Systemic pharmacological treatments for chronic plaque psoriasis: a network meta‐analysis Edited (no change to conclusions)

Abstract

Background

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 efficacy and safety of non‐biological systemic agents, small molecules, and biologics for people with moderate‐to‐severe psoriasis using a network meta‐analysis, and to provide a ranking of these treatments according to their efficacy and safety.

Search methods

For this update of the living systematic review, we updated our searches of the following databases monthly to October 2021: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase.

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 19 studies, taking the total number of included studies to 167, and randomised participants to 58,912, 67.2% men, mainly recruited from hospitals. Average age was 44.5 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo‐controlled (57%). We assessed a total of 20 treatments. Most (140) trials were multicentric (two to 231 centres). One‐third of the studies (57/167) had high risk of bias; 23 unclear risk, and most (87) low risk. Most studies (127/167) 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, except anti‐IL23. 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) 50.19, 95% CI 20.92 to 120.45), bimekizumab (RR 30.27, 95% CI 25.45 to 36.01), ixekizumab (RR 30.19, 95% CI 25.38 to 35.93), risankizumab (RR 28.75, 95% CI 24.03 to 34.39). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab showed a higher proportion of patients reaching PASI 90 than other anti‐IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, anti‐IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti‐IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti‐TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab 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 low‐ to moderate‐certainty for all the comparisons (except methotrexate versus placebo, which was high‐certainty). 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, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate‐to‐severe psoriasis on the basis of high‐certainty evidence.

This NMA 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 44.5 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice.

We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was low to moderate quality.

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 and postmarketing reports from regulatory agencies is needed.

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. 

Author(s)

Emilie Sbidian, Anna Chaimani, Ignacio Garcia-Doval, Liz Doney, Corinna Dressler, Camille Hua, Carolyn Hughes, Luigi Naldi, Sivem Afach, Laurence Le Cleach

Abstract

Plain language summary

Which medicines, taken by mouth or injected, work best to treat a skin condition called plaque psoriasis? 

Key messages 

‐ After six months of treatment, medicines called 'biologics' seem to work best to clear patches of psoriasis on the skin.

‐ Longer studies are needed to assess the benefits and potential harms of longer treatment with medicines that are injected or taken by mouth to treat psoriasis.

‐ More studies are needed that compare these types of medicines directly against each other.

What is psoriasis? 

Psoriasis is an immune condition that 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 also 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 for psoriasis depend on how bad the symptoms are. Around 10% to 20% of people with moderate or severe psoriasis will need to take medicines that affect their immune system, to help control the 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:

‐ 'biologics' – proteins, such as antibodies, that target interleukins and cytokines (parts of the immune system that affect how cells behave);-‐ small molecules – organic compounds that affect immune cells; examples include apremilast; and-‐ non‐biologic medicines – medicines that have been in use for a long time to treat psoriasis, such as methotrexate, ciclosporin and retinoids.

We wanted to find out about the benefits and potential harms 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 to treat plaque psoriasis.

How up to date is this review? 

We included evidence up to October 2021.

What did we find? 

We found 167 studies, including 19 new studies since our last search (October 2021). The studies tested 20 different medicines, covering 58,912 adults with psoriasis (average age 44.5 years) and lasted from two to six months. Of 137 studies that reported their source of funding, a pharmaceutical company provided funding for 127 studies and 10 were funded by non‐commercial organisations or academic institutions.

Most studies compared the systemic medicine against a placebo (a 'dummy' treatment that does not contain any medicine but looks identical to the medicine being tested). They used a common measurement scale called the PASI (Psoriasis Area and Severity Index) to compare how well each medicine cleared psoriasis plaques from the skin, looking for a 90% improvement (called 'PASI 90'). Few studies reported on participants' well‐being.

We compared all the medicines with each other using a mathematical method called a network meta‐analysis.

What are the main results of our review? 

All the medicines tested worked better than a placebo to treat psoriasis (measured as a 90% improvement in PASI).

Biologic medicines (that targeted interleukins 17, 23 and 12/23, and the cytokine TNF‐alpha) treated psoriasis better than the non‐biologic medicines.

Compared with placebo, four biologic medicines worked best to treat psoriasis, with little difference between them:

‐ infliximab (targets TNF‐alpha);

‐ ixekizumab and bimekizumab (targets interleukin‐17); and

‐ risankizumab (targets interleukin‐23).

We found no significant 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 safety, such as serious unwanted events. We therefore could not create a reliable risk profile of systemic medicines.

Limitations of the evidence 

We are confident in our results for the four biologic medicines (infliximab, iwekizumab, bimekizumab and risankizumab) that worked best to treat psoriasis. We are less confident in our results for serious unwanted events, because of the low number of unwanted events reported.

We are also less confident in the results for the non‐biologic 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 20 medicines included in our review. Participants 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.

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. 

Author(s)

Emilie Sbidian, Anna Chaimani, Ignacio Garcia-Doval, Liz Doney, Corinna Dressler, Camille Hua, Carolyn Hughes, Luigi Naldi, Sivem Afach, Laurence Le Cleach

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

In terms of achieving PASI 90 with induction therapy (evaluation from 8 to 24 weeks after the randomisation), we found the following results, based on network meta‐analysis.

