Rituximab is associated with worse COVID-19 outcomes in patients with rheumatoid arthritis: A retrospective, nationally sampled cohort study from the U.S. National COVID Cohort Collaborative (N3C)

Abstract

Objective: To assess whether rituximab (RTX) is associated with worse COVID-19 outcomes among patients with rheumatoid arthritis (RA).

Methods: We used the National COVID Cohort Collaborative (N3C), the largest US cohort of COVID-19 cases and controls, to identify patients with RA (International Classification of Diseases (ICD)-10 code, M05.X or M06.X). Key outcomes were COVID-19-related hospitalization, intensive care unit (ICU) admission, 30-day mortality, and World Health Organization (WHO) classification for COVID-19 severity. We used multivariable logistic regression models to assess the association between RTX use and the odds of COVID-19 outcomes compared with the use of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), adjusting for demographics, medical comorbidities, smoking status, body mass index, US region and COVID-19 treatments.

Results: A total of 69,549 patients met our eligibility criteria of which 22,956 received a COVID-19 positive diagnosis between 1/1/2020 and 9/16/2021. Median (IQR) age of the cohort was 63 (52-72) years, 76% of the cohort was female, 68% was non-Hispanic/Latinx White, and 73% was non-smokers. Prior to their first COVID-19 diagnosis, 364 patients were exposed to RTX. Compared to the use of csDMARDs, RTX use was associated with an increased odds of COVID-19-related hospitalization (adjusted odds ratio [aOR] 2.1, 95% confidence interval 1.5-3.0), ICU admission (aOR 5.2, 1.8-15.4) and invasive ventilation (aOR 2.7, 1.4-5.5). Results were confirmed in multiple sensitivity analyses.

Conclusion: Our findings can guide patients, providers, and policymakers regarding the increased risks associated with RTX use during the COVID-19 pandemic. These results can help risk stratification and prognosis-assessment.

Keywords: COVID-19; COVID-19 outcomes; Rheumatoid arthritis; Rituximab.

Fig. 1

Flow diagram showing the cohort selection Legend: ICD International Classification of diseases; RA: Rheumatoid Arthritis.

Fig. 2

Multivariable-adjusted association of baseline rituximab use and each COVID-19 outcome with csDMARD as the referent category from US N3C cohort. Legend: Figure shows A) odds ratios and 95% confidence interval for association between rituximab use and COVID-19-outcomes; B) Beta estimates (95% CI) for association between rituximab and ICU and hospital length of stay. AKI, acute kidney injury; CI: Confidence interval; ICU, intensive care unit; LOS: Length of stay. Hospitalized*: adjusted for demographics, weight categories per BMI as normal vs. underweight, overweight, and obese, smoking status, US region, and modified Deyo-Charlson index. All other outcomes: adjusted for above variables and all COVID-19 treatments Circles (red) denote significant outcomes, orange squares denote non-significant outcomes.

Fig. 3

Sensitivity analyses (S1-S7) for odds of hospitalization, ICU admission or invasive ventilation with rituximab from US N3C cohort. legend Figure shows odds ratios and 95% confidence interval for association between rituximab use and A) COVID-19-related Hospitalization; B) ICU admission, C) Invasive ventilation. New S1, sensitivity analyses 1: Deyo-Charlson overall score (with RA excluded) as 0, 1, 2 vs. 3 or more. New S2, sensitivity analyses 2: Each Deyo-Charlson comorbidity (with RA excluded). New S3, sensitivity analyses 3: RA Case definition requires at least 2 ICD codes. New S4, sensitivity analyses 4: RA Case definition requires >= 1 ICD code + any RA medication. New S5, sensitivity analyses 5: Referent is Hydroxycholoroquine, nbDMARD variable except HCQ, i.e., Methotrexate, Leflunomide, or Sulfasalazine. New S6, sensitivity analyses 6: Referent is No DMARD category. New S7, sensitivity analyses 7: Referent is TNFi-biologic category. Hospitalized*: adjusted for demographics, weight categories per BMI as normal vs. underweight, overweight, and obese, smoking status, US region, and modified Deyo-Charlson index. All other outcomes: adjusted for above variables and all COVID-19 treatments. Circles (red) denote significant outcomes, orange squares denote non-significant outcomes.