Topic Development

This report is an update of a CER completed in 2007.²² The topic of the original report and the preliminary Key Questions (KQs) arose through a public process involving the public, the Scientific Resource Center (SRC, at www.effectivehealthcare.ahrq.gov/aboutUs/index.cfm#RC) for the Agency for Healthcare Research and Quality’s (AHRQ’s) Effective Health Care program (www.effectivehealthcare.ahrq.gov), and various stakeholder groups (www.effectivehealthcare.ahrq.gov/aboutUs/index.cfm#SG). Investigators from the RTI–UNC EPC then refined the original questions, in consultation with AHRQ, the SRC, and the Technical Expert Panel (TEP) during multiple conference calls, into the KQs used for the original report. For this update, the KQs were again refined into the final set of KQs listed in the introduction. No substantive changes to the KQs were made for this update other than adding new medications that have been approved since the previous report. The protocol for the project was posted on the AHRQ Web site (http://www.effectivehealthcare.ahrq.gov). The original report included both rheumatoid arthritis (RA) and psoriatic arthritis (PsA). When updating the material, the decision was made to divide the material into two separate reports, one for RA and one for PsA. This report includes only the information related to patients with PsA. This report is intended to replace the original report; it includes the information from the original report as well as the new information we identified.

Literature Search

To identify articles relevant to each KQ, we searched MEDLINE^®, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts. The full search strategy is presented in Appendix A. We conducted this review at the same time as a review on RA; that is, we conducted the literature searches and review processes in parallel, shown in Appendix A. We used either Medical Subject Headings (MeSH or MH) as search terms when available or key words when appropriate. We combined terms for selected indications (PsA and RA), drug interactions, and adverse events with a list of included medications. We included the following medications: corticosteroids (methylprednisolone, prednisone, and prednisolone), four oral disease-modifying antirheumatic drugs (DMARDs) (methotrexate [MTX], leflunomide, sulfasalazine, and hydroxychloroquine), and nine biologic DMARDs (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, and tocilizumab). We limited the electronic searches to “human” and “English language.” For the original report, sources were searched from 1980 to September 2006. For this update, sources were searched from June 2006 to January 2011. We overlapped the update search with the original search to account for delays in indexing. We used the National Library of Medicine (NLM) publication type tags to identify reviews, randomized controlled trials (RCTs), and meta-analyses. We manually searched reference lists of pertinent review articles and letters to the editor to supplement searches for the original report. We used the Scopus abstract and citation database to supplement searches for this update. We imported all citations into an electronic database (EndNote X.0.2). Additionally, we hand-searched the Center for Drug Evaluation and Research (CDER) database to identify unpublished research submitted to the U.S. Food and Drug Administration (FDA). The SRC contacted pharmaceutical manufacturers and invited them to submit dossiers, including citations. We received dossiers from five pharmaceutical companies (Abbott, Amgen, Bristol-Myers Squibb, Centocor, and Genentech) for the original report. We received dossiers from three pharmaceutical companies (Abbott, Amgen, and Centocor) for this update. The SRC also searched the following for potentially relevant unpublished and ongoing literature: FDA Web site; Health Canada; Authorized Medicines for EU; ClinicalTrial.gov; Current Controlled Trials; Clinical Study Results; WHO Clinical Trials; Conference Papers Index; Scopus; NIH RePORTER; HSRPROJ; Hayes, Inc. Health Technology Assessment; and the New York Academy of Medicine’s Grey Literature Index.

Study Selection

We developed eligibility (inclusion and exclusion) criteria with respect to study design or duration, patient population, interventions, outcomes, and comparisons as described in Table 5 below. For efficacy and effectiveness, we focused on head-to-head trials and prospective observational studies comparing one drug with another. For biologic DMARDs, we also included placebo-controlled, double-blind RCTs. For safety and tolerability, as well as for efficacy and effectiveness in subgroups, we included head-to-head trials, high-quality systematic reviews, and prospective and retrospective observational studies.

