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Annals of the Rheumatic Diseases Jul 2009To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs)... (Comparative Study)
Comparative Study Meta-Analysis Review
Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis.
OBJECTIVE
To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis.
METHOD
A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy.
RESULTS
A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations.
CONCLUSION
In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate; Treatment Outcome
PubMed: 19054823
DOI: 10.1136/ard.2008.099861 -
Reumatologia Clinica Jul 2008Clinical experience raises suspicion that the spanish population could suffer higher rates of side effects of sulfasalazine (SSZ) therapy. We conducted a systematic...
BACKGROUND
Clinical experience raises suspicion that the spanish population could suffer higher rates of side effects of sulfasalazine (SSZ) therapy. We conducted a systematic review of existing literature to analyze the susceptibility to developing adverse events produced by SSZ in the Spanish population.
MATERIAL AND METHOD
A literature search was conducted in EMBASE, IBECS, and MEDLINE from 1973 to March 2007. The items sought were those describing adverse effects, both in text and tables, and reasons for withdrawal, the population under study and discussion of differences in side effects of the different treatment groups.
RESULTS
Of the 106 retrieved articles, 36 were selected for review and detailed analysis. 34 articles were selected from MEDLINE and EMBASE and 2 from IBECS. We did not find any study that showed that the Spanish population was more susceptible to SSZ.
CONCLUSIONS
The adverse effects of SSZ vary with the pattern of acetylation. Thus, in slow-acetylators, depending on the dosage of SSZ, the side effects increase significantly. In the Spanish population slow-acetylators prevalence is higher than in other ethnic groups. Therefore, one could infer that the incidence of adverse side effects by SSZ could be higher in the Spanish population than in others different ethnic groups. We found no evidence that the Spanish population was more likely to suffer adverse effects by SSZ than other ethnic groups.
PubMed: 21794518
DOI: 10.1016/S1699-258X(08)71821-7 -
Annals of Internal Medicine Jan 2008The comparative effectiveness of rheumatoid arthritis therapies is uncertain. (Comparative Study)
Comparative Study Review
BACKGROUND
The comparative effectiveness of rheumatoid arthritis therapies is uncertain.
PURPOSE
To compare the benefits and harms of disease-modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis.
DATA SOURCES
Records limited to the English language and studies of adults were identified by using MEDLINE, EMBASE, The Cochrane Library, and International Pharmaceutical Abstracts from 1980 to September 2007.
STUDY SELECTION
Two persons independently selected relevant head-to-head trials and prospective cohort studies with at least 100 participants and 12-week follow-up and relevant good- or fair-quality meta-analyses that compared benefits or harms of 11 drug therapies. For harms, they included retrospective cohort studies.
DATA EXTRACTION
Information on study design, interventions, outcomes, and quality were extracted according to a standard protocol.
DATA SYNTHESIS
Head-to-head trials (n = 23), mostly examining synthetic DMARDs, showed no clinically important differences in efficacy among synthetic DMARDs (limited to methotrexate, leflunomide, and sulfasalazine) or among anti-tumor necrosis factor drugs (adalimumab, etanercept, and infliximab). Monotherapy with anti-tumor necrosis factor drugs resulted in better radiographic outcomes than did methotrexate but no important differences in clinical outcomes (for example, 20%, 50%, or 70% improvement according to American College of Rheumatology response criteria). Various combinations of biological DMARDs plus methotrexate improved clinical response rates and functional outcomes more than monotherapy with either methotrexate or biological DMARDs. In patients whose monotherapy failed, combination therapy with synthetic DMARDs improved response rates. Numbers and types of short-term adverse events were similar for biological and synthetic DMARDs. The evidence was insufficient to draw conclusions about differences for rare but serious adverse events for biological DMARDs.
LIMITATION
Most studies were short-term efficacy trials conducted in selected populations with few comorbid conditions.
CONCLUSION
Limited available comparative evidence does not support one monotherapy over another for adults with rheumatoid arthritis. Although combination therapy is more effective for patients whose monotherapy fails, the evidence is insufficient to draw firm conclusions about whether one combination or treatment strategy is better than another or is the best treatment for early rheumatoid arthritis.
