About 30% of patients with rheumatoid arthritis fail to achieve a marked clinical response to tumour necrosis factor (TNF)α inhibitors.¹ Rituximab, a chimeric monoclonal antibody, selectively depletes human CD20-positive B cells.² In patients with rheumatoid arthritis with incomplete response to methotrexate (MTX), response with the addition of rituximab was superior to that with MTX alone.³ We carried out an observational study to assess the efficacy and safety of selective B cell depletion in the management of patients with rheumatoid arthritis refractory to TNFα inhibitors.

Ten patients fulfilling the 1987 American College of Rheumatology diagnostic criteria for rheumatoid arthritis⁴ and refractory to at least one anti-TNF agent for ⩾3 months were prospectively enrolled. Table 1 presents their clinical characteristics at baseline. All of them had active disease (median Disease Activity Score (DAS28) 5.28, interquartile range (IQR): 4.6–6.3).⁵

Patients received two intravenous perfusions of 1000 mg rituximab at 2-week intervals, as previously described.³ They received transient oral or intravenous corticosteroids in association with each rituximab infusion. They were treated with MTX before inclusion, and MTX (10–25 mg weekly) on stable dosage was the only disease-modifying antirheumatic drug maintained during the study.

At 3 months, 8 of 10 patients had a good or moderate DAS28 response (median DAS28 reduction 1.94, IQR: 1.18–2.53) and three were in remission.^6,7 At 6 months, this response was maintained in seven of eight patients and a disease relapse was observed in one patient (DAS28 +0.9 compared with baseline; fig 1A). Serum levels of C reactive protein and erythrocyte sedimentation rate decreased at 3 and 6 months (C reactive protein median decrease −48.5% and −69% at 3 and 6 months, respectively; trend test p = 0.029; erythrocyte sedimentation rate median decrease −56% and −50%; trend test p<0.0001; fig 1B,C). Three patients were followed up for a longer period. At 1 year, patient 4 was still in remission (DAS28 2), whereas patients 5 and 7 had relapsed (DAS28 4.36 and 4.9, respectively). These promising results are consistent with previous studies on patients with rheumatoid arthritis with incomplete response to MTX.³ As in our study, some patients had a relapse a few months after a good response to the first course of rituximab. However, re-treatment of these patients again resulted in a good response, without any major safety concerns.⁸ At the time of submission of this paper, preliminary data on a double-blind, placebo-controlled study in patients with rheumatoid arthritis refractory to TNFα inhibitors indicated that rituximab may be efficacious in these patients.⁹

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Figure 1

 Evolution of clinical response and biological markers. The clinical response was assessed according to the European League Against Rheumatism response criteria at 1, 3 and 6 months after treatment with rituximab (A). Serum concentrations of C reactive protein (CRP; B), erythrocyte sedimentation rate (ESR) values (C) and circulating levels of CD19-positive cells (D) were measured at the same time points. The horizontal line represents the lower limit value for circulating CD19-positive cells. Horizontal bars represent median values.

Consistent with a previous report,¹⁰ peripheral blood B cells fell to nearly undetectable levels at 1 and 3 months after treatment with rituximab, but started to reappear in some patients after 6 months without a clear relationship with disease activity. In addition, levels of circulating B cells were depleted, without clinical response in one of the patients (fig 1D). These results suggest that the association with B cells may vary in different patients or according to the stage of the disease, or that the levels of circulating B cells may not reflect their levels in tissues. Although B cells are present in low amounts in rheumatoid synovial tissues, some investigators have recently shown a considerable number of activated B cells in bone marrow adjacent to penetrating synovial tissue in bony erosions.¹¹ Future studies, including biopsies, may provide important information on the B cell-depleting action of rituximab in target tissues.

The side effects of rituximab were similar to those described in previous studies.³ The only infectious complication was a foot abscess that occurred 8 months after administration of rituximab in a patient with a 15-year history of diabetes and antecedent of osteomyelitis.

In conclusion, B cell depletion may represent an efficacious and safe alternative in the treatment of patients with rheumatoid arthritis resistant to TNFα inhibitors.