key: cord-0813274-509otfad
authors: Yazdany, Jinoos
title: COVID‐19 in Rheumatic Diseases: A Research Agenda
date: 2020-07-23
journal: Arthritis Rheumatol
DOI: 10.1002/art.41447
sha: c7e50546bc23ace8f22ddadda9c47eecfe4f3670
doc_id: 813274
cord_uid: 509otfad

Although only a few months have passed since the coronavirus disease 2019 (COVID‐19) pandemic began, we have learned a lot about the infection and outcomes in people with rheumatic diseases. Below I summarize recent findings as well as remaining gaps in knowledge about the epidemiology and outcomes of COVID‐19 in rheumatic diseases. I also outline a clinical research agenda for the coming months.

cohorts, including one nationwide inflammatory bowel disease cohort of TNFi and thiopurine users, the prevalence of COVID-19 was similar to that in the general population. 2, 3 The survey reported by Favalli and colleagues in this issue of the journal provides further reassurance. 4 The researchers contacted 955 individuals with inflammatory conditions seen in a biologics clinic in Pavia, Italy, achieving a remarkably high response rate of 98% over a short period. They found that <1% of patients had been diagnosed with COVID-19, and no patient required mechanical ventilation or died.

A recent study from China examined 42 families of people with rheumatic diseases in whom at least one person had COVID-19. Matching people with rheumatic disease to family members, they found a higher susceptibility to infection among those with rheumatic diseases. However, this was a small study so no definitive conclusions can be drawn. 5 Taken together, these studies suggest that the risk for acquiring COVID-19 is either similar or only slightly increased for people with rheumatic diseases. Indeed, the extremely high attack rates in vulnerable populations, such as prison inmates, homeless individuals, and nursing home residents illustrate that initial infection is most strongly associated with high-risk exposures rather than underlying conditions or immunosuppression.

The risk of severe outcomes in patients with rheumatic diseases is closely tied to age and comorbidities, similar to the general population. Population-based studies and large case series in people with rheumatic diseases have shown that older age and the presence of comorbidities such as diabetes or cardiovascular, kidney and lung disease increase the risk for hospitalization, mechanical ventilation, and death. 1, 6 Comorbidities occur at higher rates in people with rheumatic disease, either as a result of organ-manifestations of the underlying disease (e.g. lupus nephritis, interstitial lung disease) or as a complication of treatment (e.g. glucocorticoid-induced diabetes). This puts many of our patients in a high-risk group for severe COVID-19 outcomes like respiratory failure, although overall mortality has been low. Moreover, COVID-19 mortality in rheumatic diseases has been lower than in populations with cancer or organ transplants. 1 Most immunosuppressive drug regimens are not associated with a significantly increased risk of severe COVID-19 outcomes. Although more data is needed to look at specific drug categories, available studies provide some reassurance. For example, data from 600 patients in the COVID-19

Global Rheumatology Alliance (GRA) registry, a case-reporting registry for rheumatologists, shows that most immunosuppressive drugs, including biologics and targeted synthetic agents, are not associated with a significantly higher risk of hospitalization. 6 A case series of 86 patients with autoimmunity hospitalized for COVID-19 in New York had similar findings. 7 Studies using age-and Accepted Article sex-matched-control designs also suggest comparable risks of hospitalization and mortality regardless of exposure to most immunosuppressive medications. 8 Interestingly, moderate to high dose glucocorticoids are the one class of medication associated with a higher risk of hospitalization and severe outcomes in both the GRA and SECURE-Inflammatory Bowel Disease registries. 6, 9 Whether this represents a biological effect of glucocorticoids in reducing host-defenses to initial viral infection and replication, or confounding by factors such as social determinants of health (i.e. poor access to care), remains to be determined. If substantiated, these data suggest that glucocorticoids early in infection are harmful, even if trials like RECOVERY suggest a significant benefit later during the disease. 10 Although more research is needed to examine specific drug classes and drug-disease-comorbidity interactions, there is now good evidence that patients with rheumatic diseases should not discontinue immunosuppressive drugs.

