Efficacy of several biological therapies for treating moderate to severe psoriasis: A network meta‑analysis
- Authors:
- Published online on: October 15, 2018 https://doi.org/10.3892/etm.2018.6859
- Pages: 5085-5095
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Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Psoriasis is a common immune-mediated skin disease. The prevalence of psoriasis in adults ranges between 0.91 and 8.5% worldwide and the incidence of psoriasis is higher in adults than in children (1). Psoriasis is characterized by symptoms of plaque, pustular and other skin lesions. Chronic plaque psoriasis accounts for 90% of all psoriasis cases (2,3).
A number of biological therapies are used to treat moderate to severe psoriasis, including etanercept, briakinumab, ustekinumab, adalimumab and infliximab (4–8). Etanercept, adalimumab and infliximab are monoclonal antibodies against tumor necrosis factor (TNF), which function by neutralizing the biological activity of TNF for treating the TNF-mediated inflammation (5,9). By contrast, ustekinumab and briakinumab are human monoclonal antibodies against interleukin (IL)-12/23p40 (8). These biological therapies are used to treat psoriasis and improved clinical outcomes have been observed. However, the efficacy of these therapies has been not systematically reviewed.
In the present study, a network meta-analysis was performed to review and compare the efficacy of these aforementioned biological therapies of psoriasis. The Psoriasis Area and Severity Index (PASI) response (10) was used as an indicator for assessing the effect of treatment on the severity of psoriasis. PASI 50, PASI 75 and PASI 90 responses for the therapies were systematically assessed. The pooled results provide further information on selecting the most suitable treatments for moderate to severe psoriasis.
Materials and methods
Data sources
The PubMed (www.ncbi.nlm.nih.gov/pubmed) and Embase (www.elsevier.com/solutions/embase-biomedical-research) databases were systematically searched in order to select relevant studies up to February 2015. The search terms included the following: Psoriasis, methotrexate (MTX), cyclosporin A (CSA), ustekinumab, etanercept, infliximab, briakinumab and adalimumab.
Inclusion and exclusion criteria
Studies with the following characteristics were included in the current meta-analysis: i) Randomized controlled trials (RCTs) reporting the treatment of moderate to severe psoriasis with the aforementioned drugs. Moderate to severe psoriasis is defined as body surface area >10 or psoriasis area and severity index >10 and dermatology life quality index >10 (11); ii) studies including the adults as participants; and iii) studies reporting the PASI response rate (50, 75 and 90%). Any reviews, case reports and letters were excluded from the meta-analysis. Any studies investigating patients with mild psoriasis and those written in a language other than English were also excluded.
Data extraction and quality assessment
Two reviewers independently extracted the following data: The name of the first author, publication year, sample size, intervention, demographic characteristics of the included patients and PASI response rate. The controversies were discussed with a third reviewer to reach consensus. The methodological quality of the included studies was evaluated by the Cochrane Collaboration Risk of Bias Tool (12).
Statistical analysis
All analyses were performed using the ADDIS software version 1.16.5 (Drug Information and Monitoring Systems, Groningen, The Netherlands). Odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled. The network analysis performed was based on the Bayesian framework. Data were evaluated by Markov chain Monte Carlo methods and all analyses were performed using the random effects model. The consistency of the RCTs was assessed by Node-splitting analysis, and the consistency model was used if P>0.05. Otherwise, the inconsistency model was used to pool the odd ratios (13).
Results
Study selection
As presented in Fig. 1, a total of 897 studies were identified from PubMed and 917 studies from Embase by the initial search. Subsequent to excluding any duplicates, 1,113 studies remained. A total of 831 irrelevant studies were excluded by reviewing the titles and abstracts. In addition, 249 studies that did not meet the inclusion criteria were excluded. Finally, 33 RCTs were included in the present study (4–9,14–40).
Characteristics of the included studies
As presented in Table I, the demographic characteristics, including age, sex and weight of the patients in the included studies were similar. Included RCTs were published between 1994 and 2015. The mean duration of psoriasis of the included patients ranged between 11.1 and 21.5 years. Quality assessment demonstrated that the quality of the included RCTs was relatively high. With respect to random sequence generation (selection bias), a number of studies were assessed as having an unclear risk of bias. With regards to blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias) and incomplete outcome data (attrition bias), a small proportion of studies were assessed as having high risk of bias (Fig. 2) and were excluded from the current study. However, the studies by Laburte et al (25) and Cassano et al (15) were not excluded as they met with the inclusion criteria despite having quite a poor rating.
