Systemic (oral or injected) medicines for psoriasis

What is the aim of this review?

The aim of this review was to compare different systemic medicines (oral or injected medicines that work throughout the entire body) used to treat moderate-to-severe chronic plaque psoriasis in adults (over 18 years of age), to find out which are the safest and most effective at clearing psoriasis. We wanted to rank the medicines in order of their safety and how well they work, to help the development of a treatment pathway for people with chronic plaque psoriasis. We collected and analysed all relevant studies to answer this question, and found 140 studies.

Key messages

The results showed that a selection of treatments from the class of biological medicines appear to be the most effective systemic medicines for achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI). We found no significant difference in serious adverse effects (SAEs) (i.e. serious side effects) when comparing any of the assessed treatments with placebo. However, as the evidence on safety was of very low to moderate quality, we cannot be sure of these results.

For some of the interventions, we found low numbers of studies, so more research needs to be conducted to directly compare the systemic medicines with each other, rather than comparing them with placebo (an inactive substance). In addition, longer-term studies are needed to provide more evidence about the benefit and safety of systemic medicines and to compare their safety profiles. Indeed, the results of this review are limited to the induction treatment (i.e. outcomes were measured from 8 to 24 weeks after participants were allocated to their treatment group), and there was insufficient information to understand the relative benefits of treatments on longer-term outcomes for this chronic disease.

We rated the certainty of the evidence as ranging from very low (mainly conventional medicines) to high (mainly biological medicines). We downgraded the certainty of the evidence due to risks of bias (concerns with the study methods) and then for either inconsistent results or imprecision (inaccuracy).

What was studied in the review?

Psoriasis is characterised by patches of red, flaky skin covered with scales (known as plaques) or other inflammatory effects that are seen on the skin or joints, or both. Psoriasis is caused by an abnormal response within the immune system in people who may have a genetic predisposition towards the condition.

Approximately 2% of the population have psoriasis, and 90% of those people have plaque psoriasis. Around 10% to 20% of people with chronic plaque psoriasis will need to have systemic treatments. Psoriasis negatively impacts quality of life, including a person's psychosocial life.

We compared 19 systemic medicines by identifying studies that compared one or more of these medicines with either placebo or with another medicine to treat moderate-to-severe forms of plaque psoriasis in adults who were at any stage of treatment. The medicines we assessed were conventional systemic treatments (a varied group of treatments that are the oldest treatments given to clear psoriasis), biologics (treatments that use substances made from living organisms, or synthetic versions, to target the immune system), and small molecules (which affect molecules inside immune cells). We included studies whose participants may also have had psoriatic arthritis. The main outcomes we were interested in were achievement of PASI 90 and any serious side effects that were thought to be associated with the medicines.

We combined all of the studies to allow indirect analysis of the treatments, so we could compare them with each other (network meta-analysis).

What are the main results of the review?

The 140 studies enrolled 51,749 people (mainly recruited from a hospital) with moderate-to-severe psoriasis: 34,624 men and 16,529 women (unknown for the remaining 596 participants); the overall average age was 45 years, the overall mean PASI score at the start of the study was 20 (range: 9.5 to 39), indicating a high level of disease severity. Most studies (n = 82) compared the systemic medicine with a placebo treatment, 41 trials compared systemic treatments with other systemic treatments, and 17 trials compared systemic treatments with systemic treatments and placebo. Most studies were short-term; 117 trials were multicentric trials (2 to 231 centres). Most studies (107/140) declared pharmaceutical-company funding and 22 studies did not report the source of funding.

The outcomes presented here were measured from 8 to 24 weeks after the study participants were randomised (induction phase). The following results are based on network meta-analysis (a technique that synthesises direct and indirect comparisons of interventions).

The results showed that compared with placebo, all treatments (assessed in the following groupings: anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha (i.e. the treatments known as the biologics); small molecule treatments; and conventional systemic agents) were significantly more effective in treating psoriasis when assessed using an index that required 90% improvement (PASI 90).

In relation to the same outcome (PASI 90), the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha appeared to work significantly better than the small molecules and the conventional systemic agents. IL is an abbreviation of interleukin; TNF is an abbreviation of tumour necrosis factor, and both are types of cytokine. A cytokine affects the behaviour of a cell.

In terms of individual drugs, again when assessing the ability to reach PASI 90, infliximab, all of the anti-IL17 drugs (ixekizumab, secukinumab, bimekizumab, and brodalumab) and the anti-IL23 drugs (risankizumab and guselkumab, but not tildrakizumab) were significantly more effective than ustekinumab and three anti-TNF alpha agents: adalimumab, certolizumab and etanercept. Adalimumab and ustekinumab were superior to certolizumab and etanercept. We found no significant difference between tofacitinib or apremilast and two conventional drugs: ciclosporin and methotrexate.

Judged against placebo, seven biological medicines worked best at clearing psoriasis lesions (specifically, reaching PASI 90). These medicines were infliximab, ixekizumab (both based on moderate-certainty evidence), risankizumab (high-certainty evidence), bimekizumab (low-certainty evidence), guselkumab (moderate-certainty evidence), secukinumab (high-certainty evidence), and brodalumab (moderate-certainty evidence). There was little difference in how well these seven drugs worked.

For the outcomes PASI 75 and Physician Global Assessment (PGA) 0/1 (i.e. achieving 75% improvement and achieving a PGA score of 0 or 1), the results were very similar to the results for PASI 90.

We must be cautious about the results for some biologics (bimekizumab), small molecules (tyrosine kinase 2 inhibitor), and conventional systemic treatments (acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs have been evaluated in few trials in the NMA.

For the risk of serious side effects, there were no significant differences between any of the systemic medicines compared with placebo treatment. However, the number of serious side effects was very low, and our rankings are based on low- to very low- (for just under half of the results) or moderate-certainty evidence, so they should be interpreted with caution.

For all studies, little information was recorded about quality of life; several of the medicines studied had no quality-of-life data.

How up-to-date is this review?

We searched for studies that had been published up to January 2019.

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.

Authors' conclusions: 

Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab were the best choices for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence (low-certainty evidence for bimekizumab). This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice.

Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs, but the evidence for all the interventions was of very low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies.

In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents.

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.

Read the full abstract...
Background: 

Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, 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. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, 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. This is the baseline update of a Cochrane Review first published in 2017, in preparation for this Cochrane Review becoming a living systematic review.

Objectives: 

To compare the efficacy and safety of conventional systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis, and to provide a ranking of these treatments according to their efficacy and safety.

Search strategy: 

We updated our research using the following databases to January 2019: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the conference proceedings of a number of dermatology meetings. We also searched five trials registers and the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports (until June 2019). We checked the reference lists of included and excluded studies for further references to relevant RCTs.

Selection criteria: 

Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse effects (SAEs) at induction phase. We did not evaluate differences in specific adverse effects.

Data collection and analysis: 

Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse effects).

We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing.

Main results: 

We included 140 studies (31 new studies for the update) in our review (51,749 randomised participants, 68% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (59%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 19 treatments. In all, 117 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (57/140) as being at high risk of bias; 42 were at an unclear risk, and 41 at low risk. Most studies (107/140) declared funding by a pharmaceutical company, and 22 studies did not report the source of funding.

Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90.

At class level, in terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents.

At drug level, in terms of reaching PASI 90, infliximab, all of the anti-IL17 drugs (ixekizumab, secukinumab, bimekizumab and brodalumab) and the anti-IL23 drugs (risankizumab and guselkumab, but not tildrakizumab) were significantly more effective in reaching PASI 90 than ustekinumab and 3 anti-TNF alpha agents: adalimumab, certolizumab and etanercept. Adalimumab and ustekinumab were significantly more effective in reaching PASI 90 than certolizumab and etanercept. There was no significant difference between tofacitinib or apremilast and between two conventional drugs: ciclosporin and methotrexate.

Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness for these seven drugs was similar: infliximab (versus placebo): risk ratio (RR) 29.52, 95% confidence interval (CI) 19.94 to 43.70, Surface Under the Cumulative Ranking (SUCRA) = 88.5; moderate-certainty evidence; ixekizumab (versus placebo): RR 28.12, 95% CI 23.17 to 34.12, SUCRA = 88.3, moderate-certainty evidence; risankizumab (versus placebo): RR 27.67, 95% CI 22.86 to 33.49, SUCRA = 87.5, high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86, SUCRA = 83.5, low-certainty evidence; guselkumab (versus placebo): RR 25.84, 95% CI 20.90 to 31.95; SUCRA = 81; moderate-certainty evidence; secukinumab (versus placebo): RR 23.97, 95% CI 20.03 to 28.70, SUCRA = 75.4; high-certainty evidence; and brodalumab (versus placebo): RR 21.96, 95% CI 18.17 to 26.53, SUCRA = 68.7; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials.

We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to very low certainty for just under half of the treatment estimates in total, and moderate for the others. Thus, the results have to be viewed with caution and we cannot be sure of the ranking.

For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were very similar to the results for PASI 90.

Information on quality of life was often poorly reported and was absent for several of the interventions.

Share/Save