Risankizumab versus ustekinumab for plaque psoriasis: a critical appraisal A. Al-Janabi1, Z. K. Jabbar-Lopez2, C.E.M. Griffiths1, Z.Z.N. Yiu1 1. Dermatology Centre, Salford Royal Hospital, University of Manchester and the Academic Health Science Centre, Manchester, United Kingdom. 2. Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, King’s College London & Guy's and St Thomas' NHS Foundation Trust, London, U.K. British Journal of Dermatology. DOI: 10.111/bjd.17624

Introduction What’s already known? Interleukin(IL)-23 is important in the pathogenesis of plaque psoriasis. Ustekinumab, which targets the p40 subunit common to IL-12 and IL-23, is an effective biologic treatment for chronic plaque psoriasis. More recently, biologics targeting the p19 subunit specific to IL-23 have been shown to be highly effective in the treatment of moderate-to-severe plaque psoriasis.

Objective To critically appraise the UltIMMa-1 and UltIMMa-2 trials of risankziumab versus ustekinumab for the treatment of moderate-to-severe plaque psoriasis (Gordon et al, 2018).

Methods The authors reviewed and appraised the study’s internal (randomisation, blinding, intention-to-treat (ITT), power) and external (centres involved, inclusion and exclusion criteria) validity. They have considered the wider implications of the results.

Results – internal validity The study was well-randomised with similar patient characteristics across treatment arms, including stratification based on previous exposure to tumour necrosis factor inhibitors (though the nature of this exposure was not specified). The authors used an ITT analysis and documented confidence intervals. The dropout rates were low and patient numbers exceeded those required for 90% power in both studies.

Results – external validity Both trials conducted across 139 sites in 14 countries – the number of each type of site not specified. Some patients excluded from trial based on co-morbidities though not completely specified which conditions merit exclusion. Patients that have failed previous systemic treatments included in study, but no separate analysis to identify whether they respond differently. In some countries e.g. U.K., most biologic patients will have failed conventional systemic agents which could indicate a more treatment-resistant phenotype.

Results – other issues Placebo arms and having two replicate trials not necessary for comparison but likely required for drug regulatory agency approval as no prior phase III trials for risankizumab. Quality of life indicators (secondary endpoints) were only measured up to week 16. The study was sponsored by Boehringer Ingelheim (originator of risankizumab) and AbbVie (organisation marketing risankizumab) which increases risk of bias.

Discussion These trials are the first direct comparison of an IL-23 inhibitor vs combined IL-12/23 inhibitor in patients that have not received either class before. The reason why IL-23-selective blockade is more effective is unclear but could suggest IL-12 inhibition is detrimental in psoriasis treatment. Further studies needed to compare with other IL-23-selective inhibitors and other classes of biologic drugs.

Conclusions What does this study add? This is a critical appraisal of the study by Gordon et al, a parallel group, randomized, controlled trial comparing risankizumab, with ustekinumab and placebo. This is a well-conducted study with high internal validity. External validity of the trial is less clear and further information regarding the participants’ prior medical history and psoriasis treatments could help the reader apply the results to real-world populations.

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