Rheumatoid Arthritis: Towheed TE

Towheed TE, Hochberg MC, Shea BJ, Wells G. · Queen's University, Medicine and of Community Health and Epidemiology, Etherington Hall-Room 2066, Kingston, Ontario, Canada, K7L 3N6. · Cochrane Database Syst Rev. · Pubmed #17636642 No free full text.

Abstract: BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used as a pharmacologic treatment to relieve pain for patients with OA of the hip. However, these agents are associated with significant toxicity, particularly in the elderly population (age > 65 years). OBJECTIVES: To review all randomized trials of analgesics and anti-inflammatory therapy in osteoarthritis (OA) of the hip. To determine which non-steroidal, anti-inflammatory drug (NSAID) is the most effective, and which NSAID is the most toxic. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register and MEDLINE up to August 1994. Reference lists of all trials were also manually searched. SELECTION CRITERIA: All randomized controlled trials comparing non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics in patients with Osteoarthritis. The trials selected for inclusion were identified by one reviewer (TT) and rechecked by a second (MH). DATA COLLECTION AND ANALYSIS: Qualitative assessments were performed using a quality scoring system designed for NSAID trials in rheumatoid arthritis. Both the design and analysis aspects of the trials were evaluated, each aspect being rated on a scale of 0 to 8. A quantitative method, which calculates the ratio of improvement produced by one NSAID to that produced by another, was used to rate the relative efficacy of different NSAIDs with respect to pain relief. Toxicity comparisons were made according to the reviewer findings. All quality assessments were carried out independently by two reviewers (TT, BS). All data abstraction was carried out by one reviewer (TT) and rechecked by two other reviewers (BS, GW). A consensus was reached on discrepancies. MAIN RESULTS: Forty-three trials were identified, and of these, 39 evaluated NSAIDs, while four evaluated only analgesics. The median design and analysis scores were two and four respectively. Six NSAIDs were included in at least five trials. Of these, indomethacin was rated more effective in five of its seven comparisons, but more toxic in seven of 12 comparisons. Only five of the 29 (17%) NSAID comparisons found statistically significant differences in efficacy. Of the 43 RCTs identified only 17 had statistical data available for future pooling for this meta-analysis. In the case where data was missing, authors of the trials will be contacted for inclusion of data in future reviews. AUTHORS' CONCLUSIONS: NSAID trials in patients with OA of the hip appear to be weakened by the lack of standardization of case definition of OA, and also by the lack of standardization of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA can be offered at this time based on this analysis.

Garner SE, Fidan DD, Frankish RR, Judd MG, Towheed TE, Wells G, Tugwell P. · Department of Community Health Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London, UK, SW17 0RE. · Cochrane Database Syst Rev. · Pubmed #15674912 No free full text.

Abstract: BACKGROUND: Editor's note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke. Further information is available at www.vioxx.com.Rheumatoid arthritis (RA) is a systemic auto-immune disorder, in which the synovial lining of many joints and tendon sheaths are persistently inflamed. OBJECTIVES: To assess the efficacy and toxicity of rofecoxib for treating RA. SEARCH STRATEGY: We searched the following electronic databases up to December 2000: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment database. The bibliographies of retrieved papers were scanned for additional references. The manufacturers of rofecoxib, MSD, were also approached by the UK National Institute for Clinical Excellence to submit additional evidence to inform it's appraisal on the use of cyclo-oxygenase inhibitors for arthritis. SELECTION CRITERIA: We included randomised controlled trials of parallel group design evaluating the efficacy and/or toxicity of rofecoxib in RA, both placebo based and comparative trials were eligible. Relevant outcome criteria had to be available to evaluate efficacy and/or toxicity, such as the OMERACT outcomes. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers and the results were compared for the degree of agreement. A validated tool (Jadad 1996) was used to score the quality of the randomised controlled trials. The planned analysis was to pool, where appropriate, continuous outcome measures using mean or standardized mean differences, and dichotomous outcome measures using relative risk ratios. MAIN RESULTS: Two randomised controlled trials evaluating rofecoxib for the treatment of RA were identified and met the inclusion criteria. One compared rofecoxib to placebo and was designed to assess the safety and efficacy of several doses of rofecoxib. The second trial compared rofecoxib to naproxen and was primarily designed to assess the safety of rofecoxib so did not include all the recommended RA efficacy measures. The overall number of ACR 20 responders who had received 25mg (82/ 171 = 48%) or 50mg (86/161 = 53%) was statistically significantly more than those receiving placebo (58/168 = 35% ) (RR 1.39 CI: 1.07, 1.80 and RR 1.55 CI: 1.20, 1.99 respectively) with no statistically significant differences between the 25 and 50 mg doses. The safety profile of rofecoxib was similar to that of placebo. In the comparative trial, rofecoxib at a dosage of 50 mg/day demonstrated similar efficacy to naproxen at a dosage of 500 mg twice daily. However, the combined rate of clinically significant complicated gastro-intestinal events (GI) (perforations, ulcers, bleeds, or obstructions) was lower with rofecoxib than with naproxen (RR 0.46, 95% CI, 0.34 to 0.63) due to a reduction in the number of ulcers and bleeds. Compared to patients taking naproxen, patients taking rofecoxib had a greater risk of having any cardiovascular event (45/4047 = 1.1% vs 19/4029 =0.47%) (RR 2.36 CI 1.38 to 4.02) and had greater risk of having a non-fatal myocardial infarction (MI) (18/4047 =0 .44% and 4/4029 =0.1%) (RR 4.48, 95% CI, 1.52 to 13.23). AUTHORS' CONCLUSIONS: In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear.Rofecoxib was voluntarily withdrawn from global markets in October 2004. It cannot therefore be prescribed and therefore there are no implications for practice concerning its use. None the less when considering which NSAID to use, it must be borne in mind that the toxicity of NSAIDs is variable amongst patients and drugs and it tends to be dose related and associated with variation in the mode of action, absorption, distribution and metabolism.There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing. It is likely that this issue will not be resolved until research has enabled a fuller understanding of the complex mechanism by which the Cox system operates.