Network meta-analysis
Based on the results of node-splitting analysis (Table II), the effect sizes were pooled using an inconsistency model. Regarding the PASI 75 response rate, infliximab (5 mg) was the most effective option for the treatment of moderate to severe psoriasis (Table III and Fig. 3). The pooled results of the PASI 50 response rate demonstrated that infliximab (5 mg) and ustekinumab (90 mg) may be superior to other drugs for treating moderate to severe psoriasis (Table IV). In addition, regarding the PASI 90 response rate, treatment with infliximab (5 mg), ustekinumab (90 mg) and briakinumab (weeks 0 and 4, 200 mg; week 8, 100 mg) indicated improved results compared with other agents (Table V). Finally, the drugs can be ranked in the following order according to their efficacy, defined as their PASI 90 response rate: Briakinumab > ustekinumab (90 mg) > infliximab (5 mg)> ustekinumab (45 mg) > adalimumab > infliximab (3 mg)> etanercept (50 mg BIW) > CSA (5 mg) > etanercept (25 mg BIW) > MTX > etanercept (25 mg QW) > placebo (Table VI). The odds ratio value of infliximab (5 mg) compared with the other drugs was >1, therefore, infliximab (5 mg) was regarded as the best treatment agent, although it ranked as third in terms of efficacy.
 | Table V.Network meta-analysis of PASI 90 response rate between different drugs used to treat psoriasis. |
Discussion
In the present study, a network meta-analysis was performed to systematically review and compare the efficacy of seven drugs used at different doses for treating moderate to severe psoriasis. Based on the results of the network analysis, infliximab (5 mg) may be an appropriate option to treat moderate to severe psoriasis.
Psoriasis has been reported to be associated with a high concentration of TNF-α (41) and infliximab treatment can neutralize the biological activity of TNF-α (42). However, the role of the TNF-α in the pathogenesis of psoriasis remains unclear. Previous studies have reported that TNF-α may serve an important role in the upstream of the inflammatory responses of psoriasis (43,44). An in vitro study determined that infliximab was able to inhibit the activation of skin-homing T cells and impair the antigen-presenting capacity of immature dendritic cells in psoriasis patients (43). However, another TNF-α inhibitor, etanercept, has been found to be effective in the treatment of psoriasis by reducing the Th17 cell products, as well as the production of IL-17, IL-22, IL-23 and inducible NO synthase from dendritic cells (44). Thus, it has been suggested that the infliximab may serve a different role with other treatments on moderate to severe psoriasis.
Although the present meta-analysis indicated that infliximab treatment had a high PASI score, a higher percentage of adverse events were observed in infliximab-treated patients compared with those in the placebo group (18), indicating that infliximab treatment induces adverse effects. In addition, infliximab treatment increases the incidence of infusion reactions (45). However, these outcomes were not considered to be important due to the small sample size of each study or the fact that the data were unavailable. Thus, the therapeutic effect of the infliximab should be systematically assessed in further studies. Besides, the dosage and treatment duration of infliximab should be optimized according to the disease severity of psoriasis.
In the present study, briakinumab and ustekinumab (90 mg) treatments were superior to other treatments for PASI 90 response. Thus, anti-IL-12/23 monoclonal antibodies appear to be more appropriate compared with anti-TNF-α treatment for treating moderate to severe psoriasis. However, briakinumab and ustekinumab showed no significantly improved therapeutic effect in PASI 75 and PASI 50 responses when compared with the anti-TNF-α treatments. In addition, the long-term safety profile, including severe infections and cardiac disorders, should be evaluated in further studies with large sample sizes and strict study design.
To the best of our knowledge, the present study is the first network meta-analysis for evaluating the efficacy of various treatments for moderate to severe psoriasis. The current results may provide information for clinician and patients on the selection of the suitable treatment for moderate to severe psoriasis. However, there were also several limitations in the present meta-analysis. Firstly, due to unavailable data in certain included studies, confounding variables could not be adjusted and subgroup analysis was not performed to reduce the effect of the confounding variables. Secondly, due to unknown bias, the network analyses of PASI 75 and PASI 50 responses were performed using an inconsistency model. Finally, the results of the network meta-analysis should be pooled only by a random effects model. Thus, the pooled results may be conservative and certain borderline significant effects may have been ignored (46).
In conclusion, the present meta-analysis results suggested that infliximab (5 mg) may be a superior option compared with other drugs for treating moderate to severe psoriasis due to the relatively high PASI scores of patients. However, despite the high PASI 90 responses, the efficacy of ustekinumab (90 mg) and briakinumab were also high and therefore should be investigated in further studies.
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