Safety and Efficacy of Risankizumab and Infliximab in the Treatment of Plaque Psoriasis: Results From a Direct and Indirect Meta-Analysis

The objective of our study was to compare a potent drug of the anti-TNF class family, infliximab, with a potent drug of the IL-inhibitors family, risankizumab, in terms of efficacy and safety endpoints. Online databases were searched for relevant placebo-controlled, randomized trials. The following efficacy outcomes were included: PASI-75, PASI-90, and sPGA, as well as the incidence of any adverse events and serious adverse events. The risk ratios (RR) with the respective 95% confidence intervals (CIs) of different psoriasis scores were pooled in a meta-analysis model, using the Mantel-Haenszel method. The combined risk ratios (RR) showed that infliximab and risankizumab are effective in increasing the number of patients with more than 75% improvement in the PASI (RR= 26.68, 95% CI [14.98, 47.51] p<0.001) and (RR= 10.17, 95% CI [7.24, 14.30] p<0.001), respectively. Test for subgroup differences showed that risankizumab is more effective. Regarding PASI-90 outcome, risankizumab and infliximab are more effective than placebo (RR= 26.22, 95% CI [14.20, 48.41], p<0.001), and (RR= 15.18, 95% CI [8.72, 26.45], p<0.001) respectively. The results showed that risankizumab does not cause significant serious adverse events (RR = 0.59, 95% CI [0.31, 1.13], p=0.12) while, on the other hand, infliximab causes significant serious adverse events (RR = 2.30, 95% CI [1.08, 4.88], p=0.03). The test of subgroup difference showed that risankizumab is safer (p<0.001). Analysis of the incidence of any adverse events showed that risankizumab is safer as well (p=0.007). Infection rates were similar among both drugs (p=0.05). In conclusion, risankizumab is preferred for the treatment of psoriasis than infliximab, and is significantly more effective and safe.

efalizumab, and alefacept [12]. The drug has shown great success in improving DLQI scores, and the improvement is increased by increasing the dose [13].
Many studies have compared different drugs of both families in the treatment of psoriasis. However, there is no evidence of a comparison between risankizumab and infliximab. This systematic review and metaanalysis aims to perform an indirect comparison on a statistical basis between the most effective drug of the anti-TNF family, infliximab, and the family of IL-inhibitors, risankizumab.

Materials and Methods
This systematic review and meta-analysis complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. All steps were performed in accordance with the Cochrane's handbook of systematic reviews for interventions [15].

Literature Search
PubMed, Scopus, Web of Science, Virtual Health Library (VHL), Google Scholar, and Cochrane databases were searched using the following strategy "("Psoriasis" OR "psoriatic") AND [("Risankizumab " OR "BI 655066") OR ("Infliximab")]". An online search was performed on clinicaltrials.gov to ensure adequate inclusion of all studies.

Studies Selection
Two independent reviewers performed title and abstract screening for matching studies. Then, full-text papers of included titles and abstracts were retrieved and screened independently. Disagreements were settled through discussion with a third reviewer.

Data Extraction
After obtaining full-text papers, two reviewers independently performed data extraction. Baseline data including sample size, drug administered, baseline psoriasis scores, body surface area involved, body mass index, white race, and previous treatment was extracted. A third reviewer resolved any disagreement between the two reviewers.

Data Synthesis and Analysis
Review Manager Software, Version 5.3 was utilized to perform data analysis. The risk ratios (RR) with the respective 95% confidence intervals (CIs) of different psoriasis scores were pooled in a meta-analysis model, using the Mantel-Haenszel method. Homogeneous data was analyzed under the fixed-effects model and used the random-effects model for heterogeneous data. Heterogeneity was resolved using Cochrane's leaveone-out method [15].
This meta-analysis conducted a subgroup analysis according to the drug administered (risankizumab or infliximab) against placebo and tested for subgroup differences using chi-square test with its P-value. Heterogeneity among studies was assessed using I2 test and P-value from the chi-squared test of heterogeneity. Values of I2 >50 and P<0.1 are significant markers of heterogeneity among studies according to Cochrane's handbook.

Risk of Bias Assessment
Risk of bias assessment was performed using Cochrane's risk of bias tool [16]. It includes the following domains: sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other potential sources of bias. The reviewers' judgment is categorized as 'Low risk', 'High risk' or 'Unclear risk' of bias according to each domain. To assess the risk of bias within the included studies, two independent reviewers used the risk of bias assessment tool using Cochrane risk of bias tool [16]. The reviewers' judgment is categorized as 'Low risk', 'High risk' or 'Unclear risk' of bias according to each domain.

