This study aims to estimate the effect of synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) on radiographic progression and quality of life in adult patients with psoriatic arthritis. A comprehensive search was performed using MEDLINE, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials (CCRCT). Clinical trials comparing DMARDs with placebo for ≥ 12 weeks were included. The meta-analysis was conducted with a random-effects model using mean differences (MD). A total of 16 trials with overall moderate quality of evidence were included. Exposure to a biologic agent reduced radiographic progression at 24 weeks of treatment (MD: - 0.66; [95% CI - 0.97 to - 0.34]; P < .00001; I2 = 100%). The reduction of the baseline score was more than two times higher for TNF blockers compared with IL-17 and IL-12/IL-23 inhibitors (MD: - 0.94 vs - 0.41). Improvement in health-related quality of life scores was observed in biologic-treated populations (MD: - 0.21; [95% CI - 0.25 to - 0.18]; P < .00001; I2 = 97%). No sufficient data were available regarding conventional synthetic agents. Our data analyses suggest a better control of radiological damage with bDMARDs, as compared to placebo, after 24 weeks of treatment. However, the accuracy of these results in real life are jeopardized by the exceedingly high level of heterogeneity exhibited within and across included studies, and the true intervention effect cannot be determined with confidence. Further research is required to assess long-term outcomes and to control heterogeneity in the evaluation of treatments for psoriatic arthritis. PROSPERO registration number: CRD42019122223. Key Points • Radiographic progression is not the primary outcome for most efficacy studies in psoriatic arthritis; hence, baseline data are substantially diverse in major clinical trials. • The best available evidence on this particular outcome is currently at a moderate risk of bias. • Existing reports of the effect of DMARDs on structural damage must be taken with caution. • Further research is required to assess long-term outcomes and to control heterogeneity between studies.
OBJECTIVE: Biologic agents with different mechanisms of actions (inhibitors of TNF-α, interleukin-12/23 and interleukin-17) showed efficacy in randomized controlled trials in the treatment of psoriatic arthritis. We aimed to conduct a pooled meta-analysis of those agents for dactylitis and enthesitis and compare those with the American College of Rheumatology 20 (ACR20) response, and Health Assessment Questionnaire Disability Index (HAQ-DI) scores.
METHODS: A systematic literature search was performed and a pooled meta-analysis of randomized controlled trials with anti-TNF-α (infliximab, golimumab, adalimumab), antiinterleukin- 12/23 (ustekinumab) and anti-interleukin-17 (secukinumab, ixekizumab) was conducted using the random-effects model. Bias was assessed using the Cochrane Risk Of Bias tool.
RESULTS: Eighteen randomized controlled trials were included in the pooled analysis (n=6981). Both TNF-α inhibitors and novel biologics (ustekinumab, secukinumab, ixekizumab) demonstrated significant resolution of dactylitis at week 24 with pooled risk ratios (RRs) versus placebo of 2.57 (95% CI: 1.36-4.84) and 1.88 (95% CI: 1.33-2.65), respectively. For the resolution of enthesitis at week 24, RR for TNF-α inhibitors was 1.93 (95% CI: 1.33-2.79) vs 1.95 (95% CI: 1.60-2.38) for novel biologics. Both biologic categories showed overlapping ranges of ACR20 responses (TNF-α inhibitors: RR=2.23, 95% CI: 1.60-3.11, pooled interleukin-12/23 and -17: RR=2.30, 95% CI 1.94-2.72) and similar quality of life improvement scores with mean HAQ-DI score changes of -0.29 (95% CI: -0.39, -0.19) and -0.26 (95% CI: -0.31, -0.22), respectively.
CONCLUSION: The pooled analysis demonstrates that anti-TNF-α agents have the same efficacy as novel agents (ustekinumab, secukinumab, and ixekizumab) in dactylitis and enthesitis.