Table 5

Outcome measures and study eligibility criteria.

For this review, results from well-conducted, valid head-to-head trials provide the strongest evidence to compare drugs with respect to efficacy, effectiveness, and harms. We defined head-to-head trials as those comparing one drug of interest with another. RCTs or prospective cohort studies of at least 3 months’ duration and an adult study population were eligible for inclusion. For harms (i.e., evidence pertaining to tolerability, adverse effects, and adverse events), we examined data from both experimental and prospective and retrospective observational studies. We included RCTs (no sample size limit) and observational studies (with sample sizes ≥ 100 patients) that lasted at least 3 months and reported an outcome of interest.

Because equipotency among the reviewed drugs is not well established, we assumed that comparisons made within the recommended dosing ranges in the Introduction chapter are appropriate. Dose comparisons made outside the recommended daily dosing range are not in our report.

Two individuals independently reviewed abstracts. If both reviewers agreed that a study did not meet eligibility criteria, we excluded it. We obtained the full text of all remaining articles and used the same eligibility criteria to determine which, if any, to exclude at this stage. We did not include studies that met eligibility criteria but were reported as an abstract only. Appendix C lists our full bibliography and their source database. Appendix D summarizes reasons for excluding studies that were reviewed as full-text articles but did not meet eligibility criteria.

We reviewed studies that reported health outcomes for efficacy or effectiveness. For example, these outcomes included clinical response to treatment, remission, functional capacity, and quality of life. In addition, we included radiographic outcomes as intermediate outcome measures. For harms, we looked for both total adverse events and specific adverse events ranging in severity (e.g., serious infections, malignancies, hepatotoxicity, hematological adverse events, infusion and injection reactions, nausea), withdrawals attributable to adverse events, and drug interactions. We included systematic reviews and meta-analyses in our evidence report if we found them to be relevant for a KQ and of good or fair methodological quality. We did not abstract individual studies if they had been used in a systematic review or meta-analysis of good quality. However, we reviewed them to determine whether any other outcomes of interest were reported.

Data Extraction

We designed and used a structured data abstraction form to ensure consistency of appraisal for each study. Trained reviewers abstracted data from each study. A senior reviewer read each abstracted article and evaluated the completeness of the data abstraction.

We abstracted the following data from included articles: study design, eligibility criteria, intervention (drugs, dose, and duration), additional medications allowed, methods of outcome assessment, population characteristics (such as age, sex, race or ethnicity, or mean disease duration), sample size, loss to followup, withdrawals because of adverse events, results, and adverse events reported. We recorded intention-to-treat results if available. All data abstraction employed SRS 4.0, Mobius Analytics™. Evidence tables containing all abstracted data of included studies are presented in Appendix E.

Quality Assessment

To assess the quality (internal validity) of trials, we used predefined criteria based on those developed by the U.S. Preventive Services Task Force (ratings: good, fair, poor)²³ and the National Health Service Centre for Reviews and Dissemination.²⁴ Elements of quality assessment included randomization and allocation concealment, similarity of compared groups at baseline, use of ITT analysis (i.e., all patients were analyzed as randomized), adequacy of blinding, and overall and differential loss to followup.

In general terms, a “good” study has a low risk of bias and results are considered to be valid. A “fair” study is susceptible to some risk of bias but probably not sufficient to invalidate its results. The fair-quality category is likely to be broad, so studies with this rating will vary in their strengths and weaknesses. A “poor” rating indicates significant risk of bias (stemming from, e.g., serious errors in design, analysis reporting a large amount of missing information, or discrepancies in reporting) that may invalidate the study’s results.