And while reducing glucocorticoid exposure is always important, it may be especially important to minimize exposure during the pandemic. We also know very little about the long-term outcomes of people with rheumatic diseases who have recovered from COVID-19. In the general population, neurological sequelae (e.g. permanent anosmia, cognitive fogging), respiratory problems, and other organ damage (e.g. renal damage, Type 1 diabetes mellitus) have all been described. Whether these sequelae are more prevalent or severe in those with pre-existing autoimmunity or organ damage from their rheumatic disease remains to be determined.

This article is protected by copyright. All rights reserved Finally, the pandemic has again highlighted the profound impact of social determinants of health on outcomes. In rheumatology, health disparities are pervasive, and our most vulnerable patients are already suffering disproportionately during the pandemic. Racial/ethnic minorities, those living in poverty and experiencing housing and food insecurity, and those who are unable to reduce SARS-Cov-2 exposures because of work-related duties are more likely to acquire the infection, and multimorbidity and inadequate access to health care result in more severe outcomes. Indeed, in the GRA registry, U.S. patients who are racial/ethnic minorities are significantly more likely to have severe COVID-19 outcomes. Ensuring that vulnerable groups retain or gain access to rheumatology care is important to ensure that morbidity from rheumatic diseases does not increase during the pandemic.

Research Agenda for the Coming Year. As the pandemic has evolved, clinical research studies will also need to evolve (Figure) . The early phases of the pandemic were marked by an information vacuum, with virtually no data available on how people with rheumatic diseases or on immunosuppression would fare if infected. Case series, small case-control studies, and rapidlydeployed patient surveys can be assembled quickly and were appropriate to fill information needs during this phase. Now several months into the pandemic, larger case series with clearly defined denominators (i.e. a health system, hospital, or region) and larger case-control studies and patient surveys add precision to early estimates. Large registries still also have an important role in examining rare diseases or less commonly used immunosuppressive drugs. Over the coming months, investigators should increasingly shift towards conducting studies in which the denominators (populations at risk) are larger and more precise, the numerators (COVID-19 infection) are accurately captured, and control populations are available to calculate risks attributable to rheumatic diseases and immunosuppressive drugs.

In the Supplemental Table, I 

This article is protected by copyright. All rights reserved To more clearly define the risk of severe COVID-19 outcomes attributable to specific rheumatic diseases and drugs, large population-based studies are needed. The integration of multiple data sources, including those that capture social determinants of health, will be important in identifying patients at highest risk and developing population-based public health interventions to mitigate these risks.

Globally, case reporting registries such as the GRA will continue to play an important role since population-based studies with multi-source national data are sometimes unavailable in low and middle-income countries. Moving toward the systematic collection and entry of cases by rheumatologists from health systems or regions in these countries will be key to understanding the outcomes of COVID-19 in rheumatic disease populations globally. This information is likely to have a significant international impact as policy makers and physicians use local data to make important decisions about issues such as which high-risk groups to prioritize for treatment or vaccination.

Individuals with rheumatic diseases and COVID-19, particularly those with severe infection, may have long-term physical and psychological sequelae. Quantifying long-term consequences through cohort studies will help rheumatologists appropriately screen for these sequelae, manage symptoms, and refer patients to appropriate services. Similar longitudinal cohorts in the general population will also help define possible autoimmune or musculoskeletal syndromes resulting from COVID-19.

Although sample sizes will likely preclude randomized controlled trials of anti-viral or immunomodulating therapies in those with rheumatic diseases, subgroup analyses of large, welldone randomized trials may be possible to examine differential treatment responses and guide therapeutic approaches in people with autoimmunity or those who are immunocompromised.

Similarly, although it is unlikely that primary vaccine efficacy studies will be performed in patients with rheumatic diseases, randomized controlled trials examining immune responses and safety in immunocompromised people are feasible and should be conducted to inform clinical decisionmaking.

Finally, it is inevitable that the COVID-19 pandemic will have far-reaching consequences on rheumatology care and the outcomes of people with rheumatic diseases. Treatment interruptions,

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SARS-CoV-2 infection among patients with systemic autoimmune diseases

Impact of Anti-TNF and Thiopurines medications on the development of COVID-19 in patients with inflammatory bowel disease: A Nationwide VA cohort study

Cite Favalli paper in this issue

COVID-19 in patients with rheumatic disease in Hubei province, China: a multicentre retrospective observational study

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry

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Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US 'hot spot

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Coronavirus breakthrough: dexamethasone is first drug shown to save lives