Physicians' perceptions about antineutrophil cytoplasmic antibody-associated vasculitis: an online survey report in the time of the COVID-19 pandemic.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are characterized by necrotizing inflammation of small and medium-size vessels that often manifest with devastating multi-organ effects. They present with a myriad of systemic features and require potent immunosuppression. Since they are uncommonly encountered in clinical practice, it is necessary to understand physicians' knowledge and perceptions about this group of diseases. An online questionnaire was designed featuring 28 questions based on relevant global practice guidelines, recommendations, and previous online surveys on AAV. The questionnaire was validated by a core group of specialists with an interest in AAV. It was shared via social networking sites and entries were restricted to physicians. Only completed entries were analyzed with descriptive statistics. A total of 113 respondents from 21 different countries responded of whom the commonest were rheumatologists, internists, and general practitioners. Forty-five (40%) ran clinics dedicated to AAV patients as a part of their practice. They commented on organs involved in AAV; vasculitis secondary to infections, drugs or other rheumatic diseases; various tests useful for AAV diagnosis; and drug choices for induction and maintenance. They mentioned their experience regarding COVID-19 in AAV patients as well as vasculitic manifestations of COVID-19. Various methods to mitigate cardiovascular risks in AAV were mentioned. Finally, the respondents indicated how medical education needed to be strengthened to increase awareness and knowledge regarding AAV. This survey helped to inform about various perceptions regarding AAV across countries, including current practices and recent evolution of management. It also provided information on treatment of the COVID-19 in AAV patients. This survey showed that there is still a lack in understanding the prevalent definitions and there is gap between guidelines and current practice. Key Points • Perception about ANCA-associated vasculitis differ across countries. • The number of cases encountered across 21 different countries are limited implying a need for multi-national cooperation to study this disease further. • The COVID-19 pandemic has changed the approach towards ANCA-associated vasculitis by the various clinicians.

Knowledge and Perceptions of Reactive Arthritis Diagnosis and Management Among Healthcare Workers During the COVID-19 Pandemic: Online Survey.

BACKGROUND: Reactive arthritis (ReA) is an often neglected disease that received some attention during the coronavirus disease 2019 (COVID-19) pandemic. There is some evidence that infection with severe acute respiratory syndrome coronavirus 2 can lead to "reactive" arthritis. However, this does not follow the classical definition of ReA that limits the organisms leading to this condition. Also, there is no recommendation by any international society on the management of ReA during the current pandemic. Thus, a survey was conducted to gather information about how modern clinicians across the world approach ReA. METHODS: An e-survey was carried out based on convenient sampling via social media platforms. Twenty questions were validated on the pathogenesis, clinical presentation, and management of ReA. These also included information on post-COVID-19 arthritis. Duplicate entries were prevented and standard guidelines were followed for reporting internet-based surveys. RESULTS: There were 193 respondents from 24 countries. Around one-fifth knew the classical definition of ReA. Nearly half considered the triad of conjunctivitis, urethritis and asymmetric oligoarthritis a "must" for diagnosis of ReA. Other common manifestations reported include enthesitis, dermatitis, dactylitis, uveitis, and oral or genital ulcers. Three-fourths opined that no test was specific for ReA. Drugs for ReA were non-steroidal anti-inflammatory drugs, intra-articular injections, and conventional disease-modifying agents with less than 10% supporting biological use. CONCLUSION: The survey brought out the gap in existing concepts of ReA. The current definition needs to be updated. There is an unmet need for consensus recommendations for the management of ReA, including the use of biologicals.

Interplay of diabetes mellitus and rheumatic diseases amidst the COVID-19 pandemic: influence on the risk of infection, outcomes, and immune responses.