To assess the quality of observational studies, we used criteria outlined by Deeks et al.²⁵ Items assessed included selection of cases or cohorts and controls, adjustment for confounders, methods of outcomes assessment, length of followup, and statistical analysis. To assess the quality of systematic reviews and meta-analyses, we assessed the following: whether the review was based on a clear question, clear reporting of inclusion criteria, methods used for identifying literature (the search strategy), whether two reviewers independently reviewed publications to determine eligibility, whether authors used a standard method of critical appraisal (or quality rating or validity assessment), assessment of heterogeneity, assessment of publication bias, and statistical analysis. Systematic reviews were categorized as good when all criteria were met.

Two independent reviewers assigned quality ratings. They resolved any disagreements by discussion and consensus or by consulting with a third reviewer. Appendix G details the predefined criteria used for evaluating the quality of all included studies. Studies that met all criteria were rated good quality. Studies that had a fatal flaw (defined as a methodological shortcoming that leads to a very high risk of bias) in one or more categories were rated poor quality and excluded from our analyses.

Applicability Assessment

Using the parameters for evaluation in guidance provided by AHRQ’s Methods Guide for Comparative Effectiveness Reviews,²⁶ we evaluated the applicability of the included studies. Applicability is similar to generalizability or external validity of the studies included in the evidence base. We evaluated applicability using a qualitative assessment of the population, intervention/treatment, comparator, outcomes measured, timing of followup, and setting. We specifically considered whether populations enrolled in these trials or studies differed from target populations as laid out in Chapter 1, whether studied interventions are comparable with those in routine use, whether comparators reflect best alternatives, whether measured outcomes reflect the most important clinical outcomes, whether followup was sufficient, and whether study settings were representative of most settings.

Grading Strength of Evidence

We evaluated the strength of evidence based on methods guidance for the EPC program.^{26, 27} For this report, we graded the strength of evidence for the outcomes determined to be most important: measures of disease activity (e.g., Psoriasis Area and Severity Index-PASI, Disease Activity Score-DAS, Psoriasis Arthritis Response Criteria-PsARC), radiographic changes, functional capacity, quality of life, withdrawals due to adverse events, and specific adverse events if data were available (e.g., injection-site reactions, infections, malignancy). Because no head-to-head trials were identified, we graded the strength of evidence for each of the included medications compared with placebo. The strength of evidence for each outcome or comparison that we graded incorporates scores on four domains: risk of bias, consistency, directness, and precision; it can also reflect ratings for other domains that can be factored in when relevant (e.g., dose-response relationships).

As described in Owens et al.,²⁷ the evaluation of risk of bias includes assessment of study design and aggregate quality of studies. We judged good quality studies to result in evidence with low risk of bias. We graded evidence as consistent when effect sizes across studies were in the same direction. When the evidence linked the interventions directly to health outcomes, we graded the evidence as being direct. We graded evidence as being precise when results had a low degree of uncertainty. A precise estimate is an estimate that would allow a clinically useful conclusion. An imprecise estimate is one for which the confidence interval is wide enough to include clinically distinct conclusions.²⁷

We dually evaluated the overall strength of evidence for each major outcome based on a qualitative assessment of strength of evidence for each domain and reconciled all disagreements. The levels of strength of evidence are shown in Table 6.

Table 6

Strength of evidence grades and their definitions.

Data Synthesis

Throughout this CER we synthesized the literature qualitatively because there were too few studies for each of the comparisons of interest to justify combining them in quantitative analyses. We constructed tables showing the study characteristics, quality ratings, and main results for all included studies.

Peer Review

This CER underwent external peer review from individuals who were experts in rheumatology and from various stakeholder and user communities (listed in the Front Matter). The SRC oversaw the peer-review process. Peer reviewers were charged with commenting on the content, structure, and format of the evidence report; providing additional relevant citations; and pointing out issues related to how we had conceptualized and defined the topic and KQs. Our peer reviewers, also Technical Expert Panel members, gave us permission to acknowledge their review of the draft. We compiled all comments and addressed each one individually, revising the text as appropriate. AHRQ and the SRC also requested review from its own staff.