Rheumatoid arthritis (RA) is a systemic disease with chronic inflammation of the joints as its main manifestation, and its pathogenesis is not yet fully understood, hence the lack of specific therapeutic measures. The new treatment strategy for RA is to control the disease activity with effective drugs in the early stage of the disease, suppress the immune response, reduce functional impairment and prevent irreversible changes in bone and cartilage, replacing the previous progressive pyramidal treatment model. Because of the clear efficacy and good safety of rituximab (melphalan, RTX) in the treatment of rheumatoid arthritis, it is now mostly used in combination with methotrexate (MTX), which is a new option for the treatment of rheumatoid arthritis, especially for patients for whom TNF inhibitor therapy is ineffective and worthy of application. However, many patients have poor efficacy or cannot tolerate MTX, is it possible to find an alternative to MTX in combination with RTX? Leflunomide is a new type of immunosuppressant that inhibits the formation of pyrimidines by inhibiting dihydroorotic acid dehydrogenase and tyrosine kinase, resulting in impaired DNA synthesis and thus inhibiting lymphocyte activation and the resulting immune response. Multicenter randomized, double-blind controlled clinical studies have been conducted in thousands of patients with rheumatoid arthritis in China and abroad, and the results have demonstrated that the drug is better than methotrexate in slowing bone erosion and joint protection within 1 year of administration. Recently, Javier Narváez et al. from the Rheumatology Research Group in Barcelona, Spain, found similar efficacy in the LEF+RTX treatment group (32 patients) compared to the MTX+RTX treatment group (45 patients) after 6 months of treatment in 108 rheumatoid arthritis patients, with an overall efficacy rate of 77% in both DAS28 scores, compared to rituximab monotherapy (31 patients). The incidence of adverse events was similar in both groups, at 9%, including mainly gastrointestinal symptoms, but there were no cases of withdrawal due to serious adverse events. The combination of rituximab, which induces B-cell lysis by binding to CD20 on the B-cell surface, and LEF, which also inhibits B-cell proliferation, produced a synergistic effect. In contrast, MTX did not inhibit the autoreactivity of B-cell clones and could not correct the tolerance defect of B cells. Moreover, the experts concluded that there was no significant difference between rituximab combined with methotrexate and rituximab alone. In summary, the investigators stated that LEF can be an effective alternative to MTX in combination with RTX in the treatment of patients with rheumatoid arthritis.