Outcomes of COrona VIrus Disease-19 (COVID-19) in patients with rheumatic diseases (RDs) reported in various studies are heterogenous owing to the influence of age and comorbidities which have a significant bearing on the infection risk, severity, morbidity, and mortality. Diabetes mellitus (DM) and RDs are closely linked with underlying pathobiology and treatment of RDs affecting the risk for DM as well as the glycemic control. Hence, we undertook this narrative review to study the influence of DM on outcomes of COVID-19 in patients with RDs. Additionally, aspects of patient attitudes and immune response to COVID-19 vaccination were also studied. The databases of MEDLINE/PubMed, Scopus, and Directory of Open Access Journals (DOAJ) were searched for relevant articles. Studies from mixed cohorts revealed insufficient data to comment on the influence of DM on the risk of infection, while most studies showed twice the odds for hospitalization and mortality with DM. Specific cohorts of rheumatoid arthritis and systemic lupus erythematosus revealed a similar association. Poor health was noted in patients with spondyloarthritis and DM during the pandemic. The presence of DM did not affect patient attitudes towards vaccination and did not predispose to additional vaccine-related adverse effects. Immune response to inactivated vaccines was reduced but mRNA vaccines were maintained in patients with DM. Detailed assessment of DM with its duration, end-organ damage, and glycemic control along with a focused association of DM with various aspects of COVID-19 like risk, hospitalization, severity, mortality, post-COVID sequelae, immune response to infection, and vaccination are needed in the future. Key Points • Diabetes mellitus is associated with the severity of infection, COVID-19-related hospitalization, and mortality in rheumatic diseases across most studies but studies analyzing its specific role are lacking. • Poor outcomes of COVID-19 in RA and poor health in spondyloarthritis are strongly associated with diabetes mellitus. • Diabetes mellitus may negatively influence the humoral response to inactivated vaccines but does not seem to affect the immune responses to mRNA vaccines. • Diabetes mellitus does not influence the attitude towards vaccination or deviation from the prescribed medications during the pandemic.

Global Health Strategies in the Face of the COVID-19 Pandemic and Other Unprecedented Threats.

Global health is evolving as a discipline aiming at exploring needs and offering equitable health services for all people. Over the past four decades, several global initiatives have been introduced to improve the accessibility of primary health care (PHC) and solve most health issues at this level. Historically, the 1978 Alma-Ata and 2018 Astana Declarations were perhaps the most important documents for a comprehensive approach to PHC services across the world. With the introduction of the United Nations Sustainable Development Goals in 2015, developments in all spheres of human life and multi-sectoral cooperation became the essential action targets that could contribute to improved health, well-being, and safety of all people. Other global initiatives such as the Riyadh Declaration on Digital Health and São Paulo Declaration on Planetary Health called to urgent action to employ advanced digital technologies, improve health data processing, and invest more in research management. All these initiatives are put to the test in the face of the coronavirus disease 2019 (COVID-19) pandemic and other unprecedented threats to humanity.

Systemic lupus erythematosus in the light of the COVID-19 pandemic: infection, vaccination, and impact on disease management.

Patients with systemic lupus erythematosus (SLE) form a vulnerable group in terms of the impact of the COVID-19 pandemic on disease management. We conducted this overview by searches through Medline/PubMed, Scopus, and the Directory of Open Access Journals (DOAJ). The prevalence and severity of COVID-19, efficacy of COVID-19 vaccination, impact on the management of SLE, and the attitudes of SLE patients to COVID-19 and vaccination were explored. After screening and due exclusions, 198 studies were included for the final review. Patients with SLE have a greater risk of acquiring COVID-19 (0.6-22%) and related hospitalization (30%), severe disease (13.5%), and death (6.5%) than the general population. Older age, male gender, comorbidities, moderate or high disease activity, and glucocorticoid, rituximab, and cyclophosphamide use are associated with unfavorable outcomes, whereas methotrexate and belimumab use showed no association with outcomes. COVID-19 vaccines are safe in SLE with minimal risk of severe flares (< 2%). Vaccine efficacy is negatively associated with glucocorticoids. The overall attitude of patients towards vaccination is positive (54-90%). The pandemic has negatively affected access to medical care, hospitalizations, procurement of drugs, employment, and the mental health of patients which need to be addressed as part of holistic care in SLE. Key Points • Lupus patients are at a greater risk of acquiring COVID-19, related hospitalization,  severe  disease, and death than the general population. • COVID-19 vaccines are relatively safe for lupus patients with minimal risk of severe flares. • Lupus patients' attitude towards COVID-19 vaccination is predominantly positive.

Reactive arthritis before and after the onset of the COVID-19 pandemic.

