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Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Psoriatic Arthritis in Adults: Update of a 2007 Report [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Apr. (Comparative Effectiveness Reviews, No. 54.)
This publication is provided for historical reference only and the information may be out of date.
Drug Therapy for Psoriatic Arthritis in Adults: Update of a 2007 Report [Internet].
Show detailsFigure 1 documents the results of the literature search (Appendix A).We included 24 published articles reporting on 16 studies: 0 head-to-head randomized controlled trials (RCTs), 0 head-to-head nonrandomized controlled trials, 10 placebo-controlled trials, 3 meta-analyses or systematic reviews, and 3 observational studies. Our findings include studies rated good or fair for internal validity. Most studies were of fair quality; we designate in the text only those of good quality. Evidence tables for included studies can be found in Appendix E.
We included articles based on eligibility criteria or methodological criteria (quality rating) as explained in the Methods chapter.
Of the 16 included studies, 8 (50 percent) were supported by pharmaceutical companies; 4 (25 percent) were funded by governmental or independent funds; 3 (19 percent) were supported by a combination of pharmaceutical and government funding; and 1 did not report the funding source (6 percent).
This chapter is organized by Key Question (KQ). When comparative evidence is available, we discuss it before presenting placebo controlled trials. Generally, the chapter is organized by oral DMARD comparisons followed by biologic DMARD comparisons.
Across all KQs, we have included head-to-head studies, observational studies, and systematic reviews. When comparative evidence is available, we discuss it before presenting placebo-controlled trials. Table 7 gives the numbers of trials or studies for drug class comparisons; when some groupings have important subcomparisons, we note these. We do not, however, offer an exhaustive list of all possible comparisons among corticosteroids, oral DMARDs, and biologic DMARDs simply because of the sheer number of potential combinations of drugs within classes and across classes, which cannot be clearly and concisely presented here.
Table 7
Number of trials or studies by drug comparison and study design for psoriatic arthritis.
Table 8 lists abbreviations and full names of diagnostic scales and health status or quality-of-life instruments encountered in these studies, as well information about clinical significance when available. For further details about such instruments and scales, see Appendix G.
Table 8
Disease activity, radiographic progression, functional capacity, and quality-of-life measures.
KQ 1. Reductions in Disease Activity, Limitations of Disease Progression, and Maintenance of Remission
KQ 1 concerned three main topics. Specifically, “for patients with psoriatic arthritis, do drug therapies differ in their ability to reduce disease activity, to slow or limit progression of radiographic joint damage, or to maintain remission?” We use the term disease activity to refer to condition-specific measures such as the Psoriasis Area and Severity Index (PASI), the Psoriatic Arthritis Response Criteria (PsARC), or the American College of Rheumatology (ACR) response. Strength of evidence is presented, and additional tables provide selected study-specific information on outcomes, broken out by primary outcomes and radiologic outcomes. Evidence Tables in Appendix E document details about all these studies.
Overview
A total of nine placebo-controlled randomized controlled trials (RCTs), two observational studies, and three systematic reviews or meta-analyses examined symptom response, radiographic joint damage, and remission. The main drug classes compared included oral disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs (also referred to simply as biologics), and combined strategies. Overall strength of evidence is listed in Appendix I. When possible, we describe whether treatment effects reach minimal clinically important differences (MCIDs). In this section, achieving at least an ACR of 20 or above or a PASI of at least 50 percent improvement is considered minimally clinically important (Table 8).
Oral DMARD Versus Oral DMARD
We did not find any studies meeting our criteria for inclusion.
Oral DMARD Versus Placebo
Evidence from one 12-week study provides low strength of evidence that parenteral high-dose methotrexate (MTX) improves physician assessment of disease severity, compared with placebo (median change 1 vs. 0; P=0.001).39 The MCID cannot be determined from this comparison.
One systematic review found that, compared with placebo, sulfasalazine improved patient outcomes (pooled index of variables in the OMERACT: 0.38 units; 95% CI, 0.21 to 0.54).40 The MCID cannot be determined from this comparison.
Evidence from one 24-week trial provides low strength of evidence that leflunomide patients experienced improved disease activity compared with those in the placebo arm (PsARC primary outcome 58.9 percent vs. 29.7 percent, P<0.0001).41, 42 The strength of evidence is low. Improvements in additional outcomes including ACR 20 did reach MCID, but the PASI did not.
