HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Dand, Nick¹  Duckworth, Michael²  Baudry, David²  Russell, Alice²  Curtis, Charles J.^3,4,5  Lee, Sang Hyuck^3,4,5  Evans, Ian⁶  Mason, Kayleigh J.⁶  Alsharqi, Ali⁷  Becher, Gabrielle⁸  Burden, A. David⁹  Goodwin, Richard G.¹⁰  McKenna, Kevin¹¹  Murphy, Ruth^12,13,14  Perera, Gayathri K.¹⁵  Rotarescu, Radu¹⁶  Wahie, Shyamal¹⁷  Wright, Andrew^18,19  Reynolds, Nick J.^20,21,22  Warren, Richard B.⁶  Griffiths, Christopher E. M.⁶  Smith, Catherine H.²  Simpson, Michael A.¹  Barker, Jonathan N.² 

[1] Kings Coll London, Sch Basic & Med Biosci, London, England

[2] Kings Coll London, Fac Life Sci & Med, St Johns Inst Dermatol, London, England

[3] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England

[4] South London & Maudsley NHS Fdn Trust, NIHR Maudsley Biomed Res Ctr, London, England

[5] Kings Coll London, London, England

[6] Univ Manchester, NIHR Manchester Biomed Res Ctr, Manchester Acad Hlth Sci Ctr, Salford Royal NHS Fdn Trust,Dermatol Ctr, Manchester, Lancs, England

[7] Royal Liverpool & Brodgreen Univ Hosp Trusts, Liverpool, Merseyside, England

[8] West Glasgow ACH, Alan Lyell Ctr Dermatol, Glasgow, Lanark, Scotland

[9] Univ Glasgow, Inst Infect Inflammat & Immun, Glasgow, Lanark, Scotland

[10] Aneurin Bevan Univ Hlth Board, Caerleon, Gwent, Wales

[11] Belfast City Hosp, Dept Dermatol, Belfast, Antrim, North Ireland

[12] Sheffield Teaching Hosp NHS Fdn Trust, Sheffield, S Yorkshire, England

[13] Sheffield Childrens NHS Fdn Trust, Sheffield, S Yorkshire, England

[14] Nottingham Univ Hosp NHS Trust, Nottingham, England

[15] Chelsea & Westminster Hosp NHS Fdn Trust, West Middlesex Univ Hosp, London, England

[16] Univ Hosp North Midlands, Stoke On Trent, Staffs, England

[17] Univ Hosp North Durham, Durham, England

[18] Univ Bradford, Ctr Skin Sci, Bradford, W Yorkshire, England

[19] Bradford Teaching Hosp NHS Fdn Trust, St Lukes Hosp, Dermatol Dept, Bradford, W Yorkshire, England

[20] Newcastle Univ, Med Sch, Inst Cellular Med, Dermatol Sci, Newcastle Upon Tyne, Tyne & Wear, England

[21] Newcastle Hosp NHS Fdn Trust, Royal Victoria Infirm, Dept Dermatol, Newcastle Upon Tyne, Tyne & Wear, England

[22] Newcastle Univ, Newcastle MRC EPSRC Mol Pathol Node, Newcastle Upon Tyne, Tyne & Wear, England

关键词: Psoriasis;    psoriatic arthritis;    biologic therapy;    genetics;    pharmacogenetics;    treatment response;    HLA;    adalimumab;    ustekinumab;    skin disease;   

DOI  :  10.1016/j.jaci.2018.11.038

来源: Elsevier

【 摘 要 】

Background: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. Objective: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-alpha) and ustekinumab (anti-IL-12/23). Methods: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. Results: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 x 10(-7)), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 x 10(-5)). Biologic-naive patients who were HLA-C* 06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 x 10(-4)). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. Conclusion: This large observational study suggests that reference to HLA-C* 06: 02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

【 授权许可】

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