Cohort Study Reveals Patients Treated with Rituximab Have Poorer COVID-19 Outcomes

As the COVID-19 pandemic swept the world, rheumatologists wondered if their patients would be uniquely vulnerable. As time has passed, immunologists have learned that although the innate immune system and T cells are important in the early antiviral response to COVID-19, B cells also appear to be crucial—information that further suggests a special susceptibility of patients with rheumatological disease.

One of the first investigations of the vulnerabilities of patients with inflammatory rheumatic and musculoskeletal diseases used the French RMD COVID-19 cohort.¹ The objective of the data analysis of this cohort was to identify epidemiological characteristics associated with severe disease in patients with both rheumatic disease and COVID-19. That first analysis found several factors, including a signal for rituximab. However, the findings were limited because the analysis did not take into consideration the main characteristics and potential confounders of patients receiving rituximab. To date, although it was reasonable to assume rituximab’s effect on B cells may compromise a response to COVID-19, no cohort studies have specifically addressed whether rituximab adversely affects COVID-19 outcomes.

A recent analysis of the French RMD COVID-19 cohort compared COVID-19 severity in patients with inflammatory rheumatic and musculoskeletal diseases who were treated with rituximab with those who were not. The analysis revealed patients receiving rituximab therapy experience more severe COVID-19. Jerome Avouac, MD, PhD, a rheumatologist at the Centre Universite de Paris, France, and colleagues concluded from their analysis of the French COVID-19 RMD cohort that rheumatologists should use caution when prescribing rituximab to patients with inflammatory rheumatic and musculoskeletal diseases. They published the association between rituximab therapy and admission to an intensive care unit (ICU) or death online March 25 in Lancet Rheumatology.²

“The findings support what we already knew and thought,” says Cassandra Calabrese, DO, a rheumatologist at Cleveland Clinic in Ohio, noting that the study reiterates what rheumatologists have learned from the COVID-19 Global Rheumatology Alliance data. “This [association] is something we’ve been long aware of and made practice changes as a result of the knowledge.”

The COVID-19 Global Rheumatology Alliance was created in March 2020 with the mission to collect, analyze and disseminate information about COVID-19 and rheumatology to patients, physicians and other relevant groups to improve the care of patients with rheumatic disease. The international database allows any provider to enter data, and it currently includes thousands of patients, symptoms and medications. Although data from the Alliance have been analyzed and published in multiple reports, the data do not allow for a cohort study.

Findings

In the current cohort study, the investigators collected data on patients treated with rituximab, as well as a control group of patients who were eligible for rituximab therapy by indication but did not receive it. The researchers adjusted for the main comorbidities associated with COVID-19 severity and rituximab prescription, finding comorbidities had a definite effect on risk of death. The study not only revealed an association between rituximab therapy and more severe disease, but it also found the time between the last infusion of rituximab and first symptoms of COVID-19 was significantly shorter in patients who developed severe COVID-19 than those with moderate or mild forms. This finding further supports a direct relationship between rituximab and severe COVID-19 disease.

When the investigators compared hospital stays of patients who received rituximab and those who did not, they observed a prolonged hospital stay and increased risk of morbidity, mortality and potential infection-related sequelae. Although more patients treated with rituximab died, after the researchers adjusted for potential confounders, they found the risk of death did not increase significantly compared with patients not treated with rituximab, reinforcing to the authors the importance of associated comorbidities.

The authors conclude by suggesting it may be wise to delay rituximab therapy in patients with rheumatoid arthritis. However, they note the decision to delay therapy may be more difficult in patients with connective tissue disorders or vasculitis, who are at risk greater risk of disease relapse.

Additionally, Dr. Calabrese says the findings have implications for the timing and choice of COVID-19 vaccine. It appears vaccines given within five months of the last rituximab dose are not as effective. Therefore, if possible, experts recommend giving the COVID-19 vaccine at least four to six months after the last infusion and four to six weeks before the next infusion.³ Likewise, administering a two-dose vaccine may be more challenging to coordinate for patients who are due for their rituximab therapy than a single-dose vaccine. It may not be feasible for patients to delay their treatment.

“This study confirms the importance of timing of vaccines in patients receiving rituximab, especially because this group also has increased risk of poor outcomes if infected with SARS-CoV-2,” Dr. Calabrese says.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

References

1. FAI2R /SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: Data from the French RMD COVID-19 cohort of 694 patients. Ann Rheum Dis. 2020 Dec 2;80(4):527–538. Online ahead of print.
2. Avouac J, Drumez E, Hachulla E, et al. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: A cohort study. Lancet Rheumatol. 2021 Mar 25. Online ahead of print.
3. Dougados M. Managing patients with rheumatic diseases treated with rituximab during the COVID-19 pandemic. Lancet Rheumatol. 2021 Jun;3(6):e395–e396. Epub 2021 Mar 25.