Biologic DMARD + Oral DMARD Versus Biologic DMARD
We did not find any head-to-head controlled trials for any of the included drugs, but two observational cohort studies provide some evidence. One cohort study compared the combination of an anti-tumor necrosis factor (TNF) (adalimumab, etanercept, or infliximab) with MTX versus anti-TNF only and found no difference in treatment response.43 Another cohort study compared adalimumab, etanercept, and infliximab and found no differences in efficacy among the groups.44 The strength of evidence is low.
Biologic DMARD + Oral DMARD Versus Oral DMARD
A systematic review provided low strength of evidence of a comparison between TNF inhibitors (adalimumab, etanercept, and infliximab) compared with sulfasalazine and found that the TNF inhibitors were relatively effective and had the largest effect size (risk ratio: 0.25, 95% CI, 0.13 to 0.48), and sulfasalazine was moderately effective (risk ratio: 0.45, 95% CI, 0.23 to 0.89).45 The MCID cannot be determined from this comparison.
Biologic DMARD Versus Placebo
The use of four biologics—adalimumab, etanercept, golimumab, and infliximab—provided low to moderate evidence of improved disease activity compared with placebo.46–54 The magnitude of benefit for ACR 20 ranged from 39 percent to 57 percent for adalimumab, 59 percent to 65 percent for etanercept, 45 percent to 51 percent for golimumab, and 58 percent to 62 percent for infliximab.
Psoriatic Arthritis: Detailed Analysis
Oral DMARD Versus Oral DMARD
We did not find any studies meeting our criteria for inclusion. We did not identify any studies meeting our inclusion/exclusion criteria that examined the use of corticosteroids in the treatment of psoriatic arthritis (PsA). Because of the paucity of head-to-head trials, we additionally reviewed placebo-controlled trials to summarize the general efficacy of oral and biologic DMARDs. Summarizing the general efficacy, however, does not provide evidence on the comparative efficacy and tolerability of treatments for PsA.
Oral DMARD Versus Placebo
One systematic review examined the efficacy of oral DMARDs used in placebo-controlled trials.40 The investigators used data from 13 RCTs that included 1,022 adults with PsA in a meta-analysis that focused on comparisons of sulfasalazine, auranofin, etretinate, fumaric acid, intramuscular injection of gold, azathioprine, efamol marine, and MTX with placebo (Table 9). Two drugs (MTX and sulfasalazine) are of interest for our report. The primary outcome measure included individual component variables validated by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) to create a pooled index; components used include acute phase reactants, disability, pain, patient global assessment, physician global assessment, swollen joint count, tender joint count, and radiographic changes of joints in any trial of 1 year or longer. The primary outcome was change in a pooled disease index.
Table 9
Disease activity of oral DMARD versus placebo.
Methotrexate
One multicenter 12-week RCT (N=37),39 included in the systematic review described above, compared MTX (weekly dose of 7.5 mg to 15 mg) with placebo. The study reported some improvement in PsA as measured by change in grip strength, morning stiffness, and patient assessment in the drug treatment group, but statistically significant improvement compared with placebo occurred only in physician assessment of disease severity (P=0.001); there were no differences between groups in joint swelling or pain/tenderness. Psoriatic skin lesions showed no significant changes in scaling, induration, or erythema from entry appearance, but surface area involvement improved significantly compared with placebo (P=0.039) in 14 of the MTX patients assessed (Table 9). The systematic review used this single study comparing MTX with placebo to calculate an overall improvement in the OMERACT index of 0.65 units (95% CI, 0.00 to 1.30).40 The MCID cannot be determined.
Sulfasalazine
The investigators pooled six trials involving comparisons of sulfasalazine (average dose of 2 g/day to 3 g/day) with placebo (N=564). Sulfasalazine showed an improvement in the pooled index of 0.38 units (95% CI, 0.21 to 0.54).40 The MCID cannot be determined.
Leflunomide
One trial (two publications) evaluated the efficacy of leflunomide against placebo in 190 patients over 24 weeks;41, 42 PsA was defined as having at least three swollen joints and three tender or painful joints and psoriasis over at least 3 percent of the body surface area. In this study, almost 50 percent of the patients were DMARD naive. Patients who were not DMARD naive were required to discontinue all oral DMARDs as well as biologic agents and investigational drugs 28 days before baseline.
