Comparative Analysis of Risankizumab versus Ustekinumab in Plaque Psoriasis: A Detailed Evaluation

1. 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

2. 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.

3. 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).

4. 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.

5. 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.

6. 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.

7. 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 BoehringerIngelheim (originator of risankizumab) and AbbVie (organisation marketing risankizumab) which increases risk of bias.

8. 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.

9. ConclusionsWhat 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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