Since late 2019, the SARS-CoV-2 virus—cause of the COVID-19 pandemic—has wreaked havoc on the healthcare industry. For patients with rheumatoid arthritis (RA), that havoc has been acutely felt: from its onset, the data has been conflicted as to the risk that patients with RA face from a COVID-19 infection.1
Early on, some studies suggested that patients with rheumatic diseases such as RA may be at a higher risk for respiratory failure and death associated with COVID-19. 1 Conflicting evidence was later published, indicating that these patients may not actually be at a higher risk, once factors like age, comorbidities, and medication use were adjusted for, according to a paper published in Current Opinion in Rheumatology.1
“There’s been data that’s come out [showing] that…certain DMARD users may be at higher risk for poor outcomes of COVID-19, including infection and the sequela of that,” said study author Zachary S. Wallace, MD, of the Division of Rheumatology, Allergy, and Immunology and the Clinical Epidemiology Program at the Mongan Institute at Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts, in an interview with us.
“There has been at least 1 other paper published since we wrote our paper that specifically looked at patients with RA and whether or not they were at higher risk for COVID-19,” he added. “Those researchers found that there was an association between having RA and being at high risk.”
That paper, authored by Bryant R. England, MD, PhD, of the Medicine & Research Service at the VA Nebraska-Western Iowa Health Care System and the Division of Rheumatology & Immunology at the University of Nebraska Medical Center in Omaha, Nebraska,2 looked at a matched cohort of patients at a Veteran’s Affairs clinic with and without RA and found that—even after adjusting for demographics, comorbidities, health behaviors, and county-level COVID-19 rates—patients with RA were at higher risk for both COVID-19 infection and associated hospitalization or death.
Although the study population was unique—Dr Wallace pointed out that the population was primarily men, and RA usually affects women—the data raises concerns about outcomes in this population.
RA Inflammation and COVID-19
Symptoms of COVID-19 are generally heterogenous, and range from minimal symptoms—dry cough, fever, and fatigue—to hypoxia with acute respiratory distress syndrome (ARDS) and multiple organ failure.3 And although the mechanisms behind severe COVID-19 illness are still poorly understood, researchers have hypothesized that an “excessive inflammatory response to SARS-CoV-2” is a leading cause of disease severity and death.4
For patients with RA this additional inflammation can lead to significant issues.
“RA is a disease characterized by inflammation, in part,” said Dr Wallace. “We know from work that our group has done…that patients with RA and other rheumatic diseases appear to have more of an inflammatory response to COVID-19 than patients who don’t have these diseases.”
“That may be playing a role,” he added. “There’s this hyperinflammatory response that predisposes these patients to worse outcomes.”
Investigations into this hyperinflammatory response are, given the novel nature of SARS-CoV-2, ongoing. A recent study found numerous commonalities between COVID-19 and RA. Although these diseases are of course different, some similarities in pathogenesis and risk factors have been identified5—in particular, an imbalance in cytokines.
“The cytokine imbalance in COVID-19 infection is quite similar to that observed in inflammatory rheumatic diseases,” researchers wrote, which includes interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a cytokines that are similar to those identified in Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).5
According to Dr Wallace, researchers are also working to determine if the immune dysregulation experienced by those with RA—which can predispose individuals to RA itself—affects the way this patient population would respond to a viral infection.
“That’s the part we know less about,” he said. “It’s a very difficult thing to disentangle.”
In addition to broad concerns about systemic inflammation, rheumatologists remain concerned about the high rates of interstitial lung disease (ILD) in the RA population—between 10% and 66%6—which does, said Dr Wallace, lead to concerns that patients with RA and ILD will do worse following a COVID-19 infection.
These concerns were echoed by researchers in a paper published in Expert Review of Clinical Immunology,6 who noted that patients with RA are “generally more susceptible to infection events because of the autoimmune condition itself and the treatment with immunomodulary drugs.”
Early research—conducted before the COVID-19 pandemic—indicated that treatment with glucocorticoids, Janus kinase (JAK) inhibitors, and TNF inhibitors may be associated with a “higher risk of viral respiratory infections,”1,6-8 rendering glucocorticoid use in particular “highly controversial.”6 Initial studies on this treatment, wrote Dr Favalli and colleagues, were “not satisfactory,” and more recent research has emerged suggesting that the immunosuppressive effects of glucocorticoid therapy may actually mitigate hyperinflammation, reducing both mortality and length of hospitalization.6
Although these data do suggest that glucocorticoids can lead to worse outcomes, Dr Wallace points out that many of the analyses of this drug have a significant confounder: “Many people who are on steroids, are on steroids because their disease is poorly controlled. Does having poor control of your disease also predispose you to COVID-19? I think both factors probably contribute,” he said.
