Introduction: This report is an updated systematic review of rituximab done by CDR in November 2006 and also attempts to answer the 2 research questions stated below.
Rituximab is categorized as anti-neoplastic. It is indicated “in combination with methotrexate (MTX) to reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more TNF inhibitor therapies”. The recommended dose consists of two, 1000 mg IV infusions two weeks apart. Patients should receive treatment with 100 mg IV methylprednisolone 30 minutes prior to rituximab to decrease the rate and severity of acute infusion reactions. The duration of therapy is not specified.
RA is a systemic autoimmune inflammatory disease with an estimated prevalence rate of 1% of the population and is characterized by inflammation of the lining surfaces of the joints, pericardium, and pleura, rheumatoid nodules and vasculitis.
Research questions: In adult patients with RA
- Are there any clinical advantages to the use of rituximab, in combination with MTX as a second line agent, for patients who failed to respond or are intolerant to an adequate trial of one anti-tumor necrosis factor (anti-TNF) agent, compared to its use as a third line agent?
- Are there any incremental risks or potential harms associated with the use of rituximab as a second line agent, compared to the use of other biologics as second line agents?
Search strategy and findings
- Summary of manufacturer’s submission: Two of the relevant studies submitted by the manufacturer were analyzed. The first is a subgroup analysis of the REFLEX trial (rituximab versus placebo in patients who failed at least one anti-TNF agent). The author divided randomized patients in each treatment group into two subgroups: those who failed only one anti-TNF drug and those who failed two or more anti-TNF drugs. This is a hypothesis generating post-hoc analysis without adjusting the p value for multiple comparisons. The second study is a cohort study that was designed to compare rituximab with anti-TNF agent in patients who failed anti-TNF therapy. 116 patients were included. At 6 months, the mean decrease in the Disease Activity Score on 28 joints (DAS 28) was -1.61 (95% CI -1.97 to -1.25) in patients treated with rituximab versus -0.98 (-1.33 to -0.62) in patients treated with alternative anti TNF agent. However, interpretation of the results of this study is limited due to selection bias and use of invalidated outcome measure (DAS 28). This study design does not support scientifically valid conclusions between treatment options.
- Update of the November 2006 CDR Systematic review of rituximab in patients with RA who failed at least one anti-TNF agent: MEDLINE, EMBASE and CENTRAL were searched until January 2009. We did not identify any new RCT comparing rituximab to placebo or any active comparator in patients who failed at least one anti-TNF agent. Comparing rituximab as second line therapy versus rituximab as third line therapy cannot be studied in a RCT because a single population does not exist for randomization. Administrative databases (PharmaNet) can be used to conduct a pragmatic trial to produce evidence locally.
- Systematic review of all treatment in patients who failed at least one anti-TNF agent: MEDLINE, EMBASE and CENTRAL were searched until January 2009. The following studies were identified:
Rituximab vs. Placebo– one (included in the CDR report),
Dose increment of anti-TNF agent – two studies one with infliximab and the other with etanercept;
Switching to infliximab after failure on etanercept – one study.
Additional drug studies identified were using abatacept (currently being reviewed by the TI) and tocilizumab (not available in Canada).
- Extensive safety report including observational studies, case reports, published reviews and regulatory agency reveal no new safety consideration compared to the CDR report.
- In an updated systematic literature search we did not identify any new RCT compared to CDR November 2006 systematic review report. No active comparator studies in patients who failed at least one anti-TNF agent were identified.
- Rituximab as second line therapy versus rituximab as third line therapy cannot be studied in a RCT because a single population does not exist for randomization. Administrative databases can be used to conduct a pragmatic trial to produce evidence locally.
- There is insufficient evidence regarding the most appropriate sequencing of “biologic” therapies for RA, in terms of efficacy/effectiveness and harm.
- No additional safety issues were identified compared to the CDR review in 2006.
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