Review on the Influence of Protocol Design on Clinical Outcomes in Rheumatoid Arthritis Treated With Rituximab

Shawn Shetty MD; Mark C Fisher MD; A Razzaque Ahmed MD DSc


The Annals of Pharmacotherapy. 2013;47(3):311-323. 

In This Article

Abstract and Introduction


Objective: To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab.

Data sources: A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed.

Study selection and data extraction: A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data.

Data synthesis: Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-α) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the χ2 test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%).

Conclusions: In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF-α inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted.


Rheumatoid arthritis (RA) is an autoimmune disease that results in significant morbidity and crippling effects.[1,2] RA is caused by a perturbation of the immune system that results in swelling and tenderness of the joints and can progress to joint destruction.[3] Prevalence of RA is 0.5–1% of adults in the western hemisphere, is more common in women, and peaks in incidence in childhood, as well as at 40–50 years of age.[4,5] RA affects not only the musculoskeletal system, it also has several extraarticular manifestations, including effects on the cardiac, pulmonary, ocular, renal, and neurologic systems.[6] Patients with RA have poor quality of life and increased incidence of mortality due to cardiovascular events compared to the general population.[7,8]

The treatment of RA remains a challenge because the duration of response to various therapies is limited and disease progression often occurs despite treatment.[9–11] Current guidelines recommend the early introduction of disease-modifying antirheumatic drugs (DMARDs). The guidelines suggest that the first choice of drugs for treatment is nonbiologic DMARDs.[9] Nonbiologic DMARDs, such as methotrexate, azathioprine, and cyclosporine, reduce the rate of joint and bone erosion and halt the progression of RA.[12–14] However, patients may not have initial efficacy from these medications or may become refractory to treatment.[15–17] When nonbiologic DMARDs are ineffective, tumor necrosis factor-alfa (TNF-α) inhibitors are recommended.[9] Treatment for patients who do not respond to or experience significant adverse effects associated with TNF-α inhibitors then may be switched to other biological drugs. DMARDs that are biological agents target cells or cytokines that cause or worsen inflammation.[18–20] These include tocilizumab,[21] a monoclonal antibody to the interleukin 6 receptor, or abatacept,[22] which is a monoclonal antibody to the costimulator of T cells. Rituximab, a monoclonal antibody to the CD20+ glycoprotein on specific mature B-cells, has also been used.

Rituximab depletes B-cells that carry the CD20+ glycoprotein.[23] RA is characterized by the presence of the autoantibodies, rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (ACCP), which are produced by B-cells.[3] Sixty to 70% of patients with RA have RF and ACCP present in the serum, and approximately 80% of patients are positive for at least 1 of them.[24,25] This is the basis for the use of rituximab in RA. While the specific role of these autoantibodies in the pathogenesis or progression of RA has yet to be determined, improvement of RA is frequently associated with their decline.[26] Hence, when rituximab has been used in RA, it has been shown to improve clinical outcomes.[27]

In 2006, the Food and Drug Administration (FDA) approved the use of rituximab in patients with RA based on a protocol in which 1000 mg of rituximab was given on days 1 and 15 for a study period of 24 weeks.[28] Since then, several studies have been conducted in which there have been changes in the dosage, duration of study, period, and number of cycles administered.

The purpose of this review is to focus on the efficacy and safety of rituximab in patients with RA. The influences on clinical efficacy and safety by factors such as study design, dose, and frequency of rituximab use, duration of study period, and adverse events are evaluated. Cumulative data on dose, duration of study period, and number of cycles are statistically analyzed.