Most accepted definitions of reactive arthritis (ReA) consider it a type of spondyloarthritis (SpA) precipitated by a gut or urogenital infection. A wider definition considers any arthritis that occurs after a mucosal surface infection as ReA. There is limited consensus regarding a working definition, status of HLA-B27, or even classification criteria for ReA. This may also contribute to a lack of systemic studies or clinical trials for ReA, thereby reducing further treatment recommendations to expert opinions only. The emergence of post-COVID-19 ReA has brought the focus back on this enigmatic entity. Post-COVID-19 ReA can present at extremes of age, appears to affect both sexes equally and can have different presentations. Some present with small joint arthritis, others with SpA phenotype-either with peripheral or axial involvement, while a few have only tenosynovitis or dactylitis. The emergence of post-vaccination inflammatory arthritis hints at similar pathophysiology involved. There needs to be a global consensus on whether or not to include all such conditions under the umbrella of ReA. Doing so will enable studies on uniform groups on how infections precipitate arthritis and what predicts chronicity. These have implications beyond ReA and might be extrapolated to other inflammatory arthritides. Key Points • Classical reactive arthritis (ReA) has a spondyloarthritis phenotype and is preceded by symptomatic gut or urogenital infection • The demonstration of antigen and nucleic acid sequences of pathogens in synovium has blurred the difference between invasive arthritis and reactive arthritis • Post-COVID-19 ReA has a transient phenotype and can have different presentations. All reported cases are self-limiting • The large amount of literature reporting post-COVID-19 ReA calls for introspection if the existing definitions of ReA need to be updated.

Formulating Hypotheses for Different Study Designs.

Generating a testable working hypothesis is the first step towards conducting original research. Such research may prove or disprove the proposed hypothesis. Case reports, case series, online surveys and other observational studies, clinical trials, and narrative reviews help to generate hypotheses. Observational and interventional studies help to test hypotheses. A good hypothesis is usually based on previous evidence-based reports. Hypotheses without evidence-based justification and a priori ideas are not received favourably by the scientific community. Original research to test a hypothesis should be carefully planned to ensure appropriate methodology and adequate statistical power. While hypotheses can challenge conventional thinking and may be controversial, they should not be destructive. A hypothesis should be tested by ethically sound experiments with meaningful ethical and clinical implications. The coronavirus disease 2019 pandemic has brought into sharp focus numerous hypotheses, some of which were proven (e.g. effectiveness of corticosteroids in those with hypoxia) while others were disproven (e.g. ineffectiveness of hydroxychloroquine and ivermectin).

Modern Health Journalism and the Impact of Social Media.

Scholarly journals are hubs of hypotheses, evidence-based data, and practice recommendations that shape health research and practice worldwide. The advancement of science and information technologies has made online accessibility a basic requirement, paving the way for the advent of open access publishing, and more recently, to web-based health journalism. Especially in the time of the current pandemic, health professionals have turned to the internet, and primarily to social media, as a source of rapid information transfer and international communication. Hence, the current pandemic has ushered an era of digital transformation of science, and we attempt to understand and assess the impact of this digitization on modern health journalism.

Monitoring Information Flow on Coronavirus Disease 2019 (COVID-19).

The flow of information on Coronavirus Disease 2019 (COVID-19) is intensifying, requiring concerted efforts of all scholars. Peer-reviewed journals as established channels of scientific communications are struggling to keep up with unprecedented high submission rates. Preprint servers are becoming increasingly popular among researchers and authors who set priority over their ideas and research data by pre-publication archiving of their manuscripts on these professional platforms. Most published articles on COVID-19 are now archived by the PubMed Central repository and available for searches on LitCovid, which is a newly designed hub for specialist searches on the subject. Social media platforms are also gaining momentum as channels for rapid dissemination of COVID-19 information. Monitoring, evaluating and filtering information flow through the established and emerging scholarly platforms may improve the situation with the pandemic and save lives.

Mechanisms of thrombosis in ANCA-associated vasculitis.

Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial thrombotic events. Although such thrombotic events are more commonly seen during phases of active AAV, they are also recognized to occur during AAV in remission. Endothelial injury is a key pathogenic event in AAV. Endothelial injury can be caused by neutrophil activation and release of thrombogenic tissue factor into the circulation. Neutrophil activation further results in the formation of neutrophil extracellular traps (NETs). NETs contribute to thrombosis by expressing tissue factor. NETs have also been detected in cutaneous thrombi from patients with AAV induced by hydralazine. Activated neutrophils in AAV patients release thrombogenic microparticles loaded with tissue factor which further enhances clotting of blood. Antiphospholipid antibodies (APLs) have been detected in up to a third of AAV and might also be induced by drugs such as cocaine adulterated with levamisole and propylthiouracil, which are known to trigger AAV. Such APLs further drive the thrombosis in AAV. Once thrombogenesis occurs, the homeostatic mechanisms resulting in clot dissolution are further impaired in AAV due to anti-plasminogen antibodies. The ongoing pandemic of coronavirus disease 2019 (COVID-19) is associated with endothelial injury and NETosis, mechanisms which are in common with AAV. Reports of new-onset AAV following COVID-19 have been described in the literature, and there could be shared mechanisms driving these processes that require further evaluation.

