainees found that telemedicine negatively impacted supervision (50%) and the quality of clinical teaching received (70%), with only 9% reporting a positive impact. Conclusions. Despite widespread uptake of telemedicine, a low proportion of trainees received telemedicine training, and many lacked comfort in evaluating patients, particularly new patients. Inadequate supervision and clinical teaching were areas of concern. If telemedicine remains in widespread use, ensuring appropriate trainee supervision and teaching should be prioritized. No funding was received for this study. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European League Against Rheumatism, or any other organization.

Background: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjogren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.

Introduction Several months into the COVID-19 pandemic, safe and effective treatments against this global health disaster have yet to be identified. Clinical research trials around the world are underway testing a wide array of possible medications. In particular, the off-label use of hydroxychloroquine for COVID-19 prophylaxis and treatment has created many unprecedented challenges for the scientific community and the public. Areas covered We critically assessed major events from February – May 2020 that contributed to widespread use of hydroxychloroquine for the treatment and prophylaxis of COVID-19. We aimed to explore how opinions toward hydroxychloroquine may shift from early enthusiasm (based on in vitro and preliminary clinical data) to the hope for a miracle cure (through communication and promotion of questionable results) and, finally, to a rise of skepticism as more in-depth analyses are emerging. Expert opinion Mindful and rigorous acquisition of data, as well as its interpretation, are essential to an effective pandemic response. The rapid and premature promotion of results has had major implications for global crisis management, even creating distrust among the public. It is crucial for the medical and scientific community to incorporate the lessons learned from this situation.

We appreciate the interest of Lo et al in our opinion piece and thank them for the data presented in their letter.1 2 Several reports of QT prolongation and torsades de pointes in patients with COVID-19 receiving antimalarials have been published.3–5 These and other reports have indirectly raised questions regarding the arrhythmogenic potential of hydroxychloroquine (HCQ) when used to treat rheumatic disease. Lo et al used the unique resource of the National Health Insurance Research Database of Taiwan. Through propensity scores, they matched patients who used HCQ and who did not use HCQ for the treatment of newly diagnosed rheumatoid arthritis (RA). Data about other disease-modifying antirheumatic drugs used by the patients was not reported. Therefore, it is unclear if the groups were similar in their RA disease severity, although they seemed similar related to comorbidities. The authors did not find differences in the cumulative risk of arrhythmia between the two groups after 1 year of follow-up. However, a prior meta-analysis on reported cardiotoxic events of antimalarials found that cardiac conduction abnormalities were the most common cardiac adverse events and were associated with higher cumulative doses (median cumulative HCQ dose of 1235 g, …

Periodontal disease has been implicated in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease characterized by immune-mediated synovial damage, and antibodies to citrullinated antigens. Here, we investigate the association between exposure to the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the development of RA. IgM, IgG and IgA antibodies to Aa leukotoxin A (LtxA) were detected by ELISA in plasma from a cohort of Swedish adults at different stages of RA development, from before onset of symptoms to established disease. Patients with early and established RA had increased levels of anti-LtxA IgM compared with matched non-RA controls and periodontally healthy individuals. Logistic regression revealed that anti-LtxA IgM levels were associated with RA during early disease (OR 1.012, 95%CI 1.007, 1.017), which was maintained after adjustment for smoking, anti-CCP antibodies, rheumatoid factor, HLA-DRB1 shared epitope alleles and sex. We found no association between anti-LtxA IgG/IgA antibodies and RA at any stage of disease development. The data support a temporal association between anti-LtxA IgM antibodies and the development of RA, suggesting that a subset of RA patients may have been exposed to Aa around the time of transition from being asymptomatic to become a patient with RA.

The use of hydroxychloroquine (HCQ) in the prophylaxis and treatment of coronavirus disease 2019 (COVID-19) has received significant attention by politicians and media figures. This has occurred despite limited data supporting its efficacy in COVID-19 as well as considerable concern about its safety when used at high doses (>400 mg daily) and in combination with other QT interval prolonging drugs.1–4 An inaccurate narrative has emerged in recent weeks that patients with systemic lupus erythematosus (SLE) who are taking HCQ as a baseline therapy are less affected by or do not develop COVID-19.5–7 This assumption has been challenged by Monti and Montecucco,8 referencing data from the COVID-19 Global Rheumatology Alliance registry on patients with rheumatic disease that previously identified 19/110 (17%) patients with SLE.9 A case series of 17 patients with lupus or antiphospholipid syndrome who developed COVID-19 on a median HCQ dose of 400 mg daily (median HCQ blood level of 648 ng/mL) has since become available.10 As of 17 April 2020, we have now identified 80 patients with SLE and COVID-19 in the global physician-reported registry. Patients were predominantly female (72/80, 90%) and less than 65 years of age (69/80, 86%). Importantly, 64% (51/80) of patients with SLE were taking an antimalarial (HCQ or chloroquine) prior to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (30% as monotherapy). Notably, 21.1% (121/573) of all reported patients with rheumatic disease in the registry were treated with an antimalarial prior to onset of COVID-19, yet 49.6% (60/121) required hospitalisation. In patients with SLE, frequency of hospitalisation with COVID-19 …

