Indirect comparisons of the efficacy of biological agents in patients with psoriatic arthritis with an inadequate response to traditional disease-modifying anti-rheumatic drugs or to non-steroidal anti-inflammatory drugs: A meta-analysis

https://doi.org/10.1016/j.semarthrit.2015.09.004Get rights and content

Abstract

Background

While the efficacy of biologic agents for the treatment of psoriatic arthritis (PsA) has been well demonstrated in randomized controlled trials (RCTs), the data on their relative efficacy is limited. This meta-analysis is aimed at assessing the comparative efficacy of these agents in patients who had persistently active disease despite traditional non-steroidal anti-inflammatory drugs (NSAIDs)/disease-modifying anti-rheumatic drugs (DMARDs), or who could not tolerate NSAIDs/DMARDs.

Methods

RCTs examining the efficacy of biologic agents in patients with PsA who experienced inadequate response or intolerance of traditional DMARDs or NSAIDs were identified. If more than one RCT were available for a given biologic agent, the pooled risk ratio (RR) and 95% confidence interval (CI) of attaining a 20% improvement according to American College of Rheumatology criteria (ACR20) response across trials were calculated. The pooled risk ratios for each biologic agent were then compared using the indirect comparison technique.

Results

A total of 12 RCTs were identified and included in the data analyses. We found that patients who received older TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab) had a statistically significantly higher chance of achieving ACR20 response compared with apremilast, ustekinumab, and certolizumab. The likelihood of achieving ACR20 response among secukinumab users (at the dose of 150 mg and 300 mg weekly) was also higher compared with apremilast, ustekinumab, and certolizumab, though the relative risk did not always reach statistical significance.

Conclusions

Our study demonstrates that patients with PsA who experience inadequate response or intolerance of traditional DMARDs or NSAIDs have a higher probability of achieving the ACR20 response with older TNF inhibitors and secukinumab.

Introduction

Psoriatic arthritis (PsA) is a chronic seronegative inflammatory arthritis characterized by not only the presence of peripheral arthritis, but also enthesitis, dactylitis, and spondylitis [1], [2]. It is present in up to 30% of patients with psoriasis with an estimated prevalence of 0.3%–1.0% in general population [3], [4]. PsA is associated with increased morbidity and mortality, resulting in a reduced quality of life and productivity [5], [6], [7].

Non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs), particularly methotrexate, are the conventional first-line treatments for PsA although this therapeutic strategy has largely been derived from clinical experience with rheumatoid arthritis with only limited number of randomized controlled trials (RCTs) [8], [9]. The clinical response to this therapy is often unsatisfactory. In fact, a recent meta-analysis of therapies of PsA has demonstrated that the efficacy of NSAIDs, methotrexate, sulfasalazine, and leflunomide were minimal [10], leaving an unmet therapeutic need.

Over the past 2 decades, with a better understanding of the immunopathogenesis of PsA and the development of biotechnology, novel therapeutic options have been introduced. Tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, adalimumab, golimumab and more recently, certolizumab) were the first group of biologic agents approved for PsA, followed by an interleukin (IL)-12 and IL-23 inhibitor (ustekinumab), and a phosphodiesterase-4 inhibitor (apremilast). The efficacy of all of these biologic agents in patients who had persistently active disease despite traditional DMARDs/NSAIDs or who could not tolerate DMARDs/NSAIDs has been well demonstrated in RCTs [11].

The increasing availability of these biologic DMARDs suggests the need to establish the comparative efficacy of these agents. However, to date, there is only one RCT that directly compared between the three older TNF inhibitors (etanercept, infliximab, and adalimumab) [12].

Indirect comparison meta-analysis is a statistical technique used to estimate the relative effect of two interventions by comparing to a common comparator (placebo group) when a direct comparison is not available. In fact, two recent meta-analyses have utilized this technique and did not find any statistically significant difference between the response rates for the four older TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab) [13], [14]. However, the data on the relative efficacy of the more novel agents (certolizumab, ustekinumab, apremilast, and secukinumab) are not available. Therefore, we conducted this systematic review and meta-analysis to compare the relative efficacy of all available biologic agents in patients with PsA who experienced inadequate response or intolerance of traditional DMARDs or NSAIDs.

Section snippets

Search strategy

Two investigators (P.U. and C.T.) independently searched published studies indexed in Medline, Cochrane Central, and EMBASE database from inception to November, 2014 using the combination of search terms described in Supplementary data 1 without any language restrictions. References of selected articles were also manually searched.

Inclusion criteria

The inclusion criteria that were established a priori were as follows: (1) RCTs published as original studies comparing the efficacy of biologic agents to placebo in

Systematic review of the literature

Our search strategy yielded 270 potentially relevant articles. After exclusion of 77 duplicate articles, 193 articles underwent title and abstract review. A total of 144 articles were excluded based on this abstract review as they were clearly not relevant to our research question, leaving 49 articles for full-length article review. Of them, 24 articles were excluded because of duplication between databases. Nine studies were excluded because they did not report our outcome of interest, while

Discussion

PsA was once considered as a milder form of systemic arthritis. However, recent data have demonstrated that the disease is more aggressive than previously thought. In a cohort study, up to 50% of patients with early disease had radiographic erosive changes in the first 2 years [35]. This data prompts physicians to treat PsA more aggressively.