Publication Bias
For the assessment of publication bias, the pooled effect estimate was plotted against its standered error (SE) in a funnel plot generated by RevMan software. Due to the small number of included studies (less than 10), funnel-plot-based methods could not be utilized.

Results of Literature Search
Searching databases yielded a total of 709 studies. After removing duplicates, 542 studies remained for the title and abstract screening. Excluded studies compromised of 510 studies as they did not meet the inclusion criteria. Nine studies were finally included after the full-text screening. The reviewers excluded 30 full-text papers, 17 of which were animal trials, eight reviews, and six trials compared risankizumab or Infliximab with other drugs (no placebo group). Figure 1 shows a PRISMA diagram for this study.

Results of Risk of Bias Assessment
This meta-analysis found an overall low risk of bias among the included studies. All studies adequately reported randomization, allocation concealment; they were all double-blinded, with no missing data or attrition bias. Figure 2 shows a summary and graph for the risk of bias of included studies. All studies were with low risk of bias.

FIGURE 6: Forest plot of analysis of serious adverse events outcome
Source: [17][18][19][20][21][22][24][25] Incidence of any adverse event (AE): The incidence of any adverse event was reported by all studies. This meta-analysis found that infliximab and risankizumab are highly associated with an increased incidence of adverse events compared to placebo (RR=  (Figure 7). Test for subgroup differences regarding the incidence of any adverse events highly favored risankizumab (p=0.007). Pooled analysis was heterogeneous (I2 = 62%, P=0.01). Heterogeneity was best resolved by excluding Gottlieb et al. [18] Homogeneous results showed that risankizumab is still significantly safer than infliximab (p=0.03).

Discussion
The results of this meta-analysis provide a class one evidence that risankizumab is significantly superior to infliximab for the treatment of plaque psoriasis in both efficacy and safety. This meta-analysis found that, when indirectly comparing both drugs, risankizumab leads to more improved patients > 75% on the PASI score. Regarding PASI-90 and sPGA outcomes, both drugs exerted the same efficacy. As for safety endpoints, subgroup difference tests show that infliximab is significantly associated with more incidence of any adverse events and serious adverse events. Test for subgroup differences showed no significant difference between both drugs in terms of infection.
Although four of included studies used risankizumab compared to six studies used infliximab, the risankizumab trials included a larger sample size than infliximab group. The literature is full of secondary works that compare risankizumab with other drugs. A recent network meta-analysis [8] compared risankizumab with brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, and tildrakizumab. The results showed that risankizumab has the highest efficacy and lowest risks. Risankizumab 150mg has shown to improve PASI 100 scores in Japanese patients [26]. Regarding the safety profile, the drug has shown to be safe and not associated with significant side effects [27].
Another meta-analysis including 13 studies of IL-inhibitors trials found that risankizumab was better tolerated than other drugs [28]. Another recent systematic review and network meta-analysis performed including trials using IL-inhibitors found the same results [29]. A systematic review conducted last year found similar results as well .
A systematic review found that infliximab is significantly associated with relief of psoriatic symptoms and skin improvements. The study also found that infliximab causes significant pain and infusion reactions [30]. Moreover, another study found that in patients with inflammatory bowel disease, infliximab led to relief of psoriatic symptoms in 87% of participants, and that resolution occurred in 48% of cases as a result of resolution of the drug [30]. A recent network meta-analysis found that infliximab has the highest efficacy compared with other anti-TNF drugs [12]. The results from previous network meta-analysis suggests that infliximab is associated with significant side effects.
In this meta-analysis, an indirect comparison of risankizumab and infliximab provided a preliminary solution to the debate about which class is better; anti-TNFs or IL-23 inhibitors. This gives this study a point of strength. This meta-analysis included only randomized, placebo-controlled, clinical trials to provide strong evidence. All the studies were recent studies, published after the year 2000. This is evidenced by the fact that the methodology of all included trials was adequately performed, and that all studies were at low risk of bias in all domains. A total of 2673 patients were enrolled; this large sample size is also a point of strength to the evidence this paper provides.
However, the absence of clinical trials that directly compare risankizumab and infliximab is the main limitation. This study's findings are based on tests of subgroup differences. Although this meta-analysis is supported by all previous meta-analyses, a direct comparison is necessary to show the "true" findings of both drugs in terms of efficacy and safety. Another limitation is that this meta-analysis could not enter some outcomes into analysis such as dermatology life and quality index, due to the dichotomization of the outcome in some studies. Future head to head clinical trials to compare both drugs in terms of efficacy and safety outcomes is recommended.

Conclusions
Risankizumab is safer and is associated with significantly more improvements than infliximab. Future studies should provide a direct comparison between the risankizumab and infliximab in term of safety and efficacy.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.