Topics: Adult; Age Factors; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Drug Therapy, Combination; Humans; Treatment Outcome
PubMed: 18025440
DOI: 10.7326/0003-4819-148-2-200801150-00192 -
BMJ Clinical Evidence Aug 2007Rheumatoid arthritis usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions. The aims of treatment are to relieve pain and... (Review)
Review
INTRODUCTION
Rheumatoid arthritis usually starts as a symmetrical polyarthritis, and its course is marked by flares and remissions. The aims of treatment are to relieve pain and swelling, and to improve function. In addition, disease-modifying antirheumatic drugs (DMARDs) may reduce disease progression.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with rheumatoid arthritis who have not previously received any disease-modifying antirheumatic drug treatment? How do different drug treatments compare in people with rheumatoid arthritis who have either not responded to or are intolerant of first-line disease-modifying antirheumatic drugs? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2005 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 62 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adalimumab, anakinra, antimalarial drugs, azathioprine, ciclosporin, corticosteroids, cyclophosphamide, etanercept, infliximab plus methotrexate, leflunomide, methotrexate (alone; or plus sulfasalazine plus hydroxychloroquine), oral gold, parenteral gold, penicillamine, sulfasalazine.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Interleukin 1 Receptor Antagonist Protein; Methotrexate; Treatment Outcome
PubMed: 19454108
DOI: No ID Found -
Alimentary Pharmacology & Therapeutics Apr 2006Mesalazine is among the medications most commonly prescribed by gastroenterologists, having to a large extent superseded sulfasalazine (sulphasalazine). However, there... (Review)
Review
BACKGROUND
Mesalazine is among the medications most commonly prescribed by gastroenterologists, having to a large extent superseded sulfasalazine (sulphasalazine). However, there are still a number of aspects regarding its use which provoke debate and controversy.
AIM
To provide a systematic assessment of the evidence for the use of mesalazine in ulcerative colitis and Crohn's disease.
METHODS
References were identified using PubMed database. Additional references were identified with related article searches.
RESULTS
Mesalazine has a clear role in the maintenance of remission in ulcerative colitis and management of mild to moderately active disease, although the efficacy of topical preparations or combined topical and oral is clearly superior to oral alone. Evidence that increasing the dose of oral mesalazine improves efficacy is not clear-cut. The benefits of mesalazine in the management of acute Crohn's disease and the maintenance of remission are questionable and alternative treatments are usually more appropriate. Emerging evidence suggests that maintenance mesalazine reduces the risk of neoplastic progression in chronic ulcerative colitis. Compliance with therapy is thus important, as is an understanding of individuals most likely to default on this.
CONCLUSION
Evidence for a beneficial effect of mesalazine is largely confined to the management of ulcerative colitis.
Topics: Acute Disease; Administration, Oral; Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Colorectal Neoplasms; Crohn Disease; Drug Administration Schedule; Humans; Inflammatory Bowel Diseases; Mesalamine; Patient Compliance; Sulfasalazine; Treatment Outcome
PubMed: 16573787
DOI: 10.1111/j.1365-2036.2006.02846.x -
Alimentary Pharmacology & Therapeutics Jan 2004To determine whether there is a difference in short-term adverse events in patients with ulcerative colitis treated with mesalazine, olsalazine or balsalazide. (Review)
Review
AIM
To determine whether there is a difference in short-term adverse events in patients with ulcerative colitis treated with mesalazine, olsalazine or balsalazide.
METHODS
MEDLINE was searched for articles published until 2002. Randomized trials of oral mesalazine, olsalazine or balsalazide for the treatment of active disease or the maintenance of remission were included. Outcomes of interest were the frequencies of patients experiencing adverse events and those withdrawn due to adverse events.
RESULTS
Forty-six trials were included. One study of mesalazine vs. sulfasalazine for active colitis showed significantly fewer patients with adverse events with mesalazine. Both balsalazide vs. sulfasalazine studies for active disease showed significantly fewer withdrawals with balsalazide. One trial of balsalazide vs. sulfasalazine for maintenance showed significantly fewer patients with adverse events with balsalazide. Otherwise, no significant differences in safety outcomes were noted.
CONCLUSION
All three 5-aminosalicylic acid agents are safe in the short term. In mesalazine-treated patients, the frequencies of adverse events or withdrawals due to adverse events were comparable with those in placebo-treated patients and lower than those in sulfasalazine-treated patients. Overall, adverse events or withdrawals were not significantly more frequent with olsalazine than with placebo or sulfasalazine. Adverse events and study withdrawals on balsalazide were less frequent than those on sulfasalazine.
