Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene: results from a multicentre study of four European psoriasis cohorts

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BACKGROUND: Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. OBJECTIVES: To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. METHODS: This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. RESULTS: In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. CONCLUSIONS: Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein