Risk Factors Identified for Repeat COVID-19 in Patients With Systemic Autoimmune Rheumatic Diseases

Immunocompromised individuals may be especially vulnerable to contracting repeat COVID-19 infections because of reduced vaccine efficacy and waning of natural immunity over time.

Jeffrey A. Sparks, MD, MMSc, a rheumatologist in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s Hospital, Emily N. Kowalski, a research assistant in the Division, and colleagues recently completed the first study of risk factors for repeat COVID-19 and outcomes in an immunocompromised population.

In Seminars in Arthritis and Rheumatism, they report that using rituximab or methotrexate, and younger age at first infection increased the risk of repeat COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs). There was little evidence that repeat bouts of COVID-19 were more severe than initial illnesses, but the sample size was too small to draw definitive conclusions.


Since March 2020, when the COVID-19 pandemic began in Boston, investigators at Mass General Brigham have systematically identified cases of COVID-19 occurring among patients with SARDs. This study compared two groups:

  • 76 patients with a SARD who were verified to have had two episodes of COVID-19 more than 60 days apart by October 17, 2022 (cases)
  • 207 patients with a SARD who had exactly one episode of COVID-19 during the study period (controls), matched to the repeat infection cases by calendar date

The study focused on patients receiving immunosuppressive medication, so those patients with gout, pseudogout, osteoarthritis or fibromyalgia were excluded unless they also had a SARD diagnosis. The most common SARDs were rheumatoid arthritis, psoriatic arthritis/spondyloarthritis, and systemic lupus erythematosus. Percentages of each disease did not differ significantly between repeat COVID-19 case and control groups.

Odds of Repeat COVID-19

Almost all repeat COVID-19 episodes occurred after December 17, 2021, when the Omicron variant became predominant in the Boston area. In multivariable analyses, risk factors for repeat COVID-19 were:

  • Rituximab use—OR, 3.38 (95% CI, 1.26–9.08)
  • Methotrexate use—OR, 2.24 (95% CI, 1.08–4.61)

Cases were significantly younger than controls (mean age 50 vs. 60; P<0.0001), and older age was associated with lower odds of repeat COVID-19 (OR, 0.67 per 10 years; 95% CI, 0.54–0.82). The impact of age was not explained by comorbidities, specific immunomodulating drugs, or vaccination but may be explained by behavioral differences and younger people’s greater exposure to SARS-CoV-2 through social activities, work, and family.

Severity of Repeat COVID-19

Five of 76 cases (6.6%) were hospitalized during their repeat COVID-19 episode, but none died. Three cases had also been hospitalized during their first COVID-19 episode, and all three had hybrid immunity (had natural SARS-CoV-2 infection and also received vaccines before the repeat episode). Symptom counts were similar for first and repeat COVID-19 episodes.

Patient Counseling About Rituximab

This study is the first to show rituximab is associated with increased risk of repeat COVID-19. That finding was not explained by age, sex, comorbidities, SARD type, use of glucocorticoids or other disease-modifying antirheumatic drugs, symptom count at first COVID-19 episode, hospitalization status during first COVID-19 episode, or vaccination status.

Two of the five patients hospitalized for repeat COVID-19 were on rituximab and both were vaccinated. These patients should be counseled about the risk of repeat COVID-19, noting that the limited number of severe outcomes suggest that natural immunity may offer some protection.

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