Other drugs, namely JAK inhibitors, TNF inhibitors, and disease-modifying antirheumatic drugs (DMARDs) have also been investigated for their COVID-19 risk potential. DMARDs, in particular, have been examined across several studies,1 with results indicating that some—but not all—DMARDs may confer worse COVID-19 outcomes.
“Rituximab and other B-cell depleting therapies have been consistently shown to be associated with a higher risk for COVID-19,” said Dr Wallace. “There’s some concern about some of the other DMARDs…but rituximab is the one with the most data and the greatest concern.”
Studies have demonstrated the association between rituximab and serious infection risk6 and since the COVID-19 pandemic began, reports have demonstrated the higher hospitalization risk in patients with RA with COVID-19 treated with rituximab.6 Although Dr Favalli and colleagues caution that these findings should not “be considered an absolute contraindication to drug maintenance during the pandemic…[rituximab] users should be monitored even more closely for early detection of signs and symptoms of possible infection.”
Vaccination is Key
Regardless of treatment, close monitoring by a rheumatologist is key for patients with RA during the pandemic. Post-exposure prophylaxis, said Dr Wallace, is particularly important if a patient suspects that they may have been exposed.
“In your patients who are immunosuppressed, you may want to be much more aggressive about getting them post-exposure prophylaxis, like monoclonal antibody treatment to try and prevent an infection,” he said, adding that post-exposure prophylaxis is now more widely recommended following publication of more in-depth studies.
And of course, patients with RA should receive a COVID-19 vaccination as soon as possible.
“RA is not a contraindication to vaccination,” said Dr Wallace. “Everyone with RA should get vaccinated. They should speak with their rheumatologists about whether or not they should hold the dose of their medication before or after the vaccine, but everyone should get the COVID-19 vaccine.”
Social Impacts of COVID-19
In addition to clinical concerns, people living with RA have faced a myriad of social challenges, including access to care, medication shortages, and anxiety and depression stemming from long periods of social isolation.1
“Regardless of whether or not you have RA, there was a lot of impact on mental health,” said Dr Wallace. “[But] I think that the COVID-19 pandemic had a huge impact on patients with RA and other rheumatic diseases for a number of reasons.”
One reason, he added, is the immunosuppressive treatments these patients are typically prescribed.
“There was a lot of uncertainty early on—and there continues to be—about the impact of that treatment on their risk of COVID-19,” he said. “And so, a lot of people with RA from the start were very cautious: quarantining, distancing, and isolating themselves.”
One study, a series of open-ended interviews with 112 patients in New York City,1,9 found that patients with RA were experiencing increases in fatigue, anxiety, and stress, in addition to worsening musculoskeletal symptoms and cognitive function. Patients also expressed concerns about changes in their medication, family, work, and finances, which further exacerbated emotional distress. In another study,1,10 concerns that RA would lead to worse COVID-19 outcomes led to patients following “strict social distancing measures.” Although these measures help stem the spread of COVID-19, they can also, Dr Wallace wrote, “foster loneliness, which can exacerbate anxiety, depression, and rheumatic disease flares.”
Due to these concerns, Dr Wallace found that early in the pandemic, many patients were stopping their RA therapies—risking flares and other disease complications. The reasoning was multifaceted: care access, medication shortages, and, overall uncertainty.
“There is a fear that comes with living with uncertainty, and not knowing if the disease you have, and the treatments that are keeping you functioning, are going to put you at risk,” he said. The results of a cross-sectional survey, conducted during the first 2 weeks of the pandemic in the United States, showed that of 530 patients (61% with RA), 74% reported “self-imposed changes to medications or doses.”11
In the same study, 42% of all participants reported changes in care, including canceled or postponed appointments, or appointments switched to telemedicine.11
“The switch to telemedicine was difficult for a number of reasons,” said Dr Wallace, “one of them being how abrupt it was. There wasn’t really a lot of training; we were never taught how to do a physical exam virtually over video, or how to measure disease activity virtually.”
“We went into all of this kind of blind, but I think we quickly learned how we might be able to assess disease activity,” he added.
In the last year, numerous studies have addressed the challenges of telemedicine in rheumatology clinical practice.12-14 And like much of the research on the novel coronavirus, study results were mixed.
At the Hospital for Special Surgery (HSS) in New York City, study authors noted, telehealth implementation for rheumatology practice was “rapid,” aided by a pre-existing plan to implement telerheumatology into the hospital’s clinical practice. This plan allowed rheumatologists to deliver care to a significant percentage of patients in a time-efficient way, dramatically increasing the hospital’s use of telemedicine from February to May 2020—from 0% to between 70% and 80%.13
These outcomes, though, are not necessarily generalizable to other rheumatology practices, many of whom have reported challenges with the advent of telemedicine. Dr Wallace cited a lack of direct patient access, difficulty establishing a rapport with new patients, and technical challenges on both the patient and provider side as issues to be overcome.
Despite these challenges, Dr Wallace believes that there is a place for telemedicine in rheumatology care, both throughout the pandemic and beyond.
“It’s not…that every RA patient visit has to be in person,” he said. “If your RA is under good control and you’re pleased with how you’re doing, and you feel like your disease is quiescent and your function isn’t affected and you’re doing well on your medication, a telemedicine visit periodically is okay.”
And there may be one silver lining in this pandemic that has caused so much widespread death and disease: “There are so few rheumatologists in the country, and they tend to be not very evenly distributed across the US,” Dr Wallace said. “Telemedicine will enable us to provide care to people who live in more remote areas and who don’t have access as regularly to a rheumatologist.”
With the Delta variant surging and other COVID-19 variants on the rise, the pandemic—and the challenges it brought to healthcare—are not yet over. For both patients with RA and rheumatologists, a deeper understanding of the role of various RA therapies, the role of RA inflammation in COVID-19 outcomes, and the optimization of telemedicine1 will guide both treatment and management in the months to come.
- Wallace ZS, D’Silva KM. COVID-19 and rheumatoid arthritis. Curr Opin Rheumatol. 2021;33(3):255-261. doi:10.1097/BOR.0000000000000786
- England BR, Roul P, Yang Y, et al. Risk of COVID-19 in rheumatoid arthritis: A national Veterans Affairs matched cohort study in at-risk individuals. Arthritis Rheumatol. Published online May 5, 2021. doi:10.1002/art.41800
- Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020;215:108427. doi:10,1016/j.clim.2020.108427
- Merad M, Martin JC. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355-362. doi:10.1038/s41577-020-0331-4
- Elemam NM, Maghazachi AA, Hannawi. COVID-19 infection and rheumatoid arthritis: Mutual outburst cytokines and remedies. Curr Med Res Opin. 2021;37(6):929-938. doi:10.1080/03007995.2021.1906637
- Favalli EG, Maioli G, Biggioggero M, Caporai R. Clinical management of patients with rheumatoid arthritis during the COVID-19 pandemic. Expert Rev Clin Immunol. Published online April 14, 2021. Doi: 10.1080/1744666X.2021.1908887
- Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmun Rev. 2020;19(5):102523. Doi: 10.1016/j.autrev.2020.102523
- Kilian A, Chock YP, Huang IJ, et al. Acute respiratory viral adverse events during use of antirheumatic disease therapies: A scoping review. Semin Arthritis Rheum. 2020;50(5):1191-1201. Doi: 10.1016/j.semarthrit.2020.07.007
- Mancuso CA, Duculan R, Jannat-Khah D, et al. Rheumatic disease-related symptoms during the height of the COVID-19 pandemic. HSS J. 2020;16(Suppl 1):1-9. Doi: 10.1007/s11420-020-09798
- Hooijberg F, Boekel L, Vogelzang EH, et al. Patients with rheumatic diseases adhere to COVID-19 isolation measures more strictly than the general population. Lancet Rheumatol. 2020;2(10):e583-e585. Doi: 10.1016/S2665-9913(20)30286-1
- Michaud K, Wipfler K, Shaw Y, et al. Experiences of patients with rheumatic diseases in the United States during the early days of the COVID-19 pandemic. ACR Open Rheumatol. 2020;2(6):335-343. doi:10.1002/acr2.11148
- Bonfá E, Gossec L, Isenberg DA, Li Z, Raychaudhuri S. How COVID-19 is changing rheumatology clinical practice. Nat Rev Rheumatol. 2021;17(1):11-15. Doi: 10.1038/s41584-020-00527-5
- Gkrouzman E, Wu DD, Jethwa H, Abraham S. Telemedicine in rheumatology at the advent of the COVID-19 pandemic. HSS J. 2020;16(Suppl 1):1-4. doi:10.1007/s11420-020-09810-3
- Romão VC, Cordiero I, Macieira C, et al. Rheumatology practice admist the COVID-19 pandemic: A pragmatic review. RMD Open. 2020;6(2):e001314. Doi: 10.1136/rmdopen-2020-001314