Modulation of inflammatory gene transcripts in psoriasis vulgaris: Differences between ustekinumab and etanercept

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 5; pp. 1965 - 1969
• Main Authors: Brodmerkel, Carrie, Li, Katherine, Garcet, Sandra, Hayden, Karen, Chiricozzi, Andrea, Novitskaya, Inna, Fuentes-Duculan, Judilyn, Suarez-Farinas, Mayte, Campbell, Kim, Krueger, James G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2019; Elsevier Limited
• Subjects: Antagonists; Biopsy; Chemokines; Cytokines; Dendritic cells; Drugs; Etanercept; Gene expression; Genes; Helper cells; Inflammation; Interleukin 12; Interleukin 17; Interleukin 23; Lymphocytes T; Monoclonal antibodies; Patients; Psoriasis; Psoriasis vulgaris; Skin; Skin diseases; Studies; Toll-like receptors; Tumor necrosis factor
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2019.01.017

[...]the anti–IL-12/23 mAb ustekinumab has demonstrated much better “drug survival” than the TNF antagonists etanercept and adalimumab.1 Previous molecular profiling showed that etanercept strongly suppressed genes associated with the IL-23/type 17 T-cell pathway and psoriasis disease transcriptome (PSTR), but patients with resolved lesions retained expression of certain inflammatory genes (“molecular scar”) of psoriasis that could potentially reignite pathogenic skin inflammation on drug discontinuation.2 As psoriasis treatments continue to advance, it becomes even more important to identify differences between therapeutic antagonists in their ability to control pathological gene activation, particularly as treatment goals evolve toward complete disease normalization. For genes upregulated in the PSTR, overall improvements of 91% and 97% were observed for etanercept and ustekinumab, respectively (Fig 1, C; see Table E4 in this article's Online Repository at www.jacionline.org). Because both drugs induced more than 90% improvement in this study-specific disease transcriptome, one could view both agents as highly effective with relatively small mechanistic differences. Furthermore, we hypothesize that more durable control of psoriasis over years of treatment, that is, “drug survival,”4 may be related to lower expression of cytokines, chemokines, and inflammatory mediators in treated lesions and thus a more stable environment for preventing reinitiation of psoriasis from likely pathogenic TH17 T-cell clones retained in treated skin lesions.5 An alternative explanation is that IL-17 production from T cells is more consistently reduced by direct ustekinumab IL-23 blockade, while etanercept reduces IL-23 indirectly by modulating IL-23–producing dendritic cells in psoriasis lesions, which could be subject to costimulatory inputs or Toll-like receptor sensors capable of reinitiating IL-23 production over treatment periods of months-to-years.