Use of Rituximab, JAK Inhibitors at Time of COVID-19 Onset Increases Poor Outcomes

The influence of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) on COVID-19 in people with rheumatoid arthritis is unclear. Some research, including a study of the COVID-19 Global Rheumatology Alliance (C19-GRA) registry, suggests that baseline use of certain b/tsDMARDs for rheumatic diseases may be associated with less severe COVID-19 outcomes.

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However, there is also some evidence that baseline use of certain b/tsDMARDs, such as rituximab or abatacept, may increase the risk of poor COVID-19 outcomes because of impaired viral immune defenses.

Jeffrey A. Sparks, MD, MMSc, of the Division of Rheumatology, Inflammation and Immunity at Brigham and Women's Hospital, Zachary S. Wallace, MD, MSc, a physician in the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital, and the other members of the C19-GRA recently analyzed the largest cohort of individuals with rheumatoid arthritis (RA) and COVID-19 assembled to date. In Annals of the Rheumatic Diseases, they report a novel association of JAK inhibitors with COVID-19 severity and confirm increased risk with rituximab.

Study Methods

The researchers included 2,869 patients who were reported to the C19-GRA registry or the European Alliance of Associations for Rheumatology COVID-19 database between March 24, 2020, and April 12, 2021, and were using a b/tsDMARD at the time of COVID-19 onset.

• Tumor necrosis factor-α inhibitor—1,388
• JAK inhibitor—563
• Rituximab—364
• Interleukin-6 inhibitor—317
• Abatacept—237

Patients could also be using a glucocorticoid or conventional synthetic DMARD. All had a resolved clinical course.

Outcomes

The primary outcome was COVID-19 severity, ranked on an ordinal scale (mutually exclusive categories):

• No hospitalization—79%
• Hospitalization with no oxygenation—5%
• Hospitalization with oxygenation/mechanical ventilation—11%
• Death—5%

Risk of Worse Severity

Compared with users of TNF inhibitors, the odds of worse COVID-19 severity for users of other drug classes were:

• Rituximab—4.15 times greater in multivariable-adjusted analysis
• JAK inhibitors—2.06 times greater
• Abatacept—not increased
• IL-6 inhibitors—not increased

In a sensitivity analysis in which medication users were matched on demographic and clinical characteristics, the odds of worse outcomes with abatacept were 1.60 times greater than with TNF inhibitors. Results for the other drug classes were similar to the primary analyses.

Risk of Individual Levels of Severity

Compared with TNF inhibitors, rituximab and JAK inhibitors were associated with increased odds of each dichotomized COVID-19 outcome (all P<0.01):

Rituximab

• Hospitalization—OR, 4.53
• Hospitalization with oxygenation/ventilation or death—OR, 2.87
• Death—OR, 4.57
• Mechanical ventilation—OR, 4.05
• Mechanical ventilation or death—OR, 4.44

JAK Inhibitors

• Hospitalization—OR, 2.40
• Hospitalization with oxygenation/ventilation or death—OR, 1.55
• Death—OR, 2.04
• Mechanical ventilation—OR, 2.03
• Mechanical ventilation or death—OR, 2.02

Applying the Findings to the Clinic

Vaccination and COVID-19 risk mitigation measures such as mask wearing and social distancing remain paramount for patients with RA who are using rituximab or JAK inhibitors. Other interventions (e.g., monoclonal antibody treatment) might be considered for such patients with COVID-19 exposure or early symptoms.

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