The Cochrane Library, known for its high-quality evidence-based reviews and other resources that physicians can use to inform their clinical decisions, launched an online journal club in October 2009—and the complex question of biologic use in rheumatoid arthritis (RA) was first the topic of discussion.
The Cochrane Journal Club is a resource for physicians and researchers who currently participate in a journal club or who would like to start one at their institution. Each monthly issue examines a recently published Cochrane review, providing summaries and analysis of the review, together with a variety of multimedia resources—including PowerPoint discussion slides with relevant charts and tables and podcasts from the authors. The Cochrane Journal Club also provides discussion points and key critical questions to facilitate journal groups’ discussion of the review at a journal club meeting. Finally, the club Web site (www.cochranejournalclub.com) has an interactive component where visitors can ask the authors questions and view questions posed by other readers.
The pilot Cochrane Journal Club highlighted “Biologics for Rheumatoid Arthritis,” the first overview of reviews to be published in the Cochrane Library. Because the paper included both information to help rheumatologists make difficult clinical decisions and innovative methodological approaches to comparing treatments indirectly, the Journal Club discussed both the clinical and methodological aspects of the review.
“Biologics for Rheumatoid Arthritis” looked at six current Cochrane reviews on different biologic disease-modifying antirheumatic drugs (DMARDs), each assessing one DMARD compared with a placebo and including at least one randomized trial. The overview of Cochrane reviews provides a summary of the benefits and harms of each DMARD and also includes indirect comparisons between the drugs. (See “Summary of the Cochrane Review.”)
Although the DMARDs reviewed did seem to improve symptoms and prevent joint deterioration, deciding which drug to prescribe a given patient still may be a challenge for rheumatologists. “Doctors are faced with a difficult dilemma when choosing biologics to prescribe to RA patients. Our Cochrane overview cannot identify the ‘best’ biologic for any individual patient,” said Jasvinder Singh, MD—lead author of the paper, a rheumatologist at the Minneapolis VA Medical Center, and associate professor of medicine at the University of Minnesota in Minneapolis—in the Journal Club podcast. “That choice needs to use other knowledge as well. Some of that knowledge is in the individual Cochrane reviews … and some of it will need to come through local information and discussion with the patients. For example, how much experience is there with a particular biologic in the clinical team and does the patient have preferences about the different ways in which the drugs need to be taken?”
Summary of the Cochrane Review
Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD007848. DOI: 10.1002/14651858. CD007848.pub2. Copyright The Cochrane Collaboration, reproduced with permission.
To download the full review and access the Journal Club’s multimedia resources, visit www.cochranejournalclub.com.
Abstract
Background: The biologic disease-modifying antirheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA); however there is a lack of head-to-head comparison studies.
Objectives: To compare the efficacy and safety of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab in patients with RA.
Methods: This ‘Overview of Reviews’ was done by including all Cochrane Reviews on Biologics for RA available in The Cochrane Library. We included only data on standard dosing regimens for these biologic DMARDs from placebo-controlled trials. The primary efficacy and safety outcomes were ACR50 and withdrawals due to adverse events. We calculated risk ratios (RR) for efficacy, odds ratio (OR) for safety and combined estimates of events across the placebo groups as the expected control event rate (CER). Indirect comparisons of biologics were performed for efficacy and safety using a hierarchical linear mixed model incorporating the most important study-level characteristic (i.e. type of biologic) as a fixed factor and study as a random factor; reducing the between study heterogeneity by adjusting for the interaction between the proportion of patients responding on placebo and the duration of the trial.
Main results: From the six available Cochrane reviews, we obtained data from seven studies on abatacept, eight on adalimumab, five on anakinra, four on etanercept, four on infliximab, and three on rituximab. The indirect comparison estimates showed similar efficacy for the primary efficacy outcome for all biologics with three exceptions. Anakinra was less efficacious than etanercept with a ratio of RRs (95% CI; P value) of 0.44 (0.23 to 0.85; P = 0.014); anakinra was less efficacious than rituximab, 0.45 (0.22 to 0.90; P = 0.023); and likewise adalimumab was more efficacious than anakinra, 2.34 (1.32 to 4.13; P = 0.003).