The leflunomide group had significantly greater improvements in measures of disease activity than the placebo group. These improvements included response rates on a modified ACR 20 (36.3 percent vs. 20 percent; P=0.014), the PsARC (achieved in 58.9 percent vs. 29.7 percent; P=0.0001), and the PASI (17.4 percent vs. 7.8 percent reached threshold; P=0.048). The ACR 20 did reach MCID, but the PASI did not.
Biologic DMARD + Oral DMARD Versus Biologic DMARD
One retrospective cohort (N=261) of anti-TNF naive patients with active PsA in Sweden compared patients taking MTX concomitant with anti-TNF (adalimumab—40 mg every other week; etanercept—25 mg twice a week; or infliximab—3 mg/kg at 0, 2, and 6 weeks and then every 8 weeks) versus anti-TNF alone.43 Eligible patients had active PsA with high disease activity and/or unacceptably high steroid use. Over 12 months, there were no significant differences in European League Against Rheumatism response (EULAR) good or EULAR overall between patients taking MTX with anti-TNF compared with anti-TNF only, see Table 10.
Table 10
Disease activity of biologic DMARD + oral DMARD versus biologic DMARD.
Also in Table 10 is the second cohort study, conducted in Great Britain, that found no significant differences in EULAR response rates at six (P=0.679), 12 (P=0.904), and 18 (P=0.583) months between the three anti-TNF therapies of adalimumab, etanercept, and infliximab.44 Furthermore, EULAR response rates for the whole anti-TNF cohort were similar in patients receiving anti-TNF agents in combination with MTX (78.1 percent at 6 months), another DMARD (73.3 percent), or anti-TNF monotherapy (79.5 percent).44
Biologic DMARD + Oral DMARD Versus Oral DMARD
One systematic review, as seen in Table 11, included an analysis of TNF inhibitors and sulfasalazine for the treatment of PsA and examined efficacy as defined by the number of patients that withdrew because of lack of effect.45 The TNF inhibitors analysis included five studies with 882 patients and found that the risk ratio for efficacy was 0.25 (95% CI, 0.13 to 0.48). The analysis of sulfasalazine found that the risk ratio for efficacy was 0.45 (95% CI, 0.23 to 0.89). The MCID cannot be determined from this comparison.
Table 11
Disease activity of biologic DMARD + oral DMARD versus sulfasalazine.
Biologic DMARD Versus Placebo
Seven RCTs (11 articles) and 1 systematic review examined the efficacy of biologics against placebo in treating patients with PsA (Table 12).46–56 Two trials were of adalimumab, 2 of etanercept, 3 of infliximab, and 1 of golimumab. All trials allowed patients to continue an oral DMARD, usually MTX. The systematic review examined etanercept and infliximab versus placebo.55 All showed that the use of biologics led to significantly better outcomes than placebo.
Table 12
Disease activity in biologic DMARD versus placebo.
Adalimumab
Two RCTs examined the use of adalimumab (40 mg every other week) in patients suffering from moderate to severe PsA (defined as having at least three swollen joints and three tender or painful joints) who had an inadequate response or intolerance to nonsteroidal anti-inflammatory drug (NSAID) therapy46 or previous oral DMARD therapy.56 Patients were allowed to continue current MTX therapy as long as the dose had been stable for 4 weeks. In the first study,46 the double-blind phase of the study lasted 24 weeks, but patients who failed to achieve at least a 20 percent decrease in both swollen and tender joint counts on two consecutive visits could receive rescue therapy with corticosteroids or oral DMARDs. A significantly higher percentage of the adalimumab group met ACR 20/50/70 response criteria than the placebo group (all P<0.001). According to the PsARC, 60 percent of the adalimumab group and 23 percent of the placebo group responded (P=NR). PASI 75 was achieved by 59 percent of the adalimumab group and 1 percent of the placebo group (P<0.001). At 24 weeks, the changes in the modified Sharp score, erosion score, and joint space narrowing score were significantly less in adalimumab-treated than placebo-treated patients (P=0.001). The second trial56 randomized 102 patients for 12 weeks and similarly found a higher percentage of patients meeting ACR 20 at week 12 compared with placebo (39 vs. 16 percent, P=0.012).56
Etanercept
Two RCTs examined the efficacy of etanercept (25 mg twice weekly by subcutaneous injections) in a total of 265 patients with active PsA who were not adequately responding to conventional DMARD therapies.47, 48 In both studies, patients were allowed to continue MTX therapy as long as the dose had been stable for 4 weeks before entry into the study. One study lasted 12 weeks (N=60);47 the other (N=205) was double-blinded for 24 weeks.48 In both studies, the proportions of patients on etanercept meeting ACR 20 response criteria were significantly higher than those for patients on placebo. In the 12-week study, 87 percent of patients on etanercept and 23 percent of those on placebo achieved a PsARC response (P<0.0001).47 The 24-week study had similar results at 12 weeks: 72 percent of patients on etanercept and 31 percent of those on placebo achieved a PsARC response (P=NR).48 PASI 75 criteria were met by a greater proportion of patients in the etanercept groups than in the placebo groups in both studies. In the 12-week study, 26 percent of patients on etanercept met PASI 75 criteria versus zero patients on placebo (P=0.015); in the longer study, the figures were 23 percent on etanercept versus 3 percent on placebo (P<0.001). The longer study assessed the radiographic progression of disease at 24 weeks in 205 patients; the mean annualized change in the modified Sharp score was significantly lower in etanercept-treated patients (decrease of −0.03) than in placebo-treated patients (increase of 1.0; P=0.0001).49
A systematic review pooled the 12-week data from these two studies; the ACR 20 threshold for improvement was achieved by 65 percent of the etanercept groups (placebo NR), with a pooled relative risk of 4.19 (95% CI, 2.74 to 6.42) compared with placebo.55 The ACR 50 and ACR 70 criteria were achieved by 45 percent and 12 percent of those treated with etanercept, respectively. In addition, the PsARC was reached by almost 85 percent, with a pooled relative risk of 2.6 (95% CI, 1.96 to 3.45) compared with placebo (placebo NR).55
Golimumab
One 14-week RCT of 405 patients with active PsA compared golimumab (50 mg ever 4 weeks or 100 mg every 4 weeks) with placebo.54 At 14 weeks, all patients on either golimumab dose achieved a higher ACR 20 when compared with placebo (48 percent vs. 9 percent, P<0.001). Significantly greater improvements were also noted for those treated with golimumab for 75 percent improvement in the PASI (40 percent in the 50 mg group, 58 percent in the 100 mg group, and 3 percent in the placebo group; P<0.001).
Infliximab
Two RCTs (five articles) of infliximab compared with placebo included a total of 304 patients with active PsA who had not adequately responded to conventional DMARD therapies.50–53, 57 In both studies, patients were allowed to continue MTX therapy as long as the dose had been stable for 4 weeks before study entry. One RCT (N=104) was double-blinded for 16 weeks.50 The other RCT was double-blinded for 24 weeks (N=200 patients with cross-over allowed at week 16 for nonresponders); the primary outcomes were evaluated at 14 weeks and before any crossover.52 Both studies had the same dosing regimen of 5 mg/kg of infliximab at weeks 0, 2, 6, and 14; the longer study had an additional infusion at week 22. In both studies, the percentages meeting ACR 20 response criteria were significantly greater for subjects treated with infliximab than for those treated with placebo. In the shorter study, 75 percent of the patients on infliximab and 21 percent on placebo achieved a PsARC response (P<0.001). The longer study had similar results in patients achieving a PsARC response at 14 weeks: 77 percent of the patients on infliximab and 27 percent on placebo (P<0.001). PASI 75 was achieved by a greater proportion of patients in the infliximab groups than the placebo groups in both studies: for the 16-week study, 68 percent on infliximab versus zero on placebo (P<0.01) and, for the later study, 50 percent on infliximab versus 1 percent on placebo (P<0.001). Radiographic changes were also less at 24 weeks (Sharp/van der Heijde (−0.70+/−2.53 vs. 0.82+/−2.62, P<0.001).57
A systematic review described above in the etanercept studies55 pooled the 14- and 16-week data from these two infliximab studies;50, 52 the ACR 20 threshold for improvement was achieved by 62 percent of the etanercept groups (placebo NR), with a pooled relative risk of 5.75 (95% CI, 3.55 to 9.30) compared with placebo.55 In addition, the PsARC was reached by almost 76 percent, with a pooled relative risk of 3.05 (95% CI, 2.29 to 4.08) compared with placebo (placebo NR).55
KQ 2. Functional Capacity and Quality of Life
KQ 2 specifically examined the issue of whether, for patients with psoriatic arthritis (PsA), drug therapies differed in their ability to improve patient-reported symptoms, functional capacity, or quality of life. Findings are organized as for KQ 1. Table 7 lists the abbreviated and full names of all instruments and scales referred to in this chapter. Functional capacity, functional status, and functional ability are three concepts often used interchangeably to refer to similar capabilities. Quality of life is a far broader construct comprising physical health; mental or emotional health; a variety of symptom states (e.g., pain, fatigue); and coping, spiritual, and other domains. For the purposes of this report, we divided outcomes into functional capacity and health-related quality of life. We use the terms functional capacity, functional status, or functional ability to refer to condition-specific measures, such as the Health Assessment Questionnaire (HAQ), developed to assess function in patients with PsA or other types of arthritis. We use health-related quality of life when referring to generic measures, such as the Medical Outcomes Study Short Form 36 Health Survey (SF-36), that have been developed to assess quality of life in both healthy people and those with different conditions; we also use health-related quality of life when referring to measures developed to assess quality of life for a specific condition or group of conditions, such as the Dermatology Life Quality Index (DLQI), a quality-of-life instrument for dermatologic diseases. We attempted to use terminology consistent with reporting from individual studies; if the authors used the term functional ability rather than functional capacity, we used the same term. Outcomes for functional capacity and health-related quality of life were often secondary outcomes in these studies; that is, studies were not all designed to detect a difference between groups for these types of outcomes.
