Positive COVID-19 vaccine responses persist in patients with RA receiving rituximab
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In patients with rheumatoid arthritis receiving rituximab, a positive humoral response following COVID-19 vaccination persists regardless of continued rituximab infusion, according to data published in Rheumatology.
The researchers added that repeated vaccine doses administered “as late as possible” after the lowest possible rituximab (Rituxan, Genentech) dose appears to be the optimal COVID-19 vaccination strategy for this population.
“Rheumatoid arthritis (RA) patients treated with rituximab (RTX) have both an increased risk of COVID-19 hospitalization and a reduced humoral response after two-dose vaccination, when compared to other disease modifying antirheumatic drugs (DMARDs),” Celeste J.T. van der Togt, MD, of the Radboud University Medical Center, in Nijmegen, the Netherlands, and co-authors wrote. “Therefore, to optimize management of COVID-19 risk in these patients, it is important to identify strategies for increasing response in this population.”
To investigate the interactions between rituximab and the effectiveness of a third COVID-19 vaccine dose in patients with RA, van der Togt and colleagues conducted a monocenter, observational study following up on the RTC-COVAC study. The present study featured two analyses. First, patients from the COVAC cohort who failed to respond to the first two vaccine doses but then demonstrated a humoral response 2 to 6 weeks after a third dose were included in the “third vaccine” analysis. Meanwhile, those who achieved a follow-up humoral response prior to the third dose were included in the “persistence” analysis. The study was conducted from June 2021 through January 2022.
All included patients had received two doses of either the Pfizer-BioNTech, the AstraZeneca or the Moderna vaccine. For the third dose, patients received either the Pfizer-BioNTech or Moderna formulations. The researchers examined demographic and disease information, as well as treatment details, including the use of conventional synthetic disease-modifying antirheumatic drugs, prednisolone biologic DMARDs, cumulative rituximab dose and the date and dose of the last rituximab dose.
Main outcomes included the proportion of patients achieving seroconversion following a third vaccination dose, as well as the proportion of patients who achieve a persistent humoral response following a second vaccine dose.
The current study included a total of 196 patients, of whom 98 were part of the “third vaccine” analysis, and 23 were part of “persistence” analysis.
According to the researchers, 19% of patients in the “third vaccine” analysis achieved a vaccination response. In addition, the percent of patients achieving a vaccine response was higher among those receiving rituximab 200 mg, compared with 500 mg or 1,000 mg — 38% vs. 19% and 15%, respectively. Meanwhile, in the “persistence” analysis, humoral response persisted in 96% and 89% of patients who received rituximab between the two measurements, the researchers wrote.
“Our main results illustrate that humoral response after third vaccination occurs in a relevant proportion of patients who did not respond to earlier vaccination,” van der Togt and colleagues wrote. “Also, with a similar OR as in our first study — although not significantly so due to a smaller study population — humoral response was associated with 200mg RTX and a longer time between RTX infusion and vaccination. Additionally, we have shown that the persistence of humoral response is very high even in the context of intercurrent RTX infusions.
“Based on the results of our study, repeated vaccination as late as possible after the lowest RTX dose possible seems the best vaccination strategy,” they added. “Once seroconversion is achieved, humoral response persists despite RTX continuation.”
References:
Avouac J, et al. Lancet Rheumatol. 2021;doi: 10.1016/S2665-9913(21)00059-X.
Furer V, et al. Ann Rheum Dis. 2021;doi: 10.1136/annrheumdis-2021-220647.
Perspective
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As we eagerly awaited the approval of COVID-19 vaccines, several questions had yet to be answered. How would our immunocompromised patients respond to the vaccine? Would the response be dependent on the disease process or medications? Should medication doses be altered to improve response? Previously, van der Togt and colleagues studied patients with rheumatoid arthritis receiving rituximab (Rituxan, Genentech) and their response to the initial two doses of COVID-19 vaccines. Now the team has moved forward and studied the same patients and their response to a third or booster dose of the COVID-19 vaccine.
Similar to the initial study, the lowest dose of rituximab given at the longest possible interval produced a higher vaccine response. Even though the authors identify limitations to the study, the results add to the growing body of knowledge related to efficacy of COVID-19 vaccines in rheumatology patients, and can be shared when engaging in shared decision-making discussions with our patients.
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David A. McLain, MD, MACR, FACP, FRCP
In this trial, there were two ultra-low dose rituximab (Rituxan, Genentech) groups. Ultra-low dose rituximab has not been on my radar. Previously, there was a meta-analysis of studies on low-dose rituximab, defined as retreatment with 500 mg x 2 or 1,000 mg x 1, showing that these doses were non-inferior to retreatment with rituximab 1,000 mg x 2. Ultra-low dose rituximab, defined as either 200 mg or 500 mg IV for retreatment, is being studied in the REDO trial.
A recent report showed that lower doses of rituximab resulted in lower drug levels but did not significantly affect anti-drug antibody levels (ADAs) or B-cell counts. Failure to meet response criteria was seen in 3 (10.7%), 12 (20.7%) and 7 (13.0%) patients, respectively, in the 1,000 mg, 500 mg and 200 mg dosage groups. The authors concluded that drug levels, ADAs, B-cell counts and patient disease and treatment characteristics were not predictive for response to ultra-low dose rituximab.
Ultra-low dose rituximab is also being investigated in other immune mediated inflammatory diseases, such as Grave’s orbitopathy and dermatomyositis. The present study was a monocenter, observational, and small — only a total of 98 patients — analysis of responsiveness to a third COVID-19 vaccine dose in the presence of rituximab. Only 23 patients were evaluated in the persistence arm of the study.
They found that once a patient receiving rituximab developed antibodies post vaccination, it persisted in 96% despite intercurrent rituximab infusions. Of interest was the numerical difference in the humoral response between 200 mg IV and 1,000 mg IV — it was more than double in the ultra-low dose group compared with the low dose group, at 38% vs. 15%. Statistically it was not significant, at P = .06. The small sample size likely was to blame, as there were only 13 patients in the ultra-low group.
Analyzing the difference between third vaccine responders and non-responders revealed that responders had a longer interval between the last rituximab dose and vaccination, compared with non-responders — median 139 days vs. 119 days. Again, this result was not significant and likely requires a larger sample size. The authors recommend giving rituximab at the lowest possible dose and providing repeat vaccinations at the longest interval after rituximab as possible.
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