Key messages
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After six months of treatment, medicines called 'biologics' seem to work best to clear raised patches of psoriasis on the skin.
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Longer studies are needed to assess the benefits and potential unwanted effects of longer treatment with medicines taken by injection or mouth to treat psoriasis.
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More studies are needed comparing these types of medicines directly against each other.
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.
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'Biologics' – proteins, such as antibodies, that target interleukins and cytokines (parts of the immune system that affect how cells behave).
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Synthetic targeted treatments – medicines that are made by humans that affect immune cells (for example, apremilast).
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Non-targeted medicines – medicines that have been in use for a long time to treat psoriasis, such as methotrexate, ciclosporin, and retinoids.
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:
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infliximab (targets TNF-alpha);
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ixekizumab, bimekizumab, xeligekimab (targets interleukin-17); and
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risankizumab (targets interleukin-23).
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.
Read the full abstract
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. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis.
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 strategy
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.
Selection criteria
Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation).
Data collection and analysis
We conducted duplicate study selection, data extraction, risk of bias assessment, and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs).
We assessed the certainty of NMA evidence for the two primary 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).
Main results
This update includes an additional 12 studies, taking the total number of included studies to 179, and randomised participants to 62,339, 67.1% men, mainly recruited from hospitals. Average age was 44.6 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (56%). We assessed a total of 20 treatments. Most (152) trials were multicentric (two to 231 centres). One-third of the studies (65/179) had high risk of bias, 24 unclear risk, and most (90) low risk. Most studies (138/179) declared funding by a pharmaceutical company, and 24 studies did not report a funding source.
Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents.
For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 49.16, 95% CI 20.49 to 117.95), bimekizumab (RR 27.86, 95% CI 23.56 to 32.94), ixekizumab (RR 27.35, 95% CI 23.15 to 32.29), risankizumab (RR 26.16, 95% CI 22.03 to 31.07). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab and ixekizumab were significantly more likely to reach PASI 90 than secukinumab. Bimekizumab, ixekizumab, and risankizumab were significantly more likely to reach PASI 90 than brodalumab and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab, and brodalumab), and anti-IL23 drugs except tildrakizumab were significantly more likely to reach PASI 90 than ustekinumab, three anti-TNF alpha agents, and deucravacitinib. Ustekinumab was superior to certolizumab. Adalimumab, tildrakizumab, and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate.
We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with very low- to moderate-certainty evidence for all the comparisons. The findings therefore have to be viewed with caution.
For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions.
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.
