Two-dose Rituximab as Effective as Standard 4 in Severe AAV
A two-dose rituximab regimen is as safe and works as well as the standard four doses in inducing remission in adults with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), according to a review study.
While these findings support the current use of either regimen in clinical practice for treating GPA and MPA — two types of ANCA-associated vasculitis (AAV) — they highlight that patients may equally benefit from a two-dose regimen that’s more convenient and costs less.
“Our study suggests that a lower two-dose regimen may be as effective as a four-dose regimen to induce remission in patients with severe AAV,” the researchers wrote.
Still, head-to-head clinical trials are needed to confirm these results, they said, noting that some patient groups were underrepresented in their analysis, including Asians, those with obesity, and those with new onset of the disease.
The review study, “Comparison of Two Rituximab Induction Regimens for Antineutrophil Cytoplasm Antibody–Associated Vasculitis: Systematic Review and Meta-Analysis,” was published in the journal ACR Open Rheumatology.
Rituximab is an antibody-based therapy approved in the U.S., Europe, and elsewhere to treat GPA and MPA. It works by promoting the death of B-cells, the immune cells that produce antibodies, including those that wrongly attack the body’s vascular system in AAV. In both types of AAV, that immune system attack leads to increased inflammation in blood vessels.
Based on data from two previous clinical trials — the Phase 2/3 RAVE study (NCT00104299) and the RITUXVAS trial (ISRCTN28528813) — rituximab’s approved induction regimen for AAV was set at four weekly intravenous (into-the-vein) injections of 375 mg/m2.
However, rituximab is approved for the treatment of rheumatoid arthritis, another autoimmune disease, as a two-dose regimen. Arthritis patients given rituximab receive 1,000 mg on days 1 and 15.
“Several groups started to use this alternative, which was more practical and convenient for their patients with AAV,” the researchers wrote.
While some small studies had suggested that this two-dose regimen could be as effective as four doses in inducing disease remission in people with severe AAV, no appropriately controlled, head-to-head studies have compared the two rituximab regimens in this patient population.
To address this knowledge gap, researchers in Canada and France systematically reviewed published studies — in English or French — from January 2000 to October 2019, reporting the six-month safety and effectiveness of each of these induction regimens in adults with active severe GPA or MPA.
From the 226 studies accessed for eligibility, 27 were included in the analysis. Most were conducted at a single center in Northern European countries or in the U.S. Altogether they involved a total of 361 patients treated with the four-dose rituximab regimen and 145 with the two-dose regimen.
None of the included patients had received simultaneous cyclophosphamide or plasma exchange, two other standard treatments for AAV. That requirement was designed to limit potential influencing factors.
Before treatment, there were no major group differences regarding patient characteristics. The patients’ mean age at the time of rituximab initiation was 50 years, the mean time from diagnosis to rituximab therapy was six years, and 51% of the participants were women. Most had GPA (91%), relapsing disease (83–92%), and were positive for AAV-related antibodies (77–88%).
The results showed that, at six months, complete remission was achieved by 85% of patients given the four-dose rituximab regimen, and by 91% of those treated with the two-dose regimen. Notably, this difference did not reach statistical significance, suggesting that the regimens are equally effective at inducing disease remission in adults with severe AAV.
Similar findings were obtained when the four studies considered of low quality (three involving the four-dose regimen and one involving the two-dose regimen) were excluded from the analysis.
The two regimens also were associated with similar safety outcomes, including rates of infection — a known risk of rituximab treatment, which was 12% with both regimens — and of death. The rate of death was 1% in the four-dose regimen versus 0% in the two-dose regimen.
Moreover, similar mean daily doses of prednisone and comparable proportions of patients positive for AAV-associated antibodies and for B-cell depletion were found with both regimens. However, given the limited available data on these parameters, “firm conclusions could not be drawn,” the researchers wrote.
These findings suggest that the two-dose regimen “may be as effective as a four-dose” in inducing remission among people whose AAV is severe, the team wrote, noting that these results could have a profound impact on how patients are treated.
“There are several relevant socioeconomic implications arising from these results,” the researchers wrote, adding that the two-dose regimen may be associated with “one third of cost-sparing” for average patients, and that this dose and cost difference may be higher for obese patients.
“In patients with obesity, the dose and cost can be twice as high with the four-dose regimen compared to the two-dose regimen,” the team wrote.
“Considering that obesity has dramatically increased worldwide in the past few years, it should be cost-effective to determine whether the two [rituximab] regimens are equivalent in terms of efficacy and safety in patients with overweight,” they added.
Moreover, weekly infusions of rituximab for one month “involves additional fees related to repeat administration of the medication and is more time consuming for patients and health care professionals,” they wrote.
An appropriately controlled head-to-head trial comparing both regimens is needed to confirm these findings and accurately assess whether one regimen is more effective than the other in this patient population.
Further studies also are needed in AAV patients with obesity, with new-onset AAV or MPA, and in other ethnic groups, such as Asian patients, “all of whom were underrepresented in our meta-analysis population,” the researchers concluded.
While originally marketed as Rituxan (by Biogen) in the U.S., Canada, and Japan, and as MabThera (by Roche’s subsidiary Genentech) in Europe, other biosimilars of rituximab — such as Truxima, Ruxience, and Riabni — have been approved in recent years.
A biosimilar is a biologic medical product that is similar to another already approved biological medicine, analogous to generics for conventional medicines. Like generics, biosimilars are usually less expensive for consumers.