Majority of patients with RA maintain low disease activity on ultra-low dose rituximab
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In an extension of the REDO trial, most patients with rheumatoid arthritis on ultra-low-dose rituximab — either 200 or 500 mg — maintained low disease activity for up to 4 years, according to data presented at ACR Convergence 2021.
“To start off with, we didn't really know the optimal dose of rituximab in rheumatoid arthritis,” Nathan den Broeder, MSc, a PhD student at Sint Maartenskliniek, in the Netherlands, told attendees at a virtual press conference. “This is because Rximab was originally developed for another indication, namely lymphoma, and therefore no extensive dose findings took place for the rheumatoid arthritis indication. The registered dose is 2,000 mg per 6 months, and only one other dose was tried in the trials — 1,000 mg for 6 months.”
“Previous research has shown that 1,000 mg is equally effective as 2000 mg,” he added. “There were some case reports and case series, and a small study, suggesting that also much lower doses where possible. That's why we performed the REDO trial, where we compared 1,000 mg to 500 and 200 mg of rituximab for 6 months. In this trial, we saw very comparable results with regards to disease activity, but we could not formally, statistically show that the lower doses were not less effective than the higher dose.”
To confirm the effectiveness of ultra-low doses of rituximab (Rituxan; Genentech, Biogen) reported in patients with rheumatoid arthritis from the 6-month REDO trial, den Broeder and colleagues followed the participants for up to 4 years. A total of 118 out of 142 REDO participants were included in the extension. Exclusion criteria were continuing treatment elsewhere, lack of informed consent, and data yet to be collected in two study centers. The median follow-up period was 3.2 years.
Treatment decisions were at the discretion of the rheumatologist and patient. Seven participants switched to another biologic or targeted, synthetic disease-modifying antirheumatic drug and were subsequently removed from the disease activity analysis. The final rituximab dose per infusion was 200 mg in 37 participants, 500 mg in 47 participants and 1,000 mg in 34 participants. The median yearly dose was 978 mg.
The researchers collected disease activity — based on DAS28-CRP — and medication use from the start of the trial to censoring, which occurred in April. Disease activity was further analyzed using a longitudinal mixed model, with random intercepts to account for intra-patient correlations, in two ways. First, by original randomization and stratification factors, and then by time-varying total rituximab dose received in the year preceding each disease activity measurement, adjusted for current conventional, synthetic DMARD or glucocorticoid use, and rheumatoid factor and anti-citrullinated protein antibodies.
The primary outcome was disease activity, with rituximab persistence, doses and intervals, as well as the use of comedication, set as secondary outcomes.
According to the researchers, disease activity in both ultra-low dose groups was non-inferior to the 1000-mg group. During follow-up, the mean DAS28-CRP for the 1,000 mg arm was 2.2 (95% CI, 2-2.4), compared with 2.2 (95% CI, 2.1-2.4) in the 500 mg group and 2.3 (95% CI, 2.2-2.5) in the 200 mg group. Analyzed by received rituximab dose, lower doses were significantly associated with a higher DAS28-CRP — 0.15 (95% CI, 0.04-0.26) points higher per 1, 000 mg more. The upper limit for relevant doses was below the prespecified non-inferiority margin, excluding a relevant effect of dose on disease activity.
The median (IQR) final interval between infusions was 6 months (95% CI, 5.7-6.5) in the 200-mg group, 6.2 months (95% CI, 6-7.4) in the 500 mg group, and 6.4 months (95% CI, 6-9.6) in the 1,000 mg group. The rate of glucocorticoid injections was 0.38 (95% CI, 0.32-0.44) per patient-year, with an initiation rate for oral glucocorticoids of 0.05 (95% CI, 0.03-0.08) per patient-year.
“As a result of this study, we are now implementing a strategy of rituximab of dose reduction into clinical practice at our center,” den Broeder said. “What we do in this strategy is we start patients on the normal dose of 1,000 mg. If they respond well to that, we reduce them to 500 mg for 6 months. If they respond well to that as well, they go to 200 mg. With this, we hope that patients have less side effects, and we hope to reduce the cost of treatment. Also, what we instantly gain is that the infusion time for patients is also reduced.”
“What we are further looking into is, once we’ve been doing this in clinical practice for a while, do a similar study to what we did now, but then, really in the clinical practice population, evaluate the results of this strategy,” he added. “We are looking into the possibility of subcutaneous administration, so patients can have their rituximab in subcutaneous injections. This is possible because, with 200 mg, the volume of the injection that would be needed gets low enough that this is actually practical.”
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den Broeder N. Abstract 1443. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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