Overview
A total of eight RCTs examined functional capacity or quality of life in patients being treated for PsA. Details are found in the Evidence Tables in Appendix E. Tables 12 and 13 provide information on comparisons made, quality-of-life outcomes, and quality ratings. Conclusions are limited because we found no good or fair quality head-to-head studies. The available studies are all placebo-controlled studies evaluating the efficacy of one oral disease-modifying antirheumatic drug (DMARD) or one biologic DMARD. In total, we found one study (two articles) comparing an oral DMARD with placebo41, 42 and seven studies comparing a biologic DMARD with placebo. Overall results and strength of evidence are described in Appendix H.
Table 13
Oral DMARD versus placebo studies: functional capacity and health-related quality of life outcomes: leflunomide vs. placebo.
Small differences in outcome measures may be statistically significant, yet clinically unimportant. Therefore, in the text below, we describe whether treatment effects reach minimal clinically important differences (MCIDs) for the HAQ and SF-36, the two most commonly reported outcome measures in KQ2. For the HAQ, we considered a change of ≥0.22 to be an MCID.31 For the SF-36, some have suggested an improvement of 3 to 5 for the MCID.35, 58 We found no published PsA ranges but found some developed using data from clinical trials of RA patients that suggest slightly lower values, with ranges of 2.6 to 4.4 for the physical component score (PCS) and 2.2 to 4.7 for the mental component score (MCS).34 We used these lower ranges to take a conservative approach on what might be an MCID.
Head-to-Head Evidence
We did not find any head-to-head studies meeting our inclusion/exclusion criteria.
Oral DMARD Versus Placebo
Evidence from one 24-week study provides a low strength of evidence that patients treated with leflunomide had statistically significant greater improvement in functional capacity (mean change in HAQ: −0.19 vs. −0.05; P=0.027) and quality-of-life outcomes (mean change in DLQI: −1.9 vs. −0.2; P=0.017) than those treated with placebo.41, 42 However, the improvement in functional capacity did not reach the MCID (change of ≥0.22).
Biologic DMARD Versus Placebo
Evidence from seven studies comparing either adalimumab (two studies),46, 56, 59 etanercept (two studies),47–49, 60 golimumab (one study),54 or infliximab (two studies)50–53, 61 with placebo provides a low to moderate strength of evidence for the efficacy of each of these biologic DMARDs for improving functional capacity and quality of life. The magnitude of benefit in functional capacity reached the MCID (HAQ change of ≥0.22) for all but one study of adalimumab (which found a between-group difference of 0.2).56 Overall, the magnitude of benefit for functional capacity (between-group difference for improvement in HAQ) ranged from 0.2 to 0.3 for adalimumab, 0.5 to 1.1 for etanercept, 0.34 to 0.4 for golimumab, and 0.4 to 0.6 for infliximab.
The magnitude of benefit in quality of life reached the MCID for the PCS for all five studies that reported the PCS and ranged from 2.9 to 7.9 for adalimumab, was 8.6 for etanercept, 5.9 to 7.2 for golimumab, and 6.4 to 8 for infliximab. The magnitude of benefit in quality of life reached the MCID for the MCS for two of the four studies that reported the MCS48, 49, 52, 53, 60, 61 and ranged from 1.2 to 1.7 for adalimumab, was 2.8 for etanercept, and 3.5 to 5 for infliximab.
