Rationale
Psoriasis is an immune‐mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Despite multiple available treatments, their comparative efficacies and safety remain unclear due to the limited number of direct comparisons. We conducted a network meta‐analysis to comprehensively compare systemic treatments.
Objectives
To compare the benefits and harms of non‐targeted systemic agents, targeted synthetic agents, and biologic targeted treatments for people with moderate‐to‐severe psoriasis using a network meta‐analysis, and to rank these treatments according to their benefits and harms.
Search methods
For this update of the living systematic review, we updated our searches monthly up to July 2024 in the following databases and trial registers: CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP.
Eligibility criteria
Randomised controlled trials of systemic pharmacological treatments in adults over 18 years of age with moderate‐to‐severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent, irrespective of dose and duration.
Outcomes
The critical outcomes were proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 and proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation).
Risk of bias
We used the Cochrane RoB 2 tool.
Synthesis methods
We conducted study selection, data extraction, risk of bias assessment, and analysis in duplicate. We synthesised data using pairwise and network meta‐analyses to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs).
We assessed the certainty of network meta‐analysis evidence for the two critical outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing.
We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety).
Included studies
This update includes 26 new studies, taking the total number of included studies to 204, and randomised participants to 67,889 (67% men), mainly recruited from hospitals. The average age was 44.4 years, and the mean PASI score at baseline was 20.5 (range: 9.5 to 40). Most studies were placebo‐controlled (56%). We assessed 26 treatments. Most (171) trials were multicentric (2 to 231 centres).
Most studies (157/204) declared funding by a pharmaceutical company, and 27 studies did not report a funding source.
Synthesis of results
Network meta‐analysis at class level demonstrated that all interventions had a higher proportion of participants reaching PASI 90 than placebo. Anti‐interleukin (IL)17 treatment showed a higher proportion of participants reaching PASI 90 compared to all the interventions. Biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐tumour necrosis factor (TNF)‐alpha showed a higher proportion of participants reaching PASI 90 than the non‐targeted systemic agents and the targeted systemic agents.
For reaching PASI 90, the most effective drugs when compared to placebo were (in SUCRA rank order): infliximab (moderate‐certainty evidence), xeligekimab (moderate‐certainty), bimekizumab (high‐certainty), ixekizumab (moderate‐certainty), and risankizumab (moderate‐certainty). Clinical effectiveness of these drugs was similar when compared against each other. There was evidence of a difference in favour of bimekizumab, ixekizumab, and risankizumab compared to secukinumab, brodalumab, and guselkumab in achieving PASI 90. Infliximab, anti‐IL17 drugs (bimekizumab, ixekizumab, secukinumab, sonelokimab, brodalumab), and anti‐IL23 drugs (risankizumab and guselkumab) showed evidence of a difference in achieving PASI 90 compared to ustekinumab, tildrakizumab, three anti‐TNF‐alpha agents (adalimumab, certolizumab, and etanercept), and deucravacitinib. Ustekinumab was superior to certolizumab. Adalimumab, tildrakizumab, and ustekinumab were superior to etanercept, deucravacitinib, and apremilast. Ciclosporin and methotrexate were superior to apremilast for reaching PASI 90.
We found no evidence of a difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAEs analyses were based on a very low number of events with low‐certainty evidence for most comparisons. Therefore, the findings must be viewed with caution.
For PASI 90, 31% of studies (51/165) had a high risk of bias, 34% (56 studies) had some concerns, and 35% (58) had low risk. For SAEs, 57% (94/169) had a high risk of bias, 31% (53 studies) had some concerns, and 13% (22 studies) had low risk.
Authors' conclusions
Our review shows that, compared to placebo, the biologics infliximab, xeligekimab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate‐to‐severe psoriasis, with high‐certainty evidence for bimekizumab and moderate‐certainty evidence for infliximab, xeligekimab, ixekizumab, and risankizumab.
This network meta‐analysis evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer‐term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.4 years) and high level of disease severity (PASI 20.5 at baseline) may not be typical of people seen in daily clinical practice.
More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long‐term information on the safety of treatments included in this review, an evaluation of non‐randomised studies is needed.
Our confidence in the results for non‐targeted systemic treatments is limited due to concerns regarding study conduct. Further research is warranted and may modify these findings.
Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Funding
This Cochrane review obtained funding from the French Society of Dermatology and the French Ministry of Health.
Registration
The previous version of this Living Systematic Review is available via DOI 10.1002/14651858.CD011535.pub6.
Author(s)
Emilie Sbidian, Anna Chaimani, Robin Guelimi, Cheng-Chen Tai, Quentin Beytout, Cherry Choudhary, Alexia Mubuanga Nkusu, Camille Ollivier, Quentin Samaran, Carolyn Hughes, Sivem Afach, Laurence Le Cleach
Plain language summary
Which medicines, taken by mouth or injected, work best to treat plaque psoriasis (a skin condition with raised patches)?
Key messages
What is psoriasis?
The immune system keeps germs and other foreign substances out of the body and destroys any that get in. Psoriasis is an immune condition where the immune system does not function as it should. Psoriasis affects the skin and, sometimes, the joints. Psoriasis speeds up the production of new skin cells, which build up to form raised patches on the skin known as 'plaques'. Plaques can be flaky, scaly, itchy, and appear red on white skin and as darker patches on darker skin tones. Plaque psoriasis is the most common form of psoriasis.
How is psoriasis treated?
Treatments depend on how bad the symptoms are. Around one in 10 to two in 10 people with moderate or severe psoriasis will need to take medicines that affect their immune system to help control psoriasis. These medicines are called systemic treatments, because they affect the whole body. These are usually taken by mouth (orally) or injected.
Why did we do this Cochrane review?
There are three different types of systemic medicines to treat psoriasis.
We wanted to understand the benefits and potential unwanted effects of taking systemic medicines to treat psoriasis, and to see if some medicines work better than others.
What did we do?
We searched for studies that tested systemic medicines on adults with moderate‐to‐severe plaque psoriasis.
What did we find?
We found 204 studies, including 26 new studies since our last search in July 2024. The studies tested 26 different medicines, covering 67,889 adults with psoriasis (average age 44.4 years) and lasted from two to six months. Of 177 studies that reported their source of funding, pharmaceutical companies funded 157 studies, and 27 did not report a funding source.
Most studies compared the systemic medicine against a placebo (an inactive treatment that does not contain any medicine but looks identical to the medicine being tested). They used a common measurement scale called the Psoriasis Area and Severity Index to compare how well each medicine cleared psoriasis plaques from the skin, looking for a 90% improvement. Few studies reported on people's well‐being.
We compared all the medicines against each other.
What are the main results of our review?
All the medicines tested worked better than a placebo to treat psoriasis when measured as a 90% improvement on the Psoriasis Area and Severity Index.
Biologic medicines (that targeted molecules called interleukins 17, 23, 12/23, and cytokine TNF‐alpha) treated psoriasis better than the synthetic targeted treatments and the non‐targeted medicines.
Compared with placebo, five biologic medicines worked best to treat psoriasis, with little difference between them:
We found no evidence of a difference in the numbers of serious unwanted events for all systemic medicines tested when compared with a placebo. However, the studies did not consistently report results about harms, such as serious unwanted events. Therefore, we are uncertain about this.
Limitations of the evidence
We found that, compared to placebo, the biologics infliximab, xeligekimab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving a 90% improvement on the Psoriasis Area and Severity Index in people with moderate‐to‐severe psoriasis. We are confident in our results for bimekizumab, and moderately confident in our results for infliximab, ixekizumab, xeligekimab, and risankizumab.
We are less confident in our results for serious unwanted events, because of the low number that were reported.
We are also less confident in the results for the non‐targeted medicines because of concerns about how some of the studies were conducted. Further research is likely to change these results.
We did not find many studies for some of the 26 medicines included in our review. People in the studies often had severe psoriasis at the start of the study, so our results may not be useful for people whose psoriasis is less severe. Our findings relate only to treatment with systemic medicines for up to six months at most.
How up to date is this review?
We included evidence up to July 2024.
Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available.
Author(s)
Emilie Sbidian, Anna Chaimani, Robin Guelimi, Cheng-Chen Tai, Quentin Beytout, Cherry Choudhary, Alexia Mubuanga Nkusu, Camille Ollivier, Quentin Samaran, Carolyn Hughes, Sivem Afach, Laurence Le Cleach
Authors' conclusions
Implications for practice
In terms of achieving Psoriasis Area and Severity Index (PASI) 90 with induction therapy (evaluation from 8 to 24 weeks after the randomisation), we found the following results, based on network meta‐analysis.
For the other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90.
For serious adverse events (SAEs), there was no evidence of a difference between any of the assessed interventions and placebo. Nonetheless, the analyses of SAEs were based on a very low number of events with low certainty for the majority of the comparisons. Therefore, the findings must be viewed with caution. Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments had more SAEs than the other treatments: risankizumab, bimekizumab, and izokibep appeared to be the better compromise between efficacy and acceptability.
Information on quality of life was not well reported and was absent for several of the interventions.
Conservative interpretation is warranted for the results for xeligekimab, sonelokimab, netakimab, zasocitinib, JNJ‐77242113, izokibep, orismilast, roflumilast, acitretin, ciclosporin, fumaric acid esters, and methotrexate as only a few trials evaluated these drugs in the network meta‐analysis.
The evidence is limited to a selected trial population (participants were young (mean age of 44.4 years), more than 67% were males, they had a high level of disease severity (with an overall mean score of PASI 20.5 at baseline and a long history of psoriasis), and they had few major comorbidities), and the network meta‐analysis evidence was limited to the induction treatment phase (all results were measured from 8 to 24 weeks after randomisation), which is not relevant enough for a chronic disease, which would require long‐term treatment.
Our main results (i.e. superiority of benefit of the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF‐alpha compared with synthetic targeted and non‐targeted systemic treatments) do not reflect the 'real‐life' management of people in Europe or Canada, as an example. To date, biologic treatments (as well as apremilast) may be positioned as second‐line systemic therapies by regulatory bodies, with mandatory reimbursement criteria that patients must meet before being considered for these treatments (moderate‐to‐severe disease after failure, intolerance or contraindication to non‐biologic systemic agents). Such decisions were based on the lack of long‐term safety knowledge but also took into account economic considerations. In this review, we found insufficient evidence to evaluate long‐term harms, and we did not address economic considerations.
Implications for research
From a clinical point of view, we need drugs that can be administered long‐term to provide continuous effective control, because continued remission after successful treatment is as important as successful induction of remission. Moreover, treatment should be easy to use, well accepted by patients, have minimal drug‐to‐drug interactions, and should have minimal monitoring requirements, because convenience is also an important issue when dealing with chronic diseases that require prolonged treatments. Finally, the cost of the drug should be affordable by most patients and by any national health service.
Specific questions and issues in the management of psoriasis remain unmet.
Requirements for future trials