A genome-wide screen for variants influencing certolizumab pegol response in a moderate to severe rheumatoid arthritis population

PLoS One. 2022 Apr 12;17(4):e0261165. doi: 10.1371/journal.pone.0261165. eCollection 2022.

Abstract

Certolizumab pegol (CZP) is a PEGylated Fc-free tumor necrosis factor (TNF) inhibitor antibody approved for use in the treatment of rheumatoid arthritis (RA), Crohn's disease, psoriatic arthritis, axial spondyloarthritis and psoriasis. In a clinical trial of patients with severe RA, CZP improved disease symptoms in approximately half of patients. However, variability in CZP efficacy remains a problem for clinicians, thus, the aim of this study was to identify genetic variants predictive of CZP response. We performed a genome-wide association study (GWAS) of 302 RA patients treated with CZP in the REALISTIC trial to identify common single nucleotide polymorphisms (SNPs) associated with treatment response. Whole-exome sequencing was also performed for 74 CZP extreme responders and non-responders within the same population, as well as 1546 population controls. No common SNPs or rare functional variants were significantly associated with CZP response, though a non-significant enrichment in the RA-implicated KCNK5 gene was observed. Two SNPs near spondin-1 and semaphorin-4G approached genome-wide significance. The results of the current study did not provide an unambiguous predictor of CZP response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antirheumatic Agents* / therapeutic use
  • Arthritis, Rheumatoid* / chemically induced
  • Arthritis, Rheumatoid* / drug therapy
  • Arthritis, Rheumatoid* / genetics
  • Certolizumab Pegol / therapeutic use
  • Genome-Wide Association Study
  • Humans
  • Treatment Outcome
  • Tumor Necrosis Factor Inhibitors

Substances

  • Antirheumatic Agents
  • Tumor Necrosis Factor Inhibitors
  • Certolizumab Pegol

Grants and funding

This study was funded by UCB Pharma. DBG received partial salary support and funding for the research materials described in our study. The funder also provided support in the form of salaries for authors IRW, CP, CC, and DM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.