Rheumatoid Arthritis: Cranney A

Blumenauer B, Judd M, Cranney A, Burls A, Coyle D, Hochberg M, Tugwell P, Wells G. · No affiliation provided · Cochrane Database Syst Rev. · Pubmed #14584021 No free full text.

Abstract: BACKGROUND: Etanercept is a soluble tumour necrosis factor alpha-receptor DMARD for the treatment of rheumatoid arthritis (RA). OBJECTIVES: To assess the efficacy and safety of etanercept for the treatment of RA. SEARCH STRATEGY: Five electronic databases were searched from 1966 to February 2003 with no language restriction. SELECTION CRITERIA: All randomized controlled trials (minimum 6 month duration) comparing three possible combinations 1) etanercept (10 mg or 25 mg twice weekly) with methotrexate (MTX) to MTX alone 2) etanercept to MTX, or 3) etanercept to placebo were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed the methodological quality of the trails. The American College of Rheumatology (ACR) core set of disease activity measures for RA clinical trials, radiographic, withdrawals and toxicity outcomes were analyzed. MAIN RESULTS: Three trials were included in this review. Two trials compared an experimental group who were started on etanercept compared to a control group; both groups had the same ongoing background therapy of nonsteroidals in both trials plus in one trial one group was on stable methotrexate.In these two trials the ACR 20, ACR 50 and ACR 70 response rates at 6 months were statistically significantly and clinically important with etanercept 25 mg subcutaneous injections (SC) twice weekly. Sixty-four percent of people receiving etanercept ache vied an ACR 20 response compared to 15% of controls and the number needed to treat (NNT) with etanercept is 2 people. Thirty-nine percent of those receiving etanercept achieved an ACR 50 response compared to 4% of taking control treatment and the NNT is three.Fifteen percent of people taking etanercept achieved an ACR 70 compared to 1% of controls with a NNT of 7 people.In the third trial of starting etanercept compared to starting methotrexate the number of participants who achieved an ACR 20, 50 or response at 6 and 12 months were not statistically significant for either etanercept dose.Etanercept treatment showed a statistically significantly and clinically important affect on joint damage as measured by the Sharp erosion score. Among participants who received etanercept 72% had no increase in their erosion score compared to 60% of participants in the methotrexate group. Withdrawal and toxicity results were acceptable. REVIEWER'S CONCLUSIONS: Etanercept 25 mg SC twice weekly was more efficacious than control treatment for ACR 20, 50 and 70 at 6 months, and over 12 months it slowed joint damage.

Blumenauer B, Cranney A, Clinch J, Tugwell P. · Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada. · Pharmacoeconomics. · Pubmed #12959625 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, disabling, inflammatory polyarthritis that affects patient well-being and QOL. Many disease-modifying antirheumatic drugs (DMARDs) are available for treating RA but patients are often refractory to treatment. The goal of treatment is to improve both general health and health-related QOL. Generic and disease-specific instruments exist to measure QOL. Using these instruments, one can determine if QOL improves with treatment. If the minimal clinically important difference (MCID) for the instrument is known, one can determine if the change is clinically significant. The literature was reviewed in a systematic manner to determine which drugs could affect QOL in patients with refractory RA. Refractory RA is poorly defined but we used the definition of failing at least two DMARDs. Methotrexate, leflunomide, cyclosporin, glucocorticoids, etanercept and infliximab clinically and statistically significantly improved QOL in patients with RA. Gold and epoetin-alpha (erythropoietin) statistically improved QOL in patients with RA but the clinical significance of the improvements could not be determined. These studies were either in non-refractory populations or the refractoriness could not be determined. Further study is required to determine the response of QOL to treatment in patients with refractory RA and instruments with known MCIDs should be used so that the clinical significance of the improvement can be determined.

Blumenauer B, Judd M, Wells G, Burls A, Cranney A, Hochberg M, Tugwell P. · Department of Rheumatology, Ottawa Hospital, University of Ottawa. · Cochrane Database Syst Rev. · Pubmed #12137712 No free full text.

Abstract: BACKGROUND: Infliximab is a human murine chimeric anti-tumour necrosis factor alpha monoclonal antibody recently approved for the treatment of refractory RA. OBJECTIVES: To assess the efficacy and safety of infliximab for the treatment of rheumatoid arthritis. SEARCH STRATEGY: Electronic databases including Biological Abstracts, CINAHL, Current Contents, Dissertation Abstracts, EBM Reviews, HealthSTAR and MEDLINE were searched from 1966 to March 2002. Rheumatoid arthritis was searched as an exploded MESH heading. Infliximab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication. The specific search strategy is shown below. SELECTION CRITERIA: All randomized controlled trials comparing infliximab 1, 3, 5 or 10 mg/kg with methotrexate(MTX) to MTX alone, or without MTX to placebo, with a minimum duration of 6 months and at least 2 infusions were eligible. DATA COLLECTION AND ANALYSIS: Data was extracted by 2 independent reviewers and the methodological quality of the trials was assessed using a validated assessment tool scale. Outcome variables included the ACR core set of disease activity measures for RA clinical trials and radiographic outcome data. Withdrawals and toxicity were also included. End of trial results were pooled. Continuous data were pooled using weighted mean differences and dichotomous data using relative risks. MAIN RESULTS: Two trials with a total of 529 patients met the inclusion criteria. Patients fulfilling the American Rheumatism Association 1987 RA diagnostic criteria were randomized to receive either infliximab 1mg/kg (with and without MTX), 3mg/kg(with and without MTX), 10mg/kg of infliximab (with and without MTX) or placebo infusion plus MTX. Infusions were given every 4 or 8 weeks. After 6 months ACR 20, ACR 50 and ACR 70 response rates were significantly improved in all infliximab doses compared to control. The number needed to treat with infliximab to achieve an ACR 20, 50 or 70 response in patients with refractory RA under specialist care ranged from 2.9 to 3.3 for ACR 20, 3.6 to 4.8 for ACR 50 and 5.9 to 12.5 for ACR 70 depending on the dose (3mg/kg or 10mg/kg given either every 4 or 8 weeks). Total withdrawals and withdrawals due to lack of efficacy were lower for all doses of infliximab versus controls. Withdrawals for adverse events and withdrawals for other reasons were not statistically significantly different for those receiving infliximab from control. REVIEWER'S CONCLUSIONS: Treatment with infliximab for 6 and 12 months significantly reduces RA disease activity and appeared to have an acceptable safety profile in these trials. Total radiographic scores improved, fewer patients showed radiographic progression, and more patients showed radiographic improvement with infliximab treatment at 12 months compared to controls. However, only 2 trials met the inclusion criteria, and these results are largely driven by the largest trial. The available efficacy and toxicity data is relatively short-term (6-12 months). In order to detect rare events that may be associated with infliximab, larger and longer term studies are required.

Cranney A, Goldstein R, Pham B, Newkirk MM, Karsh J. · Department of Medicine, University of Ottawa, Canada. · Ann Rheum Dis. · Pubmed #10531075 links to  free full text

Abstract: OBJECTIVE: To assess factors associated with a poor outcome in rheumatoid arthritis (RA), a measure was developed of limited joint motion and deformity, a deformity index (DI), and correlated biochemical and genetic variables with the magnitude of the DI. METHODS: Forty patients were evaluated in a cross sectional study. Clinical measures included the DI and Health Assessment Questionnaire, and disease variables included the erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and HLA-DRB1 and DQB1 alleles. RESULTS: Significant correlations were noted between increasing DI and duration of RA and concentration of C reactive protein. Patients with a DQB1*301 allele or DR4 allele had a higher DI than those without, and a positive trend was noted between increasing DI and dose of DRB1 RA susceptibility alleles. The trend was lost when a non-linear regression technique was used to remove the effect attributable to C reactive protein, suggesting an interrelation between persistent inflammation and genetics in determining total joint damage. CONCLUSIONS: The DI may be useful to study interactions between genetic and inflammatory processes in rheumatoid disease progression.

Pham B, Cranney A, Boers M, Verhoeven AC, Wells G, Tugwell P. · Thomas C. Chalmers Centre for Systematic Reviews, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada. · J Rheumatol. · Pubmed #10090188 No free full text.

Abstract: There is a continuing interest in increasing the statistical efficiency of the analysis of clinically meaningful endpoints in rheumatology. One issue that is attracting increasing attention is whether the conventional practice of only reporting the outcome at the end of the study (EOS) might be replaced or complemented by a longitudinal summary that better reflects the clinical course of the disease. The area under the curve (AUC) is a summary measure that integrates serial assessments of a patient's endpoint over the duration of the study. We evaluated the utility of AUC as a summary measure for the analysis and reporting of two RA trials: (i) methotrexate combined with cyclosporine versus methotrexate and placebo in partial methotrexate responders in relatively late disease, and (ii) prednisone plus methotrexate plus sulfasalazine versus sulfasalazine alone in relatively early disease. We replicated the published results of each trial first using the conventional EOS and then AUC summaries. For each patient, the changes from baseline over time were transformed into a summary measure by calculating AUC using the trapezium rule and then standardizing it by the study duration. Using an approach similar to the index of responsiveness to change, we scaled treatment differences derived from EOS and AUC summary measures by their standard deviation of the control group. This signal-versus-noise ratio captures the treatment discrimination ability of each summary measure. Compared to EOS and within each treatment group, the AUC summary reported smaller effects (i.e., change from baseline) with reduced errors in the estimates. AUC measures preserved discriminant validity in treatment comparisons and reported smaller but more precise treatment effect estimates. In the COBRA trial with rapidly-acting medications, AUC seemed to be more sensitive than EOS to detect treatment difference. With slow acting medications and in relatively late disease patients as in the cyclosporine trial, EOS was more sensitive to detect treatment difference than was AUC. In this setting, AUC, however, still seemed to be more sensitive than EOS for the two responsive-to-change endpoints: tender joint counts and pain by visual analog scale. AUC integrates repeated assessments during the trial duration into summary measures. Compared to EOS, the report of RA trial results using AUC summary provides smaller estimates of treatment effects but with better precision. AUC summary is likely to preserve treatment group discrimination taking into account the appropriate onset and offset of the drug action. Trial reports using AUC summary have smaller effect sizes. For trials with long acting medications and short duration similar to the cyclosporine trial, AUC still preserves treatment discrimination but may not be as sensitive as EOS. The calculations of AUC require some additional work in the analysis of each endpoint.