Secukinumab improves mild-to-moderate psoriasis: A randomized, placebo-controlled exploratory clinical trial
Authors: Jaehwan Kim, Jongmi Lee, Jason E. Hawkes, Xuan Li, Norma Kunjravia, Darshna Rambhia, Inna Cueto, Ariana Moreno, Hong Hur, Sandra Garcet, Wei Zhou, Junyue Cao, James G. Krueger
Journal: Journal of the American Academy of Dermatology (2022)

To the Editor: Many effective biologic treatments have been established for moderate-to-severe psoriasis, defined in most clinical trials as psoriasis with ≥10% body surface area and psoriasis area-and-severity index (PASI) ≥12. Although patients with mild-to-moderate psoriasis constitute 82% of the total psoriasis population, mild-to-moderate psoriasis patients are not permitted entry to clinical trials of newer biologic agents.1Strober B. Ryan C. van de Kerkhof P. et al.Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council.J Am Acad Dermatol. 2020; 82: 117-122Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar In our previous studies comparing gene expression profiles of mild and severe psoriasis, the spectrum of mild-to-severe psoriasis was defined by the common activation of IL-17 pathway genes but with key differences in the immune regulatory gene expression.2Kim J. Bissonnette R. Lee J. et al.The spectrum of mild to severe psoriasis vulgaris is defined by a common activation of IL-17 pathway genes, but with key differences in immune regulatory genes.J Invest Dermatol. 2016; 136: 2173-2182Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Since the expression of immune regulatory genes is high in mild psoriasis, we hypothesized that treatment response and disease remission after IL-17A inhibition differs in mild psoriasis compared with severe psoriasis. To test the efficacy of an IL-17A antagonist in mild-to-moderate psoriasis, we conducted a randomized, double-blinded, placebo-controlled exploratory phase II clinical trial for the use of secukinumab, an IL-17A antagonist, for treatment of mild-to-moderate psoriasis (PASI >6 and <12 and a body surface area <10%; (Supplementary Fig 1 and clinical trial protocol, available via Mendeley at https://data.mendeley.com/datasets/nyhfxz8tt9/1). We also reported the gene expression modifications observed in psoriasis skin (Supplementary experiment protocol, available via Mendeley at https://data.mendeley.com/datasets/nyhfxz8tt9/1). At week 12, secukinumab treatment was more effective than placebo; secukinumab treatment (group 1) of mild-to-moderate psoriasis led to greater rates of PASI75 (72.7% in secukinumab vs 0% in placebo; P < .005), PASI90 (63.6% in secukinumab vs 0% in placebo; P < .005) and Physician Global Assessment 0/1 (81.8% in secukinumab vs 0% in placebo; P < .0005) when compared to placebo (group 2) (Fig 1 and Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/nyhfxz8tt9/1). Secukinumab treatment of mild-to-moderate psoriasis resulted in more disease improvement than placebo as early as 2 weeks after initiation of treatment (decrease in PASI and Physician Global Assessment at week 2; P < .05). All of the mild-to-moderate psoriasis patients (100%) achieved a PASI75 16 weeks after initiating injections. A gene expression study of skin biopsies revealed that the impact of systemic IL-17A inhibition on psoriasis patients' skin immunity was not confined to only blocking the major cytokine of pathogenic T cells (IL17A) (Fig 2). It extended to blocking the entire feed-forward amplification loop of psoriasis inflammation. In addition, the gene expression of a keratinocyte stem cell marker (KRT15) and cytokines that may promote skin homeostasis (IL343Lelios I. Cansever D. Utz S.G. Mildenberger W. Stifter S.A. Greter M. Emerging roles of IL-34 in health and disease.J Exp Med. 2020; 217e20190290Crossref PubMed Scopus (49) Google Scholar and IL374Rønholt K. Nielsen A.L.-L. Johansen C. et al.IL-37 Expression is downregulated in lesional psoriasis skin.Immunohorizons. 2020; 4: 754-761Crossref PubMed Scopus (15) Google Scholar) was increased in psoriasis skin after systemic IL-17A inhibition. Our study supports the increasing trend to explore systemic treatments for mild-to-moderate psoriasis. The Delphi consensus from the International Psoriasis Council recommends that psoriasis patients be classified as candidates for systemic therapy if topical therapy fails, regardless of their severity category.1Strober B. Ryan C. van de Kerkhof P. et al.Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council.J Am Acad Dermatol. 2020; 82: 117-122Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Recent studies showed that an oral phosphodiesterase-4 inhibitor (apremilast), which induces IL-17 reduction in psoriasis skin, effectively treats mild-to-moderate psoriasis.5Gold L.S. Papp K. Pariser D. et al.Efficacy and safety of apremilast in patients with mild-to-moderate plaque psoriasis: results of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.J Am Acad Dermatol. 2022; 86: 77-85Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Although our conclusions are limited by sample size, drugs that block IL-17A may be more effective for treating mild-to-moderate psoriasis than moderate-to-severe psoriasis. Dr Krueger has received research support (grants paid to the institution) from AbbVie, Amgen, BMS, Boehringer, EMD Serono, Innovaderm, Kineta, LEO Pharma, Novan, Novartis, Paraxel, Pfizer, Regeneron, and Vitae and personal fees from AbbVie, Acros, Allergan, Aurigne, BiogenIdec, Boehringer, Escalier, Janssen, Lilly, Novartis, Pfizer, Roche, and Valeant. The other authors have no conflicts of interest to declare. We thank the Rockefeller University Research Facilitation Office for the regulatory and administrative assistance. Letter from the editor: New paradigms for the treatment of psoriasisJournal of the American Academy of DermatologyVol. 88Issue 2PreviewIn this issue of the Journal of the American Academy of Dermatology, Kim et al report on the efficacy of an interleukin 17A antagonist in mild-to-moderate psoriasis. Most published trials of biologic therapy for psoriasis have focused on moderate to severe disease. This study examined outcomes in patients with milder disease, raising important questions about the future of psoriasis treatment and the role of systemic agents in the treatment of patients with limited disease. Full-Text PDF