AMARA Study: Results Mixed for Rituximab Plus Leflunomide in Patients With RA

woman with rheumatoid arthritis taking medication
woman with rheumatoid arthritis taking medication
In the AMARA study, the researchers assessed the safety and efficacy of rituximab plus leflunomide in patients with rheumatoid arthritis.

The concomitant use of leflunomide with rituximab in patients with rheumatoid arthritis (RA) demonstrated clinical benefits, but the primary endpoint was not met and concerns regarding serious adverse events were noted, according to study results published in Rheumatology.

The co-treatment of biologic agents and methotrexate in patients with RA has been found to be more effective than treatment with either agent alone. However, most studies have focused on treatment with tumor necrosis factor inhibitors compared to B-cell inhibitors, such as rituximab. Moreover, methotrexate intolerance occurs in 11% to 29% of patients with RA, though few studies have evaluated the effectiveness of co-administration of biologics with other disease-modifying antirheumatic drugs. Overall, further information is needed on different combination therapy regimens.

In the current study, the researchers investigated the efficacy and safety of combination therapy with rituximab and leflunomide in patients with RA.

Adult patients with active RA (defined as Disease Activity Score based on 28-joint count >3.2 and ≥3 tender and swollen joints) and an inadequate response to leflunomide-only therapy were enrolled in the prospective, investigator-initiated, randomized, double-blind, placebo-controlled, phase 3 clinical trial ( Identifier: NCT01244958) at 33 clinical centers in Germany, between August 8, 2010 and January 28, 2015. Patients were randomly assigned 2:1 to receive 1000 mg rituximab or placebo administered as an intravenous infusion on day 1 and 15. All patients continued receiving oral leflunomide at the pretreatment dose (10-20 mg/d) during the study period.

The primary endpoint was the difference in the percentage of patients who achieved the American College of Rheumatology (ACR) response criteria for 50% improvement in RA activity measures (ACR50) at week 24. Secondary endpoints included ACR20 and ACR70 (20% and 70% improvement in RA activity measures, respectively) responses, as well as ACR50 responses at earlier timepoints. Patients were monitored for treatment-related adverse events (AEs) and serious adverse events (SAEs).

A total of 93 and 47 study participants received rituximab and placebo, respectively, in addition to leflunomide. Co-treatment of rituximab plus leflunomide vs placebo plus leflunomide resulted in an increase in the ACR50 response rate that was significant at week 16 (32% vs 15%, respectively; P =.020), but not at the primary endpoint, week 24 (27% vs 15%, respectively; P =.081).

Researchers noted significant differences with rituximab plus leflunomide in some secondary endpoints, including ACR20 rates from weeks 12 to 24. Rates of AEs were similar between the rituximab and placebo groups (71% vs 70%, respectively); however, SAEs, including infections and musculoskeletal disorders, were higher in the rituximab vs the placebo group (20% vs 2%, respectively).

The main limitation of the study was a smaller sample size than expected due to low enrollment and high dropout that limited the statistic power for the primary endpoint of ACR50 response at week 24.

Researchers noted, “In summary, combination therapy with rituximab plus leflunomide did not achieve the primary efficacy outcome. However, key secondary outcomes suggest this may be an effective treatment regimen for some patients with active RA and an inadequate response to leflunomide alone. In particular, this regimen may provide a valuable treatment option for patients [with RA] who are likely to benefit from rituximab, but are intolerant to or have contraindications against methotrexate. Given the unexplained increase in SAEs in patients treated with this combination, we recommend close monitoring of treated patients.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.


Behrens F, Koehm M, Rossmanith T, et al. Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study). Rheumatology (Oxford). Published online March 26, 2021. doi:10.1093/rheumatology/keab153