expert roundtables

COVID-19: Considerations for Patients With Rheumatoid Arthritis

by Leonard H. Calabrese, DO; Jonathan Kay, MD; and Vibeke Strand, MD, MACR, FACP

Overview

Important differences may exist between rheumatoid arthritis (RA) therapies regarding their impact on immune function and the risk of viral infection. These differences, together with the rapidly evolving knowledge base on COVID-19, may be key considerations when choosing RA treatment during the COVID-19 era.

Q:

Are patients with RA at an increased risk for severe complications from COVID-19? What should be done with RA therapies if a patient contracts SARS-CoV-2 infection?

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“In patients with a known COVID-19 exposure, I feel very strongly that MTX should be stopped, allowing for a period of patient monitoring, because the drug may inhibit primary antibody responses to T-cell–dependent antigens.”

Leonard H. Calabrese, DO

To date, there is no smoking gun to suggest that patients with RA are more susceptible to acquiring SARS-CoV-2 infection or are more likely to succumb to COVID-19 in the absence of the well-known comorbidities already linked to COVID-19 risk, including diabetes, hypertension, morbid obesity, pulmonary disease, and others.

There are some recent data from the COVID-19 Global Rheumatology Alliance that suggest that prednisone, at doses of 10 mg/day or higher, is associated with an increased rate of hospitalization among patients with COVID-19, independent of rheumatologic disease activity. These findings were based on an analysis of a cohort of 600 patients with inflammatory rheumatic disease who were sufficiently symptomatic to receive a COVID-19 test. At this point in time, there are no data to suggest that biologics, targeted therapies, or targeted synthetic therapies pose a palpable risk, but it is all a work in progress.

A real concern is that SARS-CoV-2 infection is associated with numerous strategies to evade antiviral host defenses. Thus, one would want robust antiviral defenses to be present when one first acquires the infection; I do not see a rationale for being on any type of immunosuppressive therapy from the perspective of reducing the risk of acquiring the virus. In patients with a known COVID-19 exposure, I feel very strongly that methotrexate (MTX) should be stopped, allowing for a period of patient monitoring, because the drug may inhibit primary antibody responses to T-cell–dependent antigens.

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

 “I recommend stopping TNFi therapy if a patient with RA becomes infected because we do not know whether TNFi agents might be harmful during this phase of the infection.” 

Jonathan Kay, MD

Few data exist to guide us when treating a patient with RA who contracts COVID-19. In choosing appropriate treatment, we must consider the different stages of the viral infection. During the later cytokine release syndrome phase, anticytokine therapy (ie, agents targeting either interleukin 1 [IL-1] or interleukin 6 [IL-6]) may reduce the severity of the inflammatory response. Tumor necrosis factor inhibitor (TNFi) therapy might also have a beneficial effect during this phase, but the data are inadequate to confirm this.

A key question is what to do when a patient with RA is infected with SARS-CoV-2 and has initiated an adaptive immune response. I recommend stopping TNFi therapy if a patient with RA becomes infected because we do not know whether TNFi agents might be harmful during this phase of the infection. Based on limited collective experience, it probably is fine to continue anti–IL-6 receptor agents. Similarly, if a patient is taking a medication that inhibits IL-1, such as anakinra, which is not often used now to treat RA, it also could be continued.

Of the targeted small molecule disease-modifying antirheumatic drugs, baricitinib might be favored because of its potential to inhibit viral endocytosis by target cells. I would not continue tofacitinib or upadacitinib and might consider transitioning these patients to baricitinib. However, all of these Janus kinase inhibitors interfere with signal transduction through interferon receptors, which is an important component of host defense against viruses.

Very few patients with RA under my care are now taking hydroxychloroquine. I would not prescribe it as first-line treatment for a new patient with RA who did not have a contraindication to MTX. However, for patients with RA who are taking hydroxychloroquine, I do not recommend stopping it. Corticosteroids should always be reduced to the lowest effective dose and, if possible, should be discontinued. As stated by Dr Calabrese, it also makes sense to discontinue MTX if a patient has a known exposure to COVID-19. It is important to emphasize that none of these treatment decisions are supported by adequate clinical evidence; rather, they are based on theoretical considerations.

Vibeke Strand, MD, MACR, FACP

Adjunct Clinical Professor, Division of Immunology/Rheumatology
Stanford University School of Medicine
Biopharmaceutical Consultant
Palo Alto, CA

 “Based on the currently available data, I would agree that IL-1 inhibitors and IL-6 inhibitors should generally be continued in patients with RA and COVID-19, but we await further data.”

Vibeke Strand, MD, MACR, FACP

Corticosteroids do appear to be a risk for progression of COVID-19 infection, both in patients with RA and in those with systemic lupus erythematosus. I also agree that the risk factors for viral progression appear to be similar in patients with RA as for those with other immune-mediated inflammatory diseases, such as lupus.

With respect to hydroxychloroquine, I think it is reassuring that this drug has not been associated with an increased risk of heart failure, at least in patients with RA. As relates to anticytokine therapy, the reanalysis of a phase 3 trial with anakinra in patients with sepsis was of interest to me. In a subgroup of patients with features of macrophage activation syndrome, an entity similar to the cytokine storm, patients benefited from anakinra, with lower 28-day mortality. Since the time of that report, with the emergence of COVID-19, clinical trials have been undertaken to investigate the potential use of IL-1 inhibition, IL-6 inhibition, and numerous other treatment strategies for patients hospitalized with severe COVID-19 infection. So, based on the currently available data, I would agree that IL-1 inhibitors and IL-6 inhibitors should generally be continued in patients with RA and COVID-19. However, as noted by Dr Calabrese, this is a work in progress, and we await further data.

Regarding Janus kinase inhibitors, it is unclear to me whether there are any differences between agents with respect to COVID-19 risk; for instance, I do not know whether tofacitinib is markedly different from baricitinib at this point. However, since the interaction between the virus and RA therapies is complicated, it can be difficult to manage these patients. COVID-19 has also impacted the conduct of randomized controlled trials. For now, for the most part, we have decided to continue our trials, but we have opted for more flexibility for patients in completing their follow-up and/or having their labs performed.

References

Cavalli G, De Luca G, Campochiaro C, et al. Interlukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-e331. doi:10.1016 /S2665-9913(20)30127-2

D’Silva KM, Serling-Boyd N, Wallwork R, et al. Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US ‘hot spot.’ Ann Rheum Dis. 2020;0:1-7. doi:10.1136/annrheumdis-2020-217888

Fernandez-Ruiz R, Masson M, Kim MY, et al; NYU WARCOV Investigators. Leveraging the United States epicenter to provide insights on COVID-19 in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2020 Jul 26. doi:10.1002/art.41450

Gianfrancesco M, Hyrich KL, Al-Adely S, et al; COVID-19 Global Rheumatology Alliance. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020;79(7):859-866. doi:10.1136/annrheumdis-2020-217871

Michaud K, Wipfler K, Shaw Y, et al. Experiences of patients with rheumatic diseases in the United States during early days of the COVID-19 pandemic. ACR Open Rheumatol. 2020;2(6):335-343. doi:10.1002/acr2.11148

Mikuls TR, Johnson SR, Fraenkel L, et al. American College of Rheumatology guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic. Arthritis Rhematol. 2020;72(8):1241-1251. doi:10.1002/art.4130

Park JK, Lee YJ, Bitoun S, et al. Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis. Ann Rheum Dis. 2019;78(2):282-284. doi:10.1136/annrheumdis-2018-214025

Peterson D, Damsky W, King B. The use of Janus kinase inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). J Am Acad Dermatol. 2020;82(6):e223-e226. doi:10.1016/j.jaad.2020.03.099

Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease [published correction appears in Lancet. 2020;395(10241):1906]. Lancet. 2020;395(10223):e30-e31. doi:10.1016/S0140-6736(20)30304-4

Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: re-analysis of a prior phase III trial. Crit Care Med. 2016;44(2):275-281. doi:10.1097/CCM.0000000000001402

Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19(7):102568. doi:10.1016/j.autrev.2020.102568

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