  • At class level, all of the assessed interventions (non‐biological systemic agents, small molecules, and biological treatments) showed significant superiority compared with placebo.
  • At class level, the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF alpha showed significant superiority compared with non‐biological systemic agents; anti‐IL17 treatment was associated with a better chance of reaching PASI 90 compared to all of the interventions, except anti‐IL23.
  • For reaching PASI 90, the most effective drugs when compared to placebo were (in SUCRA (surface under the cumulative ranking curve) rank order): infliximab  (high‐certainty evidence), bimekizumab  (high‐certainty evidence), ixekizumab  (high‐certainty evidence), and risankizumab  (high‐certainty evidence). The clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab were significantly more effective in reaching PASI 90 than other anti‐IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, bimekizumab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab, tildrakizumab and the three anti‐TNF alpha agents (adalimumab, certolizumab and etanercept).
  • Anti‐IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti‐IL23 drugs (risankizumab and guselkumab) except tildrakizumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti‐TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept.
  • No significant difference was shown between apremilast and two non‐biological drugs: ciclosporin and methotrexate.

For the other efficacy outcomes (PASI 75 and PGA0/1), the results were similar to the results for PASI 90.

For serious adverse events, there was no significant difference between any of the assessed interventions and placebo. Nonetheless, analyses of SAE events were based on a very low number of events with low‐to‐moderate certainty for the majority of the comparisons. The findings therefore have to be viewed with caution. Considering both efficacy (PASI 90 outcome) and acceptability (SAE outcome), highly‐effective treatments had more SAEs than the other treatments: risankizumab and bimekizumab 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 netakimab, sonelokimab, deucravacitinib, acitretin, ciclosporin, fumaric acid esters, and methotrexate, as these drugs in the NMA have only been evaluated in few trials.

The evidence is limited to a selected trial population (participants were young (mean age of 44.5 years), had a high level of disease severity (with an overall mean score of PASI 20.4 at baseline, and were long‐time sufferers), and had few major comorbidities), and the NMA 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 efficacy of the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF alpha compared with small molecules and the non‐biological systemic agents) do not reflect the 'real life' management of patients in Europe or Canada, as an example. Currently, biological treatments (as well as apremilast) may be positioned as third‐line 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‐biological systemic agents). Such decisions were based on the lack of long‐term safety knowledge but also taking into account economic consideration. In this review, we found insufficient evidence to evaluate long‐term safety, and we did not address economic considerations, so the question of the choice of first‐line treatment for moderate‐to‐severe psoriasis is still debated.

The first choice in non‐biological systemic agents is still in question, as the limited number of trials assessing non‐biological systemic agents did not allow us to draw robust conclusions; this is also true for some small‐molecule treatments and biological treatments.

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 still remain unmet:

  • Which non‐biological systemic agents have the best benefit/risk balance?
  • Which patients are candidates for small molecule treatment?
  • Which treatments work for subgroups of patients (age, psoriasis severity, previous treatment, psoriatic arthritis, race and ethnicity)?
  • Which treatments offer the best combination of safety and efficacy in patients with major comorbidities (e.g. hepatitis B/C, latent tuberculosis, HIV, and renal, cardiac, and hepatic impairment) as well as pregnancy?
  • Adjustment of therapy for patients with stable low disease activity;
  • Add‐on therapy or switching for patients who failed with a systemic treatment;
  • Long‐term safety data for all the treatments.

1. Future trials need to ensure the following. 

  • Participants : enough information about participants is needed to enable systematic subgroup analyses for biological‐naïve patients (or non‐biological systemic‐agent‐naïve); future trials also need to provide an adequate description of data on other important potential effect modifiers such as previous systemic treatments, whether participants are overweight/obese, the duration of a participant's psoriasis, baseline psoriasis severity (efficacy differences could be expected for patients with PASI at 10 and patients with PASI at 40); race and ethnicity, and presence of psoriatic arthritis.
  • Interventions : high‐quality trials assessing the efficacy of non‐biological systemic agents are still needed.
  • Comparators : once the benefit of a treatment has been established against placebo, only head‐to‐head trials would be helpful to provide physicians with efficacy estimates between the different biologics, with stronger evidence than indirect comparisons. Head‐to‐head comparisons are lacking between the non‐biological systemic agents and small molecules and against each other. More head‐to‐head comparisons between biological agents are also needed (anti‐IL17 versus anti‐IL23, anti‐IL23 versus anti‐IL12/23, anti‐TNF alpha versus anti‐IL12/23).
  • Outcomes:  outcome measure harmonisation is needed for psoriasis.
  • Timing assessment strategy : all of the trials included in this review were limited to the induction phase (from 8 to 24 weeks). Long‐term efficacy data are critical for chronic diseases. Placebo‐controlled long‐term trials would not be ethical, due to the suffering it would entail for the people in the placebo group. However, long‐term studies comparing different drugs would be ethical and informative. Such long‐term trials could also assess the adjustment of therapy for patients with stable cleared psoriasis.

2. New trial designs  are needed, such as pragmatic trials that permit dose adjustment once in remission, switching, and additional treatments (i.e. adding two or more systemic treatments) as in normal clinical practice. All of this unmet medical need evidence would improve the management of the condition.

3. Finally, evidence‐based decision‐making and management of chronic plaque psoriasis require both efficacy AND safety data . As we already know, the limitations of network meta‐analysis and of randomised clinical trials (included in these meta‐analyses) mean we cannot reliably interpret the significance of rare events, given their current design. These studies are designed to detect differences in the severity of psoriasis in response to therapy over short periods of treatment, and are often underpowered and of insufficient duration to detect rare or long‐term adverse events. One way to counter this is to include observational cohort studies/registries in a network observational meta‐analysis.

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