Detailed Analysis
Oral DMARD Versus Placebo
We did not identify any studies that examined the use of corticosteroids in the treatment of PsA or any head-to-head studies of oral DMARDs reporting outcomes relevant for this section. One study met inclusion criteria for this section. It compared leflunomide with placebo (Table 13).41, 42
Leflunomide
One 24-week trial (two publications) evaluated the efficacy of leflunomide in PsA patients.41, 42 The study randomized 190 subjects to leflunomide or placebo; PsA was defined as having at least three swollen joints and three tender or painful joints and psoriasis over at least 3 percent of the body surface area. Almost 50 percent of the patients were DMARD naive. Those who were not DMARD naïve were required to discontinue all oral DMARDs, biologic DMARDs, and investigational drugs 28 days before baseline measures were done. At 24 weeks, subjects treated with leflunomide had greater improvement in functional capacity and quality of life than those treated with placebo.
Biologic DMARD Versus Placebo
We did not identify any head-to-head studies of biologic DMARDs reporting outcomes relevant for this section. Seven studies (13 articles) compared one biologic DMARD with placebo (Table 14).46–54, 56, 59–61
Table 14
Biologic DMARD versus placebo studies: functional capacity and health-related quality-of-life outcomes.
Adalimumab
Two RCTs compared adalimumab (40 mg every other week) with placebo.46, 56, 59 In both studies, patients were allowed to continue current MTX therapy as long as the dose had been stable. Both enrolled subjects who had an inadequate response or intolerance to previous treatments. Both studies found greater improvement in functional capacity for subjects treated with adalimumab than those treated with placebo. For health-related quality of life, several outcome measures were reported in both studies; results for each measure either statistically significantly favored adalimumab or were not statistically significantly different but point estimates favored adalimumab.
The Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) included 313 patients suffering from moderate to severe PsA, which was defined as having at least three swollen joints and three tender or painful joints, who had had an inadequate response or intolerance to NSAID therapy.46, 59 The double-blind phase of the study was 24 weeks, but patients who failed to achieve at least a 20 percent decrease in both swollen and tender joint counts on two consecutive visits could receive rescue therapy with corticosteroids or DMARDs. Subjects treated with adalimumab had greater improvements in functional capacity and two quality-of-life measures (SF-36 PCS and DLQI) than those who received placebo.
The other RCTs enrolled 102 subjects with PsA and at least three swollen joints and three tender joints who were receiving concomitant DMARD therapy or had a history of DMARD therapy with an inadequate response.56 Subjects treated with adalimumab had greater improvements in functional capacity than those who received placebo. Differences between groups for quality-of-life outcome measures were not statistically significantly different between groups, but there was a trend toward greater improvement in subjects treated with adalimumab.
Etanercept
Two studies (three articles) that examined the efficacy of etanercept included a total of 265 patients with active PsA who were not adequately responding to conventional DMARD therapies.47–49 In both studies, patients were allowed to continue MTX therapy as long as it had been stable for 4 weeks prior to enrollment. One of these trials lasted 12 weeks (N=60);47 the other was double-blinded for 24 weeks (N=205).48 Both studies had the same dosing regimen of 25 mg of etanercept twice weekly by subcutaneous injections. Functional capacity improved significantly more with etanercept than with placebo in both studies. The longer study also had an additional 24-week blinded maintenance phase and a 48-week open-label extension during which all subjects received etanercept.60 Subjects originally assigned to etanercept maintained or improved their HAQ-DI scores, SF-36 physical component summary scores, and EQ-5D scores from the double-blind period through the end of the open-label extension period. Subjects originally assigned to placebo demonstrated improvement in their HAQ-DI scores, SF-36 physical component summary scores, and EQ-5D scores during the open-label extension while receiving etanercept.
Golimumab
The “Golimumab-A Randomized Evaluation of Safety and Efficacy in Subjects with Psoriatic Arthritis Using a Human Anti-TNF Monoclonal Antibody” (GO-REVEAL) study randomized 405 subjects with active PsA to golimumab 50 mg every 4 weeks, golimumab 100 mg every 4 weeks, or placebo.54 The subjects maintained the treatment to which they were randomized for the first 14 weeks; at week 16, subjects with less than 10 percent improvement from baseline in both swollen joint count and tender joint count entered early escape, with dose escalation from placebo to 50 mg golimumab (every 4 weeks) or from 50 mg to 100 mg golimumab (every 4 weeks). Subjects in both golimumab groups had greater improvements in functional capacity and in quality of life (measured by the SF-36 PCS) than those in the placebo group.
Infliximab
Two studies, “Infliximab Multinational Psoriatic Arthritis Controlled Trial” (IMPACT) and IMPACT 2, randomized a total of 304 patients with active PsA who were not adequately responding to conventional DMARD therapies to infliximab or placebo.50, 52 Both studies permitted patients to continue MTX therapy as long as it had been stable for 4 weeks before enrollment. One trial was double-blinded for 16 weeks (N=104);50 the other was double-blinded for 24 weeks (N=200), with crossover allowed at week 16 for nonresponders on the primary outcomes measured at the 14-week evaluation.52 Both studies had the same dosing regimen of 5 mg/kg of infliximab at weeks 0, 2, 6, and 14; the longer study had an additional injection at week 22. Subjects treated with infliximab had significantly greater improvement in functional capacity than those treated with placebo in both studies. In IMPACT 2, subjects treated with infliximab had greater improvement in functional capacity and quality of life than those treated with placebo. Increases in the physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (P ≤ 0.001). These benefits were sustained through week 24. Compared with the placebo group, higher proportions of patients in the infliximab group improved employment status from unemployed at baseline to employed at week 14 and from part-time to full-time employment.
KQ 3. Harms, Tolerability, Adverse Effects, or Adherence
KQ 3 concerned the potential negative aspects of drug therapies for psoriatic arthritis (PsA) (i.e., harms, tolerability, and adverse effects), as well as patient adherence to treatments. Strength of evidence is presented and additional tables provide selected study-specific information on outcomes, broken out by overall tolerability, specific adverse events, and adherence. Evidence Tables in Appendix E document details about all of these studies.
Overview
A total of one systematic review and meta-analysis, eight randomized controlled trials (RCTs), and two observational studies compared tolerability, harms, and adherence in patients with PsA. The drugs examined in RCTs and the systematic review of RCTs included two oral disease-modifying antirheumatic drugs (DMARDs) (leflunomide and sulfasalazine) and four biologic DMARDs (adalimumab, etanercept, golimumab, and infliximab), all in comparison with placebo. Both prospective cohort studies included patients on adalimumab, etanercept, and infliximab (with or without methotrexate [MTX]), and all of these groups were compared with each other. Overall strength of evidence is insufficient (Appendix H), except for the assessment of withdrawals due to adverse events for the comparison of adalimumab, etanercept, and infliximab, and placebo comparisons of adalimumab and etanercept, which has a low strength of evidence.
Oral DMARDs Versus Placebo
The use of leflunomide versus placebo can increase the likelihood of diarrhea. It can also lead to clinically significant increases in alanine aminotransferase. The rates of adherence are similar for leflunomide and placebo. Withdrawals due to adverse events are higher with leflunomide than placebo based on a single study. Withdrawals due to adverse events with sulfasalazine are not statistically significantly greater than placebo based on a meta-analysis45 of five trials. The strength of evidence is insufficient given the indirectness of the evidence.
Biologic DMARDs Versus Placebo
Seven placebo-controlled studies of biologics, including two each on adalimumab, etanercept, and infliximab, and one on golimumab, provide indirect evidence on harms. When the individual drugs were compared with placebo, the authors reported few differences in the rate of adverse events. Exceptions to this finding were increased rates of injection-site reactions with the use of adalimumab and etanercept and increased rates of infections and malignancies with golimumab. Adalimumab-treated patients had fewer reports of aggravated psoriasis compared with placebo-treated patients. Based on data from two prospective cohort studies, etanercept had a statistically significantly lower risk of discontinuation because of adverse events than infliximab. Infusion reactions with infliximab largely contributed to this difference in withdrawal rates. No evidence addressed adherence. The strength of evidence is low for adalimumab and etanercept and insufficient for golimumab and infliximab based on placebo-controlled data and low for the observational evidence addressing withdrawals due to adverse events.
Psoriatic Arthritis: Detailed Analysis
One systematic review and meta-analysis, eight RCTs, and two observational studies compared tolerability, harms, and adherence in patients with PsA. Summary information on these studies is highlighted in Table 15, and full details are found in Evidence Tables in Appendix E.
Table 15
Studies assessing adverse events, discontinuation rates, and adherence in psoriatic arthritis.
Oral DMARDs
Overall Tolerability
We did not identify any studies meeting our inclusion/exclusion criteria that examined the use of corticosteroids in the treatment of PsA. One 24-week trial with 190 patients examined adverse events in the treatment of PsA using leflunomide versus placebo.41 The overall rates of adverse events were the same in each group: 85.4 percent of both trial arms experienced an adverse event. In meta-analyses of placebo-controlled trials, withdrawals due to adverse events were not statistically significantly more common for suflasalazine than for placebo (five studies: RR, 1.76; 95% CI 0.98 to 3.14, P=0.06) but were statistically significantly more common for leflunomide than placebo based on one contributing study (RR, 3.86; 95% CI 1.20 to 12.39, P=0.02).45
Specific Adverse Events
One trial showed some differences in specific adverse events for leflunomide, in particular diarrhea (leflunomide, 24%; placebo, 13%; P=NR) and increases in alanine aminotransferase (leflunomide, 13%; placebo, 5%; P=NR).41
Adherence
This same trial also reported adherence in the treatment of PsA.41 Over 24 weeks, treatment adherence of between 80 percent and 100 percent was reported by 85 percent of leflunomide patients and 78 percent of placebo patients (P=NR). Additionally, one patient was withdrawn by the investigator from the placebo group because of poor adherence.
Biologic DMARDs
Overall Tolerability
Based on a Swedish prospective cohort study that included patients treated with adalimumab, etanercept, and infliximab, severe adverse events occurred in 5 to 6 percent of patients per year.43 Two anaphylactic infusion reactions occurred, both with infliximab. Other adverse event rates were similar. Concomitant MTX was associated with significantly fewer withdrawals due to adverse events (HR, 0.25; 95% CI, 0.11 to 0.52; P<0.01). Compared with infliximab, etanercept had a lower risk of withdrawal because of adverse events (HR, 0.30; 95% CI, 0.11 to 0.80; P=0.02).43 Based on 3 years of data from another observational study of patients from the British Society for Rheumatology Biologics Register (BSRBR), withdrawals due to adverse events were 14.8% for ADA, 12.3% for etanercept, and 23.5% for infliximab. Differences were statistically significant for infliximab compared with etanercept (HR, 3.1; 95% CI, 1.4 to 6.2). The most common reason for discontinuation with infliximab was infusion reactions (n=12; 7.4%).63 As a class for TNF inhibitors (including adalimumab, etanercept, and infliximab), withdrawals due to adverse events were not statistically significantly more common than with placebo (RR, 2.20; 95% CI, 0.82 to 5.91, P=0.12) in a meta-analysis of five studies.45 In efficacy trials for patients with PsA, overall tolerability profiles appeared to be similar for biologic DMARDs (adalimumab, etanercept, and infliximab) and placebo.41, 46, 47, 49, 50, 52, 54, 56 Injection-site reactions, dizziness, headaches, and upper respiratory tract infections were the most commonly reported individual adverse events. Of these, injection-site reactions appeared to occur more often in the active group than in the control group.
Specific Adverse Events
Adalimumab and etanercept used to treat PsA showed some differences in injection-site reactions. In a 24-week RCT examining adalimumab versus placebo, the adalimumab group experienced more injection-site reactions (6.6 percent) than the placebo group (3.1%; P=NR).46 Two other studies comparing etanercept to placebo also showed higher rates of injection-site reactions in the active arms.47, 49 A 12-week RCT reported injection-site reaction rates of 20 percent in the etanercept group and 3 percent in the placebo group; these results were not significant, probably owing to the small sample size (N=60).47 In an RCT with 205 patients, however, the difference between these two groups was statistically different.49 In the 24-week blinded portion of this study, injection-site reactions occurred in 36 percent of the etanercept patients and 9 percent of the placebo patients (P<0.001). Infusion reactions with infliximab (n=12; 7.4%) were more common than injection-site reactions with adalimumab (n=1; 1.1%) or etanercept (n=2; 0.6%) in a 3-year observational study.63
Most studies reported no statistically significant differences in adverse events between active treatment and placebo. In the only RCT of golimumab, more infections and malignancies were reported in golimumab-treated patients than placebo-treated patients (P=NR).54
Adherence
No study specifically addressed adherence with biologic DMARDs in the treatment of PsA.
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