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Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis

Burmester, Gerd and Durez, Patrick and Shestakova, Galena and Genovese, Mark and Schulze-Koops, Hendrik and Li, Yue and Wang, Amanda and Lewitzky, Steven and Koroleva, Irina and Agarwal-Berneis, Anni and Lee, David M and Hueber, Wolfgang (2016) Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis. Rheumatology (United Kingdom), 55 (1). pp. 49-55. ISSN 14620332

Abstract

Objective. To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort. Methods. Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥ 6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP. Results. Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated. Conclusion. Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated. Trial registration: ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.

Item Type: Article
Keywords: biomarker C-reactive protein clinical trial genetic HLA interleukin-17 Rheumatoid arthritis rheumatoid factor secukinumab
Date Deposited: 25 Oct 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/24708

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