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Two reports presented at MS Virtual 2020, a joint meeting of ACTRIMS-ECTRIMS, provided an early look at relationships between anti-CD20 drugs used to treat multiple sclerosis (MS) and COVID-19: registry data from an international consortium and drug company post-marketing data about ocrelizumab (Ocrevus).

Global Registry Data

Registry data from clinicians in 21 countries participating in the suggested MS patients had a higher risk of more severe COVID-19 if they were treated with an anti-CD20 monoclonal antibody than another disease-modifying therapy (DMT) with different mechanisms.

MS patients using anti-CD20 drugs -- rituximab (Rituxan), to treat MS in the U.S., and ocrelizumab, approved for MS in 2017 -- were more likely to be hospitalized, admitted to the ICU, or require artificial ventilation than patients treated with other DMTs, reported Steve Simpson-Yap, PhD, MPH, of the University of Melbourne in Australia.

The report also examined whether risk for more severe COVID-19 was higher in MS patients treated with anti-CD20 drugs compared with other DMTs like dimethyl fumarate (Tecfidera) and natalizumab (Tysabri).

Compared with dimethyl fumarate, rituximab was associated with significantly higher risk of hospitalization, ICU admission, and ventilation. Weaker but similar associations were seen for ocrelizumab, and these did not always reach statistical significance.

Compared with natalizumab, pooled data showed the anti-CD20 drugs were associated with higher risks of hospitalization, ICU admission, and ventilation. "This comparison is particularly important because it shows that the associations found with anti-CD20 DMTs were not merely ascertainment bias due to patients having to come to the hospital for infusions" where they may have a greater chance of COVID-19 symptoms being diagnosed, Simpson-Yap told 麻豆传媒.

"There has been a great deal of discussion in the MS field whether disease-modifying therapies used to treat MS affect the susceptibility to COVID-19 or risk of severe outcomes, and if so, whether there are differences among the DMTs," noted Jeffrey Cohen, MD, of the Cleveland Clinic of Ohio, who wasn't involved with the study.

"This large registry study reported that among MS patients with more severe COVID-19 there was increased likelihood of being treated with an anti-CD20 monoclonal antibody relative to other DMTs. Some other studies have reported similar results. Given the mechanism of action and potency of the anti-CD20 monoclonal antibodies, this observation would not be unexpected," Cohen told 麻豆传媒.

But he pointed to several limitations. "Other studies have not found this association and have reported no increased risk from anti-CD20 monoclonal antibodies," Cohen said.

"It's not 100% clear that the increased risk, if it is real, is due to treatment with an anti-CD20 monoclonal antibody, per se," he added. "Although the investigators explored this point, it is very difficult to disentangle the treatment used by an individual patient from, for example, their disease characteristics, how many people are treated with the various DMTs in that location, the risk of COVID-19 in that location, etc., all of which might contribute to the association observed."

Moreover, the report looks at relative risk, while "the absolute risk of COVID-19 and of severe outcomes from it among all MS patients treated with anti-CD20 monoclonal antibodies is quite low," Cohen said.

The report included aggregated data about 476 MS patients with suspected and 776 with confirmed COVID-19. A total of 313 patients required hospital admission, 76 required ICU admission, 54 required ventilation, and 48 died.

Older age, progressive MS, and higher Expanded Disability Status Scale () scores were linked to higher frequencies of severe outcomes.

The researchers calculated adjusted prevalence ratios (aPR) for hospital admission, ICU admission, ventilation, and mortality, adjusting for age, sex, MS type, and EDSS. No associations were observed between DMTs and mortality.

Higher frequencies of the other three outcomes were seen when pooled anti-CD20 DMTs were compared with other DMTs. MS patients on anti-CD20 drugs were 1.5 times more likely to be admitted to the hospital (aPR 1.49), 2.6 times more likely to be admitted to the ICU (aPR 2.55), and 3.1 times more likely to need artificial ventilation (aPR 3.05, P<0.05 for all) than those using other drugs.

Similar trends were observed when pooled anti-CD20 DMTs were compared with natalizumab, but only hospitalization (aPR 1.99, P<0.05) reached statistical significance.

Compared with dimethyl fumarate patients, rituximab patients were 1.6 times more likely to be admitted to the hospital (aPR 1.58), 4.1 times more likely to be admitted to the ICU (aPR 4.12), and 7.3 times more likely to need ventilation (aPR 7.27; all P<0.05). Ocrelizumab patients were significantly more likely to have ICU admission (aPR 3.53, P<0.05) than those using dimethyl fumarate, but had insignificant trends for hospital admission and ventilation.

Ocrelizumab's weaker association with COVID-19 outcomes is of interest, Simpson-Yap said. "We believe this may reflect the weaker affinity of ocrelizumab to the CD20 2H7 epitope," leading to less depletion of B-lymphocytes, he noted. "This matters for the immune response to SARS-CoV-2 because B-cells are important in antigen presentation, so their absence would hinder the immune response and control of the virus."

Ocrelizumab Post-Marketing Data

The second report about drugs targeting CD20 in MS and COVID-19 included drug company pharmacovigilance data about ocrelizumab.

Richard Hughes, MD, principal medical safety director of F. Hoffmann-La Roche in Basel, Switzerland, presented post-marketing reports of 307 cases of ocrelizumab-treated patients with COVID-19 (263 confirmed; 44 suspected) through July.

COVID severity was not reported in 26.1% of the cases. About one-third (34.2%) were mild COVID-19 cases, 9.1% were moderate, 16.9% were severe, 4.9% were critical, and 5.5% were fatal.

"The pharmacovigilance data for ocrelizumab shows a 5.5% death rate for those assumed to be positive for SARS-CoV-2 and reported to them," said John Corboy, MD, of the University of Colorado in Aurora, who wasn't involved with the report. "Data of this type has very little utility given the many biases and limitations."

But the registry data show that "effect sizes are significant, especially for use of assisted ventilation," Corboy told 麻豆传媒. "It will be important to determine if the apparent worse outcomes with rituximab versus ocrelizumab are real and why that is the case."

A limitation of the registry report is "the denominator of who has actually been exposed is completely unclear, as asymptomatic and minimally symptomatic individuals are likely not included," he noted. "As this is registry data, there is no control group of matched individuals without MS and not on MS drugs, so comparisons to those without MS and not on these medications are lacking."

With all their limitations, however, "the studies suggested practitioners may wish to counsel patients that the risks of anti-CD20 agents may be greater than those with other MS medications if they are exposed to SARS-CoV-2," Corboy said.

What's not addressed is the effect anti-CD20 or other MS drugs may have on SARS-CoV-2 vaccination, he added. "Previous studies with other vaccines suggest vaccination of those on anti-CD20 molecules may well be associated with a lower response rate to the vaccine," Corboy pointed out. "The combination of potentially worse outcomes if exposed to SARS-CoV-2, and less responsiveness to vaccination for SARS-CoV-2 and other vaccines such as influenza, may prompt some to delay or discontinue anti-CD20 molecules going forward."

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