The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS), and interleukin (IL)-6 levels are predictors of COVID-19 severity and in-hospital mortality. Targeting hyper-inflammation in COVID-19 may be critical for reducing mortality. Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (α1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the α1-AR antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. These findings offer a rationale for studying α1-AR antagonists in the prophylaxis of patients with COVID-19-CSS and ARDS. As high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate COVID-19 severity and reduce excessive mortality are desperately needed. We hypothesize that treatment with prazosin of individuals who test positive for SARS-CoV-2 could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. To investigate a potential role for α1-AR antagonists in preventing poor outcomes in ARDS, we conducted a retrospective analysis of hospitalized patients diagnosed with ARDS. Using data from the Truven Health MarketScan Research Database (2010-2017), we identified 13,125 men (age 45-64) with ARDS, of whom 655 patients (5.0%) were prescribed α1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of α1-AR antagonists had lower odds of invasive mechanical ventilation compared to non-users (adjusted OR=0.75, 95% CI 0.59-0.95, p=0.019). Perhaps more importantly, those patients had a ~36% lower incidence of both being ventilated and dying in the hospital (adjusted OR=0.59, 95% CI 0.34-0.95, p=0.042). By contrast, prior use of beta-adrenergic receptor (β-AR) antagonists was not correlated with either outcome. We extended these analyses to patients admitted with pneumonia. Of 108,956 subjects in this cohort, 5,498 patients (5.0%) were taking α1-AR antagonist. Similar to ARDS, patients with pneumonia on α1-AR antagonists (but no β-AR antagonists) had a lower odds of mechanical ventilation (adjusted OR=0.83, 95% CI 0.75-0.92, p

Background: Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis (RA) pathogenesis. Although mechanistic and clinical association studies implicate Aa infection in the initiation of autoimmunity in RA, direct evidence in humans is lacking. Case: We describe a 59-year-old man with anti-citrullinated protein antibody (ACPA)-positive RA who presented for evaluation of refractory disease. He was found to have Aa endocarditis. Following antibiotic treatment, joint symptoms resolved and ACPAs normalized. Given the implications for RA immunopathogenesis, we further investigated the bacterial, genetic and immune factors that may have contributed to the patient's clinical and autoimmune phenotypes. Methods: DNA was extracted from serum and used to amplify the Aa leukotoxin (tx) promoter region by PCR, which was further analyzed by Sanger sequencing. High-resolution identification of HLA alleles was performed by sequenced based typing (SBT). TNF-alpha, IFN-gamma, GM-CSF, IL-1 beta, IL-6, IL-8, IL-17A, IL-18, IL-21, and IL-22 were quantified in serum by a multiplex immunoassay. IgG and IgA antibodies to Aa LtxA were assayed by ELISA. Results: Aa genotyping confirmed infection with a highly leukotoxic strain carrying a 530-bp /tx promoter deletion, shown to result in 10- to 20-fold higher bacterial expression of LtxA. lmmuno-phenotyping showed high anti LtxA antibodies, elevated cytokines implicated in RA pathogenesis (Th1/Th17), and specific host susceptibility conferred by three HLA alleles strongly linked to ACPAs and RA (DRB1*04:04:04, DRB1*15:01, and DPB1*04:01). One year after eradication of Aa, the patient remained free of arthritis and anti-CCP antibodies. Conclusion: In the context of genetic risk for RA, systemic subacute infection with a leukotoxic strain of Aa can drive ACPA production and a clinical phenotype similar to RA.

Dermatomyositis (DM) is characterized by proximal muscle weakness and characteristic skin rash. Pain is a less common feature and usually indicates inflammation of extramuscular structures such as fascia. Here we report a rare case of subscapular bursitis in a 48-year-old woman with DM. She initially presented with severe, sharp, stabbing pain in her right shoulder that worsened with shoulder movement. Magnetic resonance imaging (MRI) revealed inflammation in the right subscapular bursae. A few months later, the patient developed periungual erythema, Gottron's papules, and shawl sign with muscle pain in her thighs. DM was diagnosed based on the presence of interface dermatitis on skin biopsy and diffuse muscle inflammation on MRI. Bursitis and myalgia responded incompletely to nonsteroidal anti-inflammatory drugs but promptly to corticosteroids. Here we report a case of subscapular bursitis as a rare manifestation of DM. Pain in patients with DM may warrant physicians to evaluate for the presence of additional inflammatory processes in the perimuscular structures.

Background Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. Objectives To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). Methods PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPAD C351S ), and N-terminal truncated PPAD (rPPAD Ntx ) were cloned and expressed in Escherichia coli . Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPAD C351S by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. Results PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli , full-length rPPAD, but not truncated (fully active) rPPAD Ntx , is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD. Conclusions PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.