Background: Tofacitinib and other new treatments approved for use in psoriatic arthritis have only recently been included in psoriatic arthritis treatment guidelines, and studies evaluating the relative efficacy of available therapies are important to inform treatment decisions by healthcare professionals. Objective: To perform a network meta-analysis to evaluate the efficacy and safety profiles of tofacitinib, biologic disease-modifying antirheumatic drugs (bDMARDs), and apremilast in patients with psoriatic arthritis naïve to tumor necrosis factor inhibitor therapy (TNFi-naïve) or with an inadequate response (TNFi-IR). Methods: A systematic literature review used searches of MEDLINE, Embase, and The Cochrane Library on October 9, 2017. Randomized controlled trials including adult patients with psoriatic arthritis receiving treatment administered as monotherapy or with conventional synthetic DMARDs were selected. Efficacy outcomes included American College of Rheumatology 20 response, change from baseline in Health Assessment Questionnaire-Disability Index, ≥75% improvement in Psoriasis Area and Severity Index, and change from baseline in Dactylitis Severity Score and Leeds Enthesitis Index. Treatment effects were evaluated during placebo-controlled phases, using a binomial logit model for binary outcomes and a normal identify link model for other outcomes. Discontinuations due to adverse events and serious infection events were assessed as safety outcomes. Results: The network meta-analysis included 24 published randomized controlled trials, of which 13 enrolled TNFi-naïve patients only, 3 enrolled TNFi-IR patients only, and 8 enrolled both TNFi-naïve and TNFi-IR patients. Placebo-controlled treatment durations ranged from 12 to 24 weeks. Indirect comparisons showed tofacitinib 5 and 10 mg BID to have similar efficacy compared with most bDMARDs and apremilast in improving joint symptoms (based on American College of Rheumatology 20 response), and with some bDMARDs in improving skin symptoms (based on Psoriasis Area and Severity Index) (tofacitinib 10 mg BID only in TNFi-IR) in patients with psoriatic arthritis who were TNFi-naïve or TNFi-IR. Results also showed that, compared with placebo, the improvement in physical functioning (based on Health Assessment Questionnaire-Disability Index) with tofacitinib 5 and 10 mg BID was similar to that observed with most bDMARDs and apremilast in TNFi-naïve patients, and similar to that observed with all bDMARDs with available data in the TNFi-IR population. Improvements in Dactylitis Severity Score and Leeds Enthesitis Index scores were comparable between treatments. Tofacitinib 5 and 10 mg BID were median-ranked 8 and 15, respectively, for discontinuation due to any adverse events, and 5 and 16, respectively, for a serious infection event out of a total of 20 treatments in the network (lower numbers are more favorable). Conclusions: Tofacitinib provides an additional treatment option for patients with psoriatic arthritis, both in patients naïve to TNFi and in those with TNFi-IR. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)
BACKGROUND: The comparative efficacy and safety of small molecule and biological agents in the treatment of psoriatic arthritis (PsA) remain unknown.
OBJECTIVES: To compare the efficacy and safety of 14 small molecule and biological agents by network meta-analysis (NMA).
METHODS: Relevant randomized controlled trials involving biological treatments for PsA were identified by searching PubMed, Cochrane Library, EMBASE, Web of Science, and Clinicaltrials.gov and by manual retrieval, up to June 2018. NMA was conducted with Stata 14.0 based on the frequentist method. Effect measures were odds ratios (ORs) with 95% confidence intervals (CIs). Intervention efficacy and safety were ranked according to the surface under the cumulative ranking curve (SUCRA).
RESULTS: A total of 30 studies involving 10,191 adult subjects were included. According to NMA, ≥ 20% improvement in modifed American College of Rheumatology response criteria (ACR20) response, Psoriasis Area and Severity Index 75 (PASI75) response, and serious adverse events rate (SAEs) were observed. In direct comparisons, most of the biologics performed better than placebo in terms of ACR20 response rate and PASI75 response rate. Additionally, all medicines were comparable to placebo in terms of SAEs except secukinumab. In terms of mixed comparisons, with regard to the ACR20 response, etanercept (ETN) and infliximab (IFX) were more effective than golimumab (GOL), with ORs of 3.33 (95% CI: 1.17-9.48) and 1.24 (95% CI: 0.61-2.52), respectively. For PASI75 response, IFX was superior to certolizumab pegol (OR = 10.08, 95% CI: 1.54-75.48). In addition, these medicines were comparable to each other in terms of SAEs. ETN and IFX were shown to have the most favorable SUCRA for achieving improved ACR20 and PASI75 responses, respectively, while ABT-122 exhibited the best safety according to the SUCRA for SAEs. Considering both the efficacy (ACR20, PASI75) and safety (SAEs), GOL, ETN, and IFX are the top 3 treatments.
CONCLUSIONS AND IMPLICATIONS: Direct and indirect comparisons and integrated results suggested that the 3 anti- tumor necrosis factor -α biologics (GOL, ETN, and IFX) can be considered the best treatments for PsA after comprehensive consideration of efficacy and safety.
Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement. Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10–16 weeks). Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes. Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform.
OBJECTIVES: There is no hierarchy in the use of biotherapies (bDMARDs) in psoriatic arthritis (PsA) and no published head-to-head comparative studies. Our purpose is to evaluate the respective efficacy of TNF inhibitors, IL12/23 inhibitors (ustekinumab), IL17 inhibitors (secukinumab, ixekizumab) and CTLA4Ig (abatacept) on articular, enthesitis, dactylitis, skin and functional outcomes in PsA.