Topics: Administration, Oral; Aminosalicylic Acids; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Colitis, Ulcerative; Double-Blind Method; Humans; Mesalamine; Phenylhydrazines; Randomized Controlled Trials as Topic
PubMed: 14723609
DOI: 10.1111/j.0269-2813.2004.01827.x -
The Cochrane Database of Systematic... 2003Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Leflunomide, as an inhibitor of pyrimidine synthesis, has a different mechanism of action than other... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Leflunomide, as an inhibitor of pyrimidine synthesis, has a different mechanism of action than other existing disease modifying anti-rheumatic drugs (DMARD).
OBJECTIVES
To determine the efficacy and toxicity of leflunomide compared to placebo or other DMARDs in the treatment of RA.
SEARCH STRATEGY
We conducted a search in MEDLINE, EMBASE, Current Contents and the Cochrane Controlled Trial Register for trials up to December 2001. We also hand-searched reference lists and consulted content experts.
SELECTION CRITERIA
Two independent reviewers selected the trials that met predetermined inclusion criteria.
DATA COLLECTION AND ANALYSIS
Two independent reviewers extracted data and assessed methodologic quality using standardized forms.
MAIN RESULTS
Six trials were included in this review. Using the ACR20 improvement criteria, there was an absolute difference in improvement of 28% (95% confidence interval: 21 - 35%) favouring leflunomide (232 out of 413 leflunomide treated patients compared to 89 out of 311 placebo patients met the criteria). There was no difference in ACR20 response rate between the patients treated with leflunomide and SSZ or MTX at 6 and 12 months. Other clinical outcomes were improved significantly in the leflunomide group compared to placebo but not different from SSZ or MTX. Withdrawals due to adverse events with leflunomide were 10% greater than placebo (70 out of 416 compared to 18 out of 311 respectively). Important adverse events included gastrointestinal symptoms, elevated liver function tests, alopecia, and infections. Overall adverse events and withdrawals in the leflunomide group were not significantly different from SSZ or MTX.
REVIEWER'S CONCLUSIONS
Leflunomide appears to improve all clinical outcomes and delay radiologic progression at both 6 and 12 months of treatment compared to placebo. Its efficacy and adverse events at 2 years of treatment are comparable to SSZ and MTX. Long-term efficacy and toxicity remains to be established.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Isoxazoles; Leflunomide; Methotrexate; Randomized Controlled Trials as Topic; Sulfasalazine
PubMed: 12535423
DOI: 10.1002/14651858.CD002047 -
Alimentary Pharmacology & Therapeutics Jan 2003: To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA) formulations... (Review)
Review
AIM
: To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro-drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis.
METHODS
: Selected articles had: (1) adult healthy volunteers or patients with ulcerative colitis and (2) quantification of pharmacokinetic data to include, at a minimum, urinary excretion of total 5ASA [5ASA plus N-Acetyl-5ASA (N-Ac-5ASA)].
DATA COLLECTION AND ANALYSIS
: Pharmacokinetic data (Tmax, Cmax, AUC, urinary excretion, faecal excretion) of 5ASA, its major metabolite N-Acetyl-5ASA, total 5ASA, and the parent pro-drug compounds was extracted.
MAIN RESULTS
: The summary results for urinary excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 11-33% or median 22%; olsalazine mean 14-31% or median 16-27%; balsalazide mean 12-35% or median 20%; Asacol mean 10-35% or median 18-40%; Pentasa mean 15-53% or median 23-34%; Salofalk, Mesasal and Claversal mean 27-56% or median 31-44%. The summary results for faecal excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 23-75% or median 38%; olsalazine mean 47-50% or median 17-36%; balsalazide mean 46% or median 22%; Asacol mean 40-64% or median 20-56%; Pentasa mean 12-51% or median 39-59%; Salofalk, Mesasal and Claversal mean 37-44% or median 23-35%.
CONCLUSIONS
: The systemic exposure to 5ASA, as measured by urinary excretion of total 5ASA, and the faecal excretion of total 5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus, selection of a mesalazine therapy for the treatment of ulcerative colitis should be based on other factors such as efficacy, dose-response, toxicity of the parent compound and its metabolites, compliance issues related to dose forms and dosing schedules, and costs.
Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Feces; Humans; Mesalamine; Prodrugs
PubMed: 12492730
DOI: 10.1046/j.1365-2036.2003.01408.x -
The Cochrane Database of Systematic... 2000To estimate the short-term effects of cyclophosphamide for the treatment of rheumatoid arthritis. (Review)
Review
OBJECTIVES
To estimate the short-term effects of cyclophosphamide for the treatment of rheumatoid arthritis.
SEARCH STRATEGY
We searched the Cochrane Musculoskeletal Group's Register, the Cochrane Controlled Trials Register, Medline and Embase up to and including July 1997. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search.
SELECTION CRITERIA
All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing oral cyclophosphamide against placebo (or an active drug at a dosage considered to be ineffective) in patients with rheumatoid arthritis.
DATA COLLECTION AND ANALYSIS
Data abstraction was carried out independently by two reviewers. The same two reviewers using Jadad's scale (Jadad 1995) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for baseline and end-of-study. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout.
MAIN RESULTS
A total of 70 patients were included in the pooled analysis of two trials, 31 receiving cyclophosphamide. A statistically significant benefit was observed for cyclophosphamide when compared to placebo for tender and swollen joint scores: SMDs were -0.57 and -0.59 respectively. The difference in ESR also favoured the active drug but did not reach statistical significance (-12 mm, 95%CI: -26 to 2.5). One trial reported the number of patients developing new or worse erosions: the OR for cyclophosphamide compared to placebo was 0.17 (95% CI: 0.05 to 0.57). Patients receiving placebo were six times more likely to discontinue treatment because of lack of efficacy than patients receiving cyclophosphamide. Withdrawals from adverse reactions were higher in the cyclophosphamide group (Odds ratio=2.9), although this difference was not statistically significant. Side effects from cyclophosphamide included hemorrhagic cystitis, nausea, vomiting, leucopenia, thrombocytopenia, alopecia, amenorrhea and herpes zoster infections.
REVIEWER'S CONCLUSIONS
Cyclophosphamide appears to have a clinically and statistically significant benefit on the disease activity of patients with RA, similar to some disease modifying antirheumatic drugs (DMARDs) such as antimalarials or sulfasalazine, but lower than methotrexate. Toxicity however is severe, limiting its use given the low benefit-risk ratio compared to other antirheumatic agents.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cyclophosphamide; Humans
PubMed: 10796419
DOI: 10.1002/14651858.CD001157 -
The Cochrane Database of Systematic... 2000To estimate the short-term efficacy and toxicity of sulfasalazine for the treatment of rheumatoid arthritis (RA). (Review)
Review
OBJECTIVES
To estimate the short-term efficacy and toxicity of sulfasalazine for the treatment of rheumatoid arthritis (RA).
SEARCH STRATEGY
We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles.
SELECTION CRITERIA
All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing sulfasalazine against placebo in patients with RA.
DATA COLLECTION AND ANALYSIS
Two reviewers determined the studies to be included based on inclusion and exclusion criteria (GW, MSA). Data were independently abstracted by two reviewers (EB, MSA), and checked by a third reviewer (BS) using a pre-developed form for the rheumatoid arthritis sub-group of the Cochrane Musculoskeletal Group. The same two reviewers, using a validated scale (Jadad 1996) assessed the methodological quality of the RCTs and CCTs independently. Rheumatoid arthritis outcome measures were extracted from the publications. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts, pain, and global and functional assessments. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios (OR) for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout and random effects for outcomes showing heterogeneity.
MAIN RESULTS
Six trials, including 468 patients were included. A statistically significant benefit was observed for sulfasalazine when compared to placebo for tender and swollen joint scores, pain and ESR. The standardized weighted mean difference between treatment and placebo was -0.49 for tender and swollen joint scores, and -0.42 for pain. The difference for ESR was -17.6mm. Withdrawals from adverse reactions were significantly higher in the sulfasalazine group (OR=3.0). Patients receiving placebo were four times more likely to discontinue treatment because of lack of efficacy than patients receiving sulfasalazine.
REVIEWER'S CONCLUSIONS
Sulfasalazine appears to have a clinically and statistically significant benefit on the disease activity of patients with RA. Its effects on overall health status and radiological progression are not clear at this time, but would appear to be modest.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Sulfasalazine
PubMed: 10796400
DOI: 10.1002/14651858.CD000958