COVID-19 and the clinical course of rheumatic manifestations.

The manifestations of COVID-19 have been evolving over time. Various post-COVID-19 syndromes are being recognised. Various viruses have been implicated in the pathogenesis of autoimmune diseases, and we expect a similar outcome with the severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 virus penetrates various tissues and organs and has a predisposition to lead to endotheliitis that may cause vascular manifestations including thrombosis. SARS-CoV-2 has been shown to activate Toll-like receptors and the complement system. It perpetuates NETosis and leads to autoantibody formation. These predispose to systemic autoimmunity. Both reactive arthritis and connective tissue disorders such as lupus and inflammatory myositis have been reported after COVID-19. Other reported autoimmune disorders include haemolytic anaemia, immune thrombocytopenia, cutaneous vasculitis, and Guillain Barré-like acute demyelinating disorders. The multi-system inflammatory syndrome in children and its adult counterpart are another post-COVID-19 entity that presents as an admixture of Kawasaki disease and staphylococcal toxic shock syndrome. Patients with preexisting rheumatic diseases may flare during the SARS-CoV-2 infection. They may develop novel autoimmune features also. The immune-suppressants used during the acute COVID-19 illness may confound the outcomes whereas comorbidities present in patients with rheumatic diseases may mask them. There is an urgent need to follow-up patients recovering from COVID and monitor autoantibody production in the context of rheumatic manifestations. Key Points • COVID-19 is associated with both innate and acquired immune reactions and production of various autoantibodies. • Various immune-mediated manifestations such as arthritis, myositis, haemolytic anaemia, thrombocytopenia, and acute demyelination may develop after COVID-19. • Longitudinal cohort data are warranted to describe, predict, and test prevent various rheumatic manifestations in post-COVID-19 subjects.

Comorbidities in rheumatic diseases need special consideration during the COVID-19 pandemic.

Comorbidities in rheumatic and musculoskeletal diseases (RMDs) not only increase morbidity and mortality but also confound disease activity, limit drug usage and increase chances of severe infections or drug-associated adverse effects. Most RMDs lead to accelerated atherosclerosis and variable manifestations of the metabolic syndrome. Literature on COVID-19 in patients with RMDs, and the effects of various comorbidities on COVID-19 was reviewed. The initial data of COVID-19 infections in RMDs have not shown an increased risk for severe disease or the use of different immunosuppression. However, there are some emerging data that patients with RMDs and comorbidities may fare worse. Various meta-analyses have reiterated that pre-existing hypertension, cardiovascular disease, stroke, diabetes, chronic kidney disease, heart failure, lung disease or obesity predispose to increased COVID-19 mortality. All these comorbidities are commonly encountered in the various RMDs. Presence of comorbidities in RMDs pose a greater risk than the RMDs themselves. A risk score based on comorbidities in RMDs should be developed to predict severe COVID-19 and death. Additionally, there should be active management of such comorbidities to mitigate these risks. The pandemic must draw our attention towards, and not away from, comorbidities.

Scholarly publishing and journal targeting in the time of the Coronavirus Disease 2019 (COVID-19) pandemic: a cross-sectional survey of rheumatologists and other specialists.