METHODS: Randomised controlled trials assessing bDMARDs in PsA were selected through the MedLine, Cochrane and Embase databases. ACR20/50/70 and PASI75/90 response rates, enthesitis and dactylitis reduction rates and HAQ-DI mean reductions were collected. Pooled meta-analyses were performed to assess relative risks (RR) with their 95% confidence interval (95%CI) for each class of bDMARDs in comparison with placebo.
RESULTS: 17 RCTs were analysed. Compared to placebo, all bDMARDs showed higher ACR20 response rates, with RRs ranging from 1.77 (1.31, 2.39) to 3.21 (2.52, 4.08), and a greater HAQ-DI mean reduction. TNF inhibitors, secukinumab and IL17 inhibitors showed higher ACR50/70 and PASI75/90 response rates. TNF inhibitors, secukinumab and IL17 inhibitors showed higher enthesitis resolution rates and only TNF inhibitors and IL17 inhibitors showed higher dactylitis resolution rates, with RRs ranging from 1.41 (1.02, 1.95) to 2.31 (1.60, 3.34) and from 2.07 (1.38, 3.12) to 2.65 (1.79, 3.94), respectively.
CONCLUSIONS: All bDMARDs showed higher ACR20 response rates and better HAQ-DI mean reduction compared to placebo. This meta-analysis highlights the variability of bDMARD efficacy on ACR50/70, PASI75/90 and enthesitis or dactylitis response rates. Head-to-head studies are needed to draw definitive conclusions on potential efficacy-related differences between bDMARDs in PsA.
BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs are used in patients with psoriatic arthritis (PsA), but few studies directly compare their clinical efficacy. In such situations, network meta-analysis (NMA) can inform evidence-based decision-making.
OBJECTIVE: To evaluate the comparative efficacy and safety of approved bDMARDs in patients with PsA.
METHODS: Bayesian NMA was conducted to compare the clinical efficacy of bDMARDs at weeks 12‒16 in bDMARD-naïve patients with PsA in terms of American College of Rheumatology (ACR) criteria, Psoriatic Arthritis Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI). Safety end points were evaluated in the overall mixed population of bDMARD-naive and bDMARD-experienced patients.
RESULTS: For ACR, all treatments except abatacept were statistically superior to placebo. Infliximab was most effective, followed by golimumab and etanercept, which were statistically superior to most other treatments. Ixekizumab 80 mg every 2 weeks (Q2W) was statistically superior to abatacept subcutaneous, apremilast and both regimens of ustekinumab; similar findings were observed for ixekizumab 80 mg Q4W. For PsARC response, ixekizumab did not significantly differ from other therapies, except for golimumab, infliximab and etanercept, which were superior to most other agents including ixekizumab. For PASI response, infliximab was numerically most effective, but was not statistically superior to ixekizumab, which was the next best performing agent. Analysis of safety end points identified few differences between treatments.
CONCLUSION: Our NMA confirms the efficacy and acceptable safety profile of bDMARDs in patients with active PsA. There were generally few statistically significant differences between most treatments.
Psoriatic arthritis (PsA) is associated with progressive joint destruction and reduced quality of life. The time until a drug treatment starts to show an effect (TOA) is important for preventing joint destruction. The objective was to assess the time until onset of action of drugs when treating PsA. A systematic review of PsA drug trials was performed. Outcomes were: time until 25% of patients (TOA) reached (1) ≥ 20%, (2) ≥ 50% improvement in modified American College of Rheumatology response criteria (ACR), (3) ≥ 75% reduction in Psoriasis Area and Severity Index (PASI75). 95% confidence intervals were calculated extracting data from graphs using a novel method. Meta-analysis was conducted. Two head-to-head trials show no difference between ixekizumab and adalimumab or adalimumab and tofacitinib for TOA-ACR outcomes. For PASI75, ixekizumab had a faster onset than adalimumab. Infliximab plus MTX was faster than MTX alone. Pooled results from 32 study arms for TOA-ACR20 (week [95% CI]) are: < 2 weeks: infliximab (1.18 [0.72-1.65]), ixekizumab (1.04 [0.80-1.28]), tofacitinib (10 mg 1.56 [1.14-1.98]); ≤ 4 weeks: adalimumab (1.95 [1.35-2.55]), secukinumab (75 mg 1.89 [0.16-3.62], 150 mg 2.13 [1.34-2.91], 300 mg 2.26 [1.75-2.76]), tofacitinib (5 mg 2.20 [1.41-2.99]); 4 + weeks: apremilast, ustekinumab. For TOA-ACR50, all pooled point estimates are > 4 weeks. For TOA-PASI75, the range is between 2.24 [1.65-2.84] for ixekizumab and 6.03 [3.76-8.29] for adalimumab. Indirect, mixed comparison suggest a faster onset of infliximab, ixekizumab and tofacitinib compared to apremilast, methotrexate and ustekinumab for ACR20, not ACR50. For PASI75, ixekizumab is faster than adalimumab.
OBJECTIVE: To summarize and investigate the comparative efficacy and safety of targeted disease-modifying antirheumatic drugs (DMARDs) for active psoriatic arthritis (PsA).
METHODS: Randomized clinical trials (RCTs) evaluating efficacy and safety of targeted synthetic DMARDs (tofacitinib, apremilast) as well as biological DMARDs (guselkumab, ustekinumab, secukinumab, ixekizumab, brodalumab, clazakizumab, abatacept, adalimumab, etanercept, infliximab, certolizumab, and golimumab) were identified by systemic literature review. Traditional meta-analysis and network meta-analysis using a random effects model were performed to estimate pooled odds ratios (OR) and 95% CI to compare and rank these treatments according to ACR20 response, 75% improvement in psoriasis area and severity index (PASI75), numbers of adverse events (AE) and serious adverse events (SAE). Similar analyses were conducted among biologic-naïve population and biologic-experienced/failed population.
RESULTS: We deemed 29 RCTs eligible, including 10,204 participants and 17 treatments. During induction therapy (first 12-16 weeks), all treatments except clazakizumab were more efficacious than placebo in achieving ACR20 and PASI75. Although tofacitinib, apremilast, and ixekinumab 80 mg every 2 weeks had a higher rate of AE, no significant difference was revealed for SAE among all treatments. Network meta-analysis demonstrated that infliximab, golimumab, etanercept, adalimumab, guselkumab, and secukinumab 300 mg outperformed other drugs in achieving both ACR20 and PASI75. Infliximab, guselkumab, adalimumab, golimumab, secukinumab (300 mg and 150 mg), and ustekinumab (45 mg and 90 mg) are characterized by both high efficacy and safety. Similar rankings were observed in the analysis among biologic-naïve patients. Moreover, ustekinumab, secukinumab (300 mg and 150 mg), ixekizumab, abatacept, certolizumab pegol, tofacitinib, and apremilast were still associated with higher ACR20 compared to placebo while ustekinumab, secukinumab (300 mg), ixekizumab and tofacitinib with higher PASI75 among biologic-experienced/failed patients.
CONCLUSION: Regarding the overall risk-benefit profile, infliximab, guselkumab, adalimumab, golimumab, secukinumab, and ustekinumab may be safer and more efficacious treatments than the other targeted DMARDs for active PsA during induction therapy.
This study aims to estimate the effect of synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) on radiographic progression and quality of life in adult patients with psoriatic arthritis. A comprehensive search was performed using MEDLINE, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials (CCRCT). Clinical trials comparing DMARDs with placebo for ≥ 12 weeks were included. The meta-analysis was conducted with a random-effects model using mean differences (MD). A total of 16 trials with overall moderate quality of evidence were included. Exposure to a biologic agent reduced radiographic progression at 24 weeks of treatment (MD: - 0.66; [95% CI - 0.97 to - 0.34]; P < .00001; I2 = 100%). The reduction of the baseline score was more than two times higher for TNF blockers compared with IL-17 and IL-12/IL-23 inhibitors (MD: - 0.94 vs - 0.41). Improvement in health-related quality of life scores was observed in biologic-treated populations (MD: - 0.21; [95% CI - 0.25 to - 0.18]; P < .00001; I2 = 97%). No sufficient data were available regarding conventional synthetic agents. Our data analyses suggest a better control of radiological damage with bDMARDs, as compared to placebo, after 24 weeks of treatment. However, the accuracy of these results in real life are jeopardized by the exceedingly high level of heterogeneity exhibited within and across included studies, and the true intervention effect cannot be determined with confidence. Further research is required to assess long-term outcomes and to control heterogeneity in the evaluation of treatments for psoriatic arthritis. PROSPERO registration number: CRD42019122223. Key Points • Radiographic progression is not the primary outcome for most efficacy studies in psoriatic arthritis; hence, baseline data are substantially diverse in major clinical trials. • The best available evidence on this particular outcome is currently at a moderate risk of bias. • Existing reports of the effect of DMARDs on structural damage must be taken with caution. • Further research is required to assess long-term outcomes and to control heterogeneity between studies.