In terms of safety, adalimumab was more likely to lead to withdrawals compared to etanercept, with a ratio of ORs of 1.89 (1.18 to 3.04; P = 0.009); anakinra more likely than etanercept, 2.05 (1.27 to 3.29; P = 0.003); and likewise etanercept less likely than infliximab, 0.37 (0.19 to 0.70; P = 0.002).
Authors’ conclusions: Based upon indirect comparisons, anakinra seemed less efficacious than etanercept, adalimumab, and rituximab and etanercept seemed to cause fewer withdrawals due to adverse events than adalimumab, anakinra, and infliximab. Significant heterogeneity in characteristics of trial populations imply that these finding must be interpreted.
Plain Language Summary
This summary of a Cochrane review presents what we know from research about the effect of biologics on rheumatoid arthritis (RA).
The review shows that in people with RA:
- Abatacept, adalimumab, etanercept, infliximab, and rituximab probably improve signs of rheumatoid arthritis such as the number of tender or swollen joints and other outcomes such as pain and disability.
- Anakinra probably improve signs of rheumatoid arthritis such as the number of tender or swollen joints and other outcomes such as pain and disability (but not as well as the others).
We do not have precise information about possible side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include a serious infection or upper respiratory infection. Rare complications may include certain types of cancer.
What is rheumatoid arthritis (RA) and what are biologics?
When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints making them inflamed. This inflammation causes your joints to be hot, swollen, stiff, and painful. The small joints of your hands and feet are usually affected first. If the inflammation goes on without treatment, it can lead to damaged joints. Once the joint is damaged it cannot be repaired, so treating rheumatoid arthritis early is important.
Biologics are a group of medications that suppress the immune system and reduce the inflammation in the joints. Even though suppressing the immune system can make it slightly harder to fight off infections, it also helps to stabilize an overactive immune system. By reducing the inflammation, the aim is to help prevent damage to the joints.
Best estimate of what happens to people with rheumatoid arthritis who take biologics:
ACR50 (number of tender or swollen joints and other doctor- or patient-assessed aspects of rheumatoid arthritis)*
- Among people who took abatacept, 47 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 21 people out of 100 who took a placebo (26% absolute improvement).
- Among people who took adalimumab, 63 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 21 people out of 100 who took a placebo (42% absolute improvement).
- Among people who took anakinra, 27 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 21 people out of 100 who took a placebo (6% absolute improvement).
- Among people who took etanercept, 61 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 21 people out of 100 who took a placebo (40% absolute improvement).
- Among people who took infliximab, 45 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 21 people out of 100 who took a placebo (24% improvement).
- Among people who took rituximab, 60 people out of 100 experienced improvement in the signs of their rheumatoid arthritis compared to 9 people out of 100 who took a placebo (51% improvement).
Side effects
- Among people who took adalimumab, eight people out of 100 dropped out of the study because of the side effects compared to five people out of 100 who took a placebo (3% absolute difference).
- Among people who took anakinra, nine people out of 100 dropped out of the study because of the side effects compared to five people out of 100 who took a placebo (4% absolute difference).
- Among people who took infliximab, 11 people out of 100 dropped out of the study because of the side effects compared to five people out of 100 who took a placebo (6% absolute difference).
- There may be little or no difference in people who dropped out because of side effects with abatacept, etanercept, and infliximab compared to people who took a placebo (fake pill).
*Editor’s note: The ACR50 was used to measure the efficacy of the DMARDs and was defined as 50% improvement in both tender and swollen joint counts and 50% improvement in three of the five following five variables: patient global assessment, physician global assessments, pain scores, Health Assessment Questionnaire score, and acute phase reactants (erythrocyte sedimentation rate or C-reactive protein).