The evolving research landscape in the time of the Coronavirus disease 2019 (COVID-19) pandemic calls for greater understanding of the perceptions of scholars regarding the current state and future of publishing. An anonymised and validated e-survey featuring 30 questions was circulated among rheumatologists and other specialists over social media to understand preferences while choosing target journals, publishing standards, commercial editing services, preprint archiving, social media and alternative publication activities. Of 108 respondents, a significant proportion were clinicians (68%), researchers (60%) and educators (47%), with median 23 publications and 15 peer-review accomplishments. The respondents were mainly rheumatologists from India, Ukraine and Turkey. While choosing target journals, relevance to their field (69%), PubMed Central archiving (61%) and free publishing (59%) were the major factors. Thirty-nine surveyees (36%) claimed that they often targeted local journals for publishing their research. However, only 18 (17%) perceived their local society journals as trustworthy. Occasional publication in the so-called predatory journals (5, 5%) was reported and obtaining support from commercial editing agencies to improve English and data presentation was not uncommon (23, 21%). The opinion on preprint archiving was disputed; only one-third believed preprints were useful. High-quality peer review (56%), full and immediate open access (46%) and post-publication social media promotion (32%) were identified as key anticipated features of scholarly publishing in the foreseeable future. These perceptions of surveyed scholars call for greater access to free publishing, attention to proper usage of English and editing skills, and a larger role for engagement over social media.

Moving towards online rheumatology education in the era of COVID-19.

The coronavirus disease-2019 (COVID-19) pandemic has unsettled conventional medical education, hastening a switch to digital platforms and open-access publishing. Rheumatology is a fast evolving academic discipline that stands to gain by this switch. Most rheumatology textbooks are now available in digital formats, and these are complemented with live updating educational hubs such as UpToDate and ClinicalKey. Emerging topics of COVID-19 on these proprietary platforms are now freely available to all specialists. Social media channels, particularly Twitter, are becoming major players in the era of COVID-19 by offering online journal clubs, enabling fast dissemination of influential articles, and facilitating interactive education. Indexed rheumatology journals, in turn, aid online education by opening access to recommendations and other materials that are rapidly changing research and practice worldwide. Research peer review additionally offers learning experience to novice and seasoned researchers and authors. Global rheumatology societies have online learning resources, which are changing their format and geographic reach to meet the changing needs in the times of pandemic. While online teaching lacks emotional connections between mentors and mentees, switch to a more interactive format of education and regular contacts may partly solve the issue. Rheumatologists can take the lead in these challenging times and contribute more to online scholarly activities which are aimed to maintain and enrich education. Key Points • Disparities in rheumatology education are likely to be widened during the COVID-19 pandemic. • Barriers to rheumatology education include limited number of instructors and their limited experience in online teaching. • Online textbooks, didactic materials of indexed rheumatology journals, and frequently updated online educational hubs such as UpToDate serve as a foundation of online rheumatology education. • Online rheumatology education is enriched by peer review and social media activities, which are becoming major players in the time of the COVID-19 pandemic.

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates.

Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.

Information and Misinformation on COVID-19: a Cross-Sectional Survey Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a large volume of publications, a barrage of non-reviewed preprints on various professional repositories and a slew of retractions in a short amount of time. METHODS: We conducted an e-survey using a cloud-based website to gauge the potential sources of trustworthy information and misinformation and analyzed researchers', clinicians', and academics' attitude toward unpublished items, and pre- and post-publication quality checks in this challenging time. RESULTS: Among 128 respondents (mean age, 43.2 years; M:F, 1.1:1), 60 (46.9%) were scholarly journal editors and editorial board members. Social media channels were distinguished as the most important sources of information as well as misinformation (81 [63.3%] and 86 [67.2%]). Nearly two in five (62, 48.4%) respondents blamed reviewers, editors, and misinterpretation by readers as additional contributors alongside authors for misinformation. A higher risk of plagiarism was perceived by the majority (70, 58.6%), especially plagiarism of ideas (64.1%) followed by inappropriate paraphrasing (54.7%). Opinion was divided on the utility of preprints for changing practice and changing retraction rates during the pandemic period, and higher rejections were not supported by most (76.6%) while the importance of peer review was agreed upon by a majority (80, 62.5%). More stringent screening by journal editors (61.7%), and facilitating open access plagiarism software (59.4%), including Artificial Intelligence (AI)-based algorithms (43.8%) were among the suggested solutions. Most (74.2%) supported the need to launch a specialist bibliographic database for COVID-19, with information indexed (62.3%), available as open-access (82.8%), after expanding search terms (52.3%) and following due verification by academics (66.4%), and journal editors (52.3%). CONCLUSION: While identifying social media as a potential source of misinformation on COVID-19, and a perceived high risk of plagiarism, more stringent peer review and skilled post-publication promotion are advisable. Journal editors should play a more active role in streamlining publication and promotion of trustworthy information on COVID-19.

Thrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow's triad.

The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy.