Response to Anti-IL17 Therapy in Inflammatory Disease is Not Strongly Impacted by Genetic Background

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2023 Sep 2

PMID 37659414

Authors

Cong Zhang

Konstantin Shestopaloff

Benjamin Hollis

Chun Hei Kwok

Claudia Hon

Nicole Hartmann

Chengeng Tian

Magdalena Wozniak

Luis Santos

Dominique West

Stephen Gardiner

Ann-Marie Mallon

Aimee Readie

Ruvie Martin

Thomas Nichols

Michael T Beste

Jonas Zierer

Enrico Ferrero

Marc Vandemeulebroecke

Luke Jostins-Dean

Affiliations

Soon will be listed here.

Abstract

Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual's genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases.

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References

Meerman J, Ter Hark S, Janzing J, Coenen M . The Potential of Polygenic Risk Scores to Predict Antidepressant Treatment Response in Major Depression: A Systematic Review. J Affect Disord. 2022; 304:1-11. DOI: 10.1016/j.jad.2022.02.015. View

Ramonda R, Lorenzin M, Chimenti M, DAngelo S, Marchesoni A, Salvarani C . Effectiveness and safety of secukinumab in axial spondyloarthritis: a 24-month prospective, multicenter real-life study. Ther Adv Musculoskelet Dis. 2022; 14:1759720X221090310. PMC: 9058366. DOI: 10.1177/1759720X221090310. View

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View

Rao T, Province M . A Framework for Interpreting Type I Error Rates from a Product-Term Model of Interaction Applied to Quantitative Traits. Genet Epidemiol. 2015; 40(2):144-53. PMC: 4738444. DOI: 10.1002/gepi.21944. View

van der Heijde D, van t Hof M, van Riel P, Theunisse L, Lubberts E, van Leeuwen M . Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990; 49(11):916-20. PMC: 1004262. DOI: 10.1136/ard.49.11.916. View

Parkes M, Cortes A, van Heel D, Brown M . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013; 14(9):661-73. DOI: 10.1038/nrg3502. View

Mirkov M, Cui J, Vermeulen S, Stahl E, Toonen E, Makkinje R . Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis. Ann Rheum Dis. 2012; 72(8):1375-81. PMC: 4169706. DOI: 10.1136/annrheumdis-2012-202405. View

Ha E, Bae S, Kim K . Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2020; 80(5):558-565. PMC: 8053349. DOI: 10.1136/annrheumdis-2020-219065. View

Voorman A, Lumley T, McKnight B, Rice K . Behavior of QQ-plots and genomic control in studies of gene-environment interaction. PLoS One. 2011; 6(5):e19416. PMC: 3093379. DOI: 10.1371/journal.pone.0019416. View

10.

Liu M, Degner J, Davis J, Idler K, Nader A, Mostafa N . Identification of HLA-DRB1 association to adalimumab immunogenicity. PLoS One. 2018; 13(4):e0195325. PMC: 5882140. DOI: 10.1371/journal.pone.0195325. View

11.

Hassler S, Bachelet D, Duhaze J, Szely N, Gleizes A, Hacein-Bey Abina S . Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium. PLoS Med. 2020; 17(10):e1003348. PMC: 7598520. DOI: 10.1371/journal.pmed.1003348. View

12.

Parkes M . IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn's and Colitis. Gut. 2019; 68(9):1537-1540. PMC: 6709775. DOI: 10.1136/gutjnl-2019-318835. View

13.

Tsoi L, Spain S, Knight J, Ellinghaus E, Stuart P, Capon F . Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012; 44(12):1341-8. PMC: 3510312. DOI: 10.1038/ng.2467. View

14.

Blanco F, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M . Secukinumab in Active Rheumatoid Arthritis: A Phase III Randomized, Double-Blind, Active Comparator- and Placebo-Controlled Study. Arthritis Rheumatol. 2017; 69(6):1144-1153. DOI: 10.1002/art.40070. View

15.

Massey J, Plant D, Hyrich K, Morgan A, Wilson A, Spiliopoulou A . Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis. Pharmacogenomics J. 2018; 18(5):657-664. PMC: 6150911. DOI: 10.1038/s41397-018-0040-6. View

16.

Liu T, Li S, Ying S, Tang S, Ding Y, Li Y . The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front Immunol. 2020; 11:594735. PMC: 7705238. DOI: 10.3389/fimmu.2020.594735. View

17.

Roda G, Jharap B, Neeraj N, Colombel J . Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016; 7:e135. PMC: 4737871. DOI: 10.1038/ctg.2015.63. View

18.

FREDRIKSSON T, Pettersson U . Severe psoriasis--oral therapy with a new retinoid. Dermatologica. 1978; 157(4):238-44. DOI: 10.1159/000250839. View

19.

Cortes A, Hadler J, Pointon J, Robinson P, Karaderi T, Leo P . Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013; 45(7):730-8. PMC: 3757343. DOI: 10.1038/ng.2667. View

20.

Creemers M, van t Hof M, Franssen M, van de Putte L, Gribnau F, van Riel P . Disease activity in ankylosing spondylitis: selection of a core set of variables and a first set in the development of a disease activity score. Br J Rheumatol. 1996; 35(9):867-73. DOI: 10.1093/rheumatology/35.9.867. View