DMARDs, particularly methotrexate, and NSAIDs are generally used as the first-line therapy for PsA as reflected in the Group for Research and Assessment of

Conclusion

Our study demonstrated that patients with PsA who did not have an adequate response from or could not tolerate DMARDs/NSAIDs had a higher probability of achieving the ACR20 response with older TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab) and secukinumab at the dose of 150 mg and 300 mg weekly, compared with apremilast, certolizumab, and ustekinumab. However, this analysis has some limitations. Therefore, head-to-head comparisons are required to confirm these findings.

Acknowledgment

Patompong Ungprasert: Study design, literature search, statistical analysis, and writing article.

Charat Thongprayoon: Literature search and revising article.

John Davis: Study design and revising article.

References (44)

  • J.A. Walsh et al.

    Work productivity loss and fatigue in psoriatic arthritis

    J Rheumatol

    (2014)
  • P. Ungprasert et al.

    Psoriasis and risk of venous thromboembolism: a systematic review and meta-analysis

    QJM

    (2014)
  • A. Jamnitski et al.

    Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review

    Ann Rheum Dis

    (2013)
  • G.H. Kingsley et al.

    A randomized placebo-controlled trial of methotrexate in psoriatic arthritis

    Rheumatology (Oxford)

    (2012)
  • R.F. Willkens et al.

    Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis

    Arthritis Rheum

    (1984)
  • E.R. Soriano et al.

    Therapies for peripheral joint disease in psoriatic arthritis. A systematic review

    J Rheumatol

    (2006)
  • I. Olivieri et al.

    Advances in the management of psoriatic arthritis

    Nat Rev Rheumatol

    (2014)
  • M. Atteno et al.

    Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drugs

    Clin Rheumatol

    (2010)
  • S. Fénix-Caballero et al.

    Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis

    J Clin Pharm Ther

    (2013)
  • L.L. Lemos et al.

    Treatment of psoriatic arthritis with anti-TNF agents: a systematic review and meta-analysis of efficacy, effectiveness and safety

    Rheumatol Int

    (2014)
  • D.T. Felson et al.

    The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials

    Arthritis Rheum

    (1993)
  • L.V. Hedges et al.

    Fixed- and random-effects models in meta-analysis

    Psychol Methods

    (1998)
  • Cited by (34)

    • Psoriatic arthritis and psoriasis in the era of COVID-19

      2022, Autoimmunity, COVID-19, Post-COVID19 Syndrome and COVID-19 Vaccination
    • Recommendations for psoriatic arthritis management: A joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology

      2021, Journal of the Formosan Medical Association
      Citation Excerpt :

      In case of contraindication, intolerance, or inadequate response to TNFi or IL-17i, IL-12/23 inhibitors (IL-12/23i) may be considered.76 Although there is insufficient evidence to recommend the use of any single biologic over another biologic, a recent systematic review and network meta-analysis of 29 randomized controlled trials (RCTs) comprising 10,204 participants and 17 treatments found that infliximab, adalimumab, golimumab, secukinumab, and ustekinumab were relatively safer and more efficacious in the treatment of active PsA, as compared to other biologics or tsDMARDs,77 and earlier meta-analyses also provide support for these results.78,79 For enthesitis and dactylitis, a recent systematic review and meta-analysis of 18 RCTs involving 6981 patients found that newer agents such as ixekizumab, secukinumab, and ustekinumab had the same efficacy as TNFi (infliximab, golimumab, and adalimumab), and there was no evidence to recommend any biologic over another as initiation therapy.80

    • Network Meta-Analysis of Tofacitinib, Biologic Disease-Modifying Antirheumatic Drugs, and Apremilast for the Treatment of Psoriatic Arthritis

      2020, Current Therapeutic Research - Clinical and Experimental
      Citation Excerpt :

      Although these results support our findings for ACR20, a strength of the current NMA is that it assessed the relative efficacy of multiple active treatments across several end points. Additionally, a published meta-analysis has shown that indirect comparisons of the TNFi agents etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol with apremilast, ustekinumab, and secukinumab demonstrated that patients with PsA have a higher probability of achieving ACR20 with etanercept, infliximab, adalimumab, golimumab, and secukinumab than other agents.44 Another meta-analysis conducted indirect comparisons of 4 non-TNFi bDMARDs (ie, abatacept, apremilast, secukinumab, and ustekinumab) and reported that the likelihood of achieving ACR20 in the TNFi-IR population with PsA did not differ significantly between these agents.45

    View all citing articles on Scopus

    Conflict of interest statement: John M. Davis is a site investigator for trials sponsored by Pfizer and Roche/Genentech. Division of Rheumatology, Mayo clinic receives research funding from Pfizer for John M. Davis׳s role on a grant.

    View full text