Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. The Cochrane Skin Group has produced some of the largest Cochrane reviews, providing a “one stop shop” for people interested in a wide range of interventions for a particular skin condition. One such example is the review of systemic medicines to treat psoriasis, which was updated for the fourth time in May 2022. We asked two of the authors, Laurence Le Cleach, head of the French satellite of the Cochrane Skin group and dermatologist at Henri Mondor hospital, AP-HP in France and Emilie Sbidian, a dermatologist working at the same hospital, to describe the findings. Here's Laurence to begin.

Laurence: First of all, a bit about what psoriasis is and why it's challenging to choose between the treatments.  Psoriasis is a chronic inflammatory skin disease, affecting up to one person in eleven with a major impact on quality of life. Its severity varies over time, from minor localized patches to complete body coverage and there is currently no cure, but various treatments can help to control the symptoms.
The chosen treatment will usually depend on how bad the symptoms are. For example, 10% to 20% of people with moderate or severe psoriasis will need to take medicines that affect their immune system. These medicines are called systemic treatments, because they affect the whole body. They are usually taken by mouth or injected, and there are three main types:
- non-biologic medicines, which have been in use for a long time to treat psoriasis;
- small molecules, which are organic compounds that affect immune cells; and
- 'biologics', which are proteins, such as antibodies, that affect biological targets called interleukins and cytokines, (parts of the immune system that affect how cells behave).
In the 20th century, the development of these biological treatments expanded the therapeutic spectrum of systemic treatments for psoriasis and, currently, eighteen systemic agents have been approved to treat psoriasis but the choice of drug to use for any individual patient is not clear.
In daily practice, the treatment strategy usually involves an induction therapy to bring about remission of the disease, and a maintenance therapy, to maintain this remission.

Emilie: In 2017, we started to review the effects of these various interventions, using the findings of trials from throughout the world and we've performed this living Cochrane review and network meta-analysis since then to compare the potential benefits and harms of non-biologic systemic treatments, small molecules, and biologics for people with moderate-to-severe plaque psoriasis and to rank these treatments according to their effects. Following the first version, we published updates in 2020, 2021 and now, in 2022.
We focus on an efficacy outcome of the psoriasis being declared clear or almost clear and a safety outcome of the proportion of patients experiencing a serious adverse effect. In the included trials, these primary outcomes were assessed during the induction phase, from 8 to 24 weeks after randomization.
The statistical method we use, called network meta-analysis, allows multiple treatments to be compared at the same time using direct evidence obtained from the pairwise comparisons in randomized trials and indirect evidence which is mathematically deduced when interventions have been compared to a common comparator, but in separate trials. It allows us to rank the treatments, thus answering an important question for physicians, patients and guideline writers: among all available treatments, which works best?

Laurence: In the latest up-date, we found 167 trials which had tested 20 different medicines, including nearly 60,000 people with psoriasis. Most studies compared the systemic medicine against a placebo, which is a 'dummy' treatment that does not contain any medicine but looks identical to the medicine being tested.
All the medicines tested were better than a placebo for treating psoriasis, and the biologic medicines were usually better than the small-molecule and non-biologic medicines.
Compared with placebo, four biologic medicines worked best, with little difference between them. These were infliximab, ixekizumab, bimekizumab and risankizumab.
Turning to the potential harms, 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 on safety and we cannot create a reliable risk profile for these systemic medicines.

Emilie: In summary, this means that we are confident in our results for the four biologic medicines that worked best to treat psoriasis but less confident in our results for serious unwanted events. Also, because participants in the trials often had severe psoriasis when they joined their study, our results may not be useful for people whose psoriasis is less severe. It's also important to note that our findings relate only to treatment with systemic medicines for six months at most, which is not sufficient for a chronic disease, such as psoriasis.
In terms of future research, randomized trials directly comparing active agents are necessary. These should also include subgroup analyses that would take account of, for example, previous treatments, psoriasis severity and the presence of psoriatic arthritis.

Laurence: Finally, our findings continue to be used into guidelines worldwide, covering America, Germany, Finland, the UK and Europe more generally in 2021 and 2022.
We thank you for listening and if you would like to read more about our review, how the biologic agents might work and our recommendations for future research, you can find it at Cochrane Library dot com with a simple search for 'network meta-analysis for psoriasis'.