Rituximab likely raises risk of hospital death in COVID-19 patients

NEW YORK (Reuters) – In hospitalized COVID-19 patients on immunosuppressive therapy, only those taking rituximab had an increased risk of in-hospital death in a retrospective analysis.

“In this analysis of a large and diverse cohort … long-term use of most immunosuppressive medications was not associated with increased risk of severe COVID-19 or death,” Dr. Caleb Alexander and Dr. Kathleen Andersen, both of Johns Hopkins University, Baltimore, told Reuters Health by email. “Only 1 of 303 drugs examined, rituximab, was associated with an increased risk of in-hospital death … both when used for rheumatologic as well as for cancer therapy.”

As reported Nov. 15 in The Lancet Rheumatology, the researchers analyzed data from 42 health systems in the National COVID Cohort Collaborative (N3C) from January 2020 to June 2021, comparing adults with and without long-term immunosuppressive medication regimens.

Among more than two million potentially eligible adults in the N3C repository with confirmed or suspected COVID-19 during the study period, 22,2575 met the inclusion criteria (mean age, 59; 50%, men; about 46% non-Hispanic white). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%).

A total of 16,494 (7%) had been on long-term immunosuppression for diverse conditions, including rheumatologic disease (33%), solid organ transplant (26%), and cancer (22%).

Medications included rheumatologic drugs such as interleukin inhibitors, Janus kinase inhibitors, or tumor necrosis factor inhibitors; antimetabolite drugs such as azathioprine or calcineurin inhibitors; cancer therapies such as anthracyclines, checkpoint inhibitors or cyclophosphamide; rituximab; targeted cancer therapies; and oral glucocorticoids.

In a propensity score-matched cohort that included close to 13,000 immunosuppressed and 30,000 nonimmunosuppressed patients, immunosuppression was associated with a reduced risk of invasive ventilation (hazard ratio, 0.89), and no overall association was seen between long-term immunosuppression and the risk of in-hospital death.

None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation.

No statistically significant association was seen between most drugs and in-hospital death; however, increases were found with rituximab for rheumatologic disease (HR, 1.72) and for cancer (HR, 2.57).

Results were similar across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions.

Dr. Alexander and Dr. Andersen said, “Our findings underscore the importance of local and state health departments prioritizing anti-SARS-CoV-2 monoclonal antibody treatments for rituximab patients if they are infected. Further, given rituximab patients may not mount a strong immune response from vaccination, these findings further emphasize the importance of vaccination for people around rituximab patients.”

Indeed, a study published a week earlier in The Lancet Rheumatology found that, after two doses of vaccine, 3 (30%) of 10 patients on rituximab were seronegative, 1 had no detectable T-cell response and only 1 had detectable neutralizing antibodies. All seronegative patients and those with B-cell depletion after two doses remained seronegative after the third vaccine dose. The authors suggest delaying a third dose in such patients until B-cell repopulation.

Dr. Philip Robinson of the University of Queensland in Brisbane and Dr. David Liew of Austin Health in Melbourne, coauthors of an editorial published with the Nov. 15th paper, commented in a joint email to Reuters Health. “Rituximab, one of the highest-grossing drugs of all-time, is used extensively in rheumatology, immunology and oncology, and often where no effective alternative therapies exist. Similar drugs are used in neurology, with similar problems.”

“All these drugs have two problems: they both increase risk for poor outcomes in COVID-19 and also impair vaccine responses for COVID-19 vaccines,” they said. “While others will be able to continue on with relative confidence, patients on rituximab and similar drugs can therefore be doubly vulnerable to sickness and death following COVID-19.”

“It is clear we need better strategies, potentially involving early treatment, postexposure prophylaxis, and pre-exposure prophylaxis,” they said. “This might come in the form of infusions of neutralizing monoclonal antibodies for these patients.”

“There also needs to be further work on trying to ascertain if vaccine responses can be improved by timing the vaccinations better (including before rituximab treatment) and/or giving additional doses,” they noted.

“All these therapies are currently expensive, and there also remains a moral obligation for high-income countries to support the global burden of disease and find affordable therapies for use in uninsured patients and low-middle income countries,” Dr. Robinson and Dr. Liew concluded.