Emery P, Kong SX, Ehrich EW, Watson DJ, Towheed TE. · Rheumatology and Rehabilitation Research Unit, Research School of Medicine, University of Leeds, United Kingdom. · Clin Ther. · Pubmed #12240779 No free full text.

Abstract: BACKGROUND: Many clinicians believe that higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are more effective than lower doses for the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA) but are associated with higher rates of adverse events (AEs). However, there is a lack of consensus on dose-effect relationships with the NSAIDs. OBJECTIVE: The purpose of this review was to investigate evidence for the relationship between NSAID dose, efficacy, and the occurrence of AEs from clinical trials of RA and OA of the hip and knee. METHODS: Relevant English-language publications were identified through a search of EMBASE, MEDLINE, and REFLINE using the terms aceclofenac, diclofenac, etodolac, ibuprofen, isoxicam, lornoxicam, meloxicam, nabumetone, naproxen, piroxicam, tenidap, tenoxicam, arthritis, OA (hip and knee), RA, rheumatic disorders, and musculoskeletal disorders for the period January 1970 to December 1997 (this review was conducted in 1998). Bibliographies of retrieved publications were reviewed for other potentially relevant articles. Selected publications were evaluated for quality (likelihood of bias) based on 4 factors (randomization procedure; completeness of patient and treatment information; standardization and completeness of outcome data; and reporting of attrition data). RESULTS: This review included 99 publications concerning clinical trials conducted in 24 countries and enrolling 28,239 patients. The majority of reports were published in the 1990s, particularly in the latter half of that decade. The average quality of the publications improved over time, with a significant increase in mean quality score from 5.43 in the 1970s to 9.21 during the last half of the 1990s (P < 0.05). Only 8 reports directly compared high and low doses of the same drug in relation to efficacy. CONCLUSIONS: Data on the relationship of NSAID dose to efficacy and the incidence of AEs were limited. There is a need for clinical trials directly addressing dose-effect relationships of NSAIDs, as well as reviews of more current literature and reports in languages other than English.

Cranney AB, Harrison A, Ruhland L, Vaidyanath C, Graham I, Man-Son-Hing M, Jaffey J, Towheed TE, Anastassiades TP, Dwosh II. · Ottawa Health Research Institute, Ottawa, Canada. · J Rheumatol. · Pubmed #16331759 No free full text.

Abstract: OBJECTIVE: To assess driving problems experienced by patients with rheumatoid arthritis (RA) and to examine the relationship between functional status and driving difficulty. METHODS: Using the South Eastern Ontario Medical Organization (SEAMO) database, we identified 721 patients with RA from both urban and rural backgrounds. They completed a cross-sectional, self-administered mail survey that included the Health Assessment Questionnaire (HAQ-DI) and a co-morbidity questionnaire. We assessed the proportion of drivers versus non-drivers and patients who reported difficulty driving and who used vehicle adaptations. RESULTS: Survey response rate was 74% and 92.2% of the subjects were current drivers. Fifty percent of the current drivers reported a little difficulty, 6.8% reported quite a bit of difficulty, and 1.5% a great deal of difficulty driving. Major reasons given for why RA limited their driving were stiffness and pain. Frequent use of mobility aids (adjusted odds ratio, OR: 5.85), HAQ-DI > or = 1 (adjusted OR: 3.40), and older age (adjusted OR: 1.04) were significant predictors of an individual with RA discontinuing driving. Higher levels of disability (HAQ-DI) were associated with a greater number of problems reported with driving and with curtailment of driving. A multivariate logistic regression determined that having a HAQ-DI > or = 1 (adjusted OR: 4.3) and difficulties sitting in the vehicle (adjusted OR: 2.9) were associated with RA limiting driving. CONCLUSION: Over 50% of respondents reported some degree of difficulty driving due to their RA. Scores on HAQ-DI > or = 1 were associated with difficulty driving. Further validation of our findings needs to be performed.