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

Nick Dand; Michael Duckworth; David Baudry; Alice Russell; Charles J. Curtis; Sang Hyuck Lee; Ian Evans; Kayleigh J. Mason; Ali Alsharqi; Gabrielle Becher; A. David Burden; Richard G. Goodwin; Kevin McKenna; Ruth Murphy; Gayathri K. Perera; Radu Rotarescu; Shyamal Wahie; Andrew Wright; Nick J. Reynolds; Richard B. Warren; Christopher E.M. Griffiths; Catherine H. Smith; Michael A. Simpson; Jonathan N. Barker

doi:10.1016/j.jaci.2018.11.038

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

Nick Dand, Michael Duckworth, David Baudry, Alice Russell, Charles J. Curtis, Sang Hyuck Lee, Ian Evans, Kayleigh J. Mason, Ali Alsharqi, Gabrielle Becher, A. David Burden, Richard G. Goodwin, Kevin McKenna, Ruth Murphy, Gayathri K. Perera, Radu Rotarescu, Shyamal Wahie, Andrew Wright, Nick J. Reynolds, Richard B. WarrenChristopher E.M. Griffiths, Catherine H. Smith, Michael A. Simpson, Jonathan N. Barker

Research output: Contribution to journal › Article › peer-review

122 Citations (Scopus)

272 Downloads (Pure)

Abstract

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-α) 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 × 10⁻⁷), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 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 × 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.

Original language	English
Pages (from-to)	2120-2130
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	6
Early online date	20 Dec 2018
DOIs	https://doi.org/10.1016/j.jaci.2018.11.038
Publication status	Published - Jun 2019

Keywords

psoriasis
psoriatic arthritis
biologic therapy
genetics
pharmacogenetics
treatment response
HLA
adalimumab
ustekinumab
skin disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jaci.2018.11.038

HLA-C*06:02 genotype_DAND_Accepted27Nov2018_GREEN AAMAccepted author manuscript, 2.92 MBLicence: CC BY-NC-ND

Cite this

Dand, N., Duckworth, M., Baudry, D., Russell, A., Curtis, C. J., Lee, S. H., Evans, I., Mason, K. J., Alsharqi, A., Becher, G., Burden, A. D., Goodwin, R. G., McKenna, K., Murphy, R., Perera, G. K., Rotarescu, R., Wahie, S., Wright, A., Reynolds, N. J., ... Barker, J. N. (2019). HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis. Journal of Allergy and Clinical Immunology, 143(6), 2120-2130. https://doi.org/10.1016/j.jaci.2018.11.038

@article{fae5343d16984c82b93da4ed0ec413cc,

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

abstract = "BackgroundBiologic 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.ObjectiveWe 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-α) and ustekinumab (anti–IL-12/23).MethodsThis 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.ResultsHLA-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 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 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 × 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.ConclusionThis large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.",

keywords = "psoriasis, psoriatic arthritis, biologic therapy, genetics, pharmacogenetics, treatment response, HLA, adalimumab, ustekinumab, skin disease",

author = "Nick Dand and Michael Duckworth and David Baudry and Alice Russell and Curtis, {Charles J.} and Lee, {Sang Hyuck} and Ian Evans and Mason, {Kayleigh J.} and Ali Alsharqi and Gabrielle Becher and Burden, {A. David} and Goodwin, {Richard G.} and Kevin McKenna and Ruth Murphy and Perera, {Gayathri K.} and Radu Rotarescu and Shyamal Wahie and Andrew Wright and Reynolds, {Nick J.} and Warren, {Richard B.} and Griffiths, {Christopher E.M.} and Smith, {Catherine H.} and Simpson, {Michael A.} and Barker, {Jonathan N.}",

year = "2019",

month = jun,

doi = "10.1016/j.jaci.2018.11.038",

language = "English",

volume = "143",

pages = "2120--2130",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "MOSBY, INC",

number = "6",

}

Dand, N , Duckworth, M , Baudry, D , Russell, A , Curtis, CJ , Lee, SH, Evans, I, Mason, KJ, Alsharqi, A, Becher, G, Burden, AD, Goodwin, RG, McKenna, K, Murphy, R, Perera, GK, Rotarescu, R, Wahie, S, Wright, A, Reynolds, NJ, Warren, RB, Griffiths, CEM, Smith, CH , Simpson, MA & Barker, JN 2019, 'HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis', Journal of Allergy and Clinical Immunology, vol. 143, no. 6, pp. 2120-2130. https://doi.org/10.1016/j.jaci.2018.11.038

TY - JOUR

T1 - HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis

AU - Dand, Nick

AU - Duckworth, Michael

AU - Baudry, David

AU - Russell, Alice

AU - Curtis, Charles J.

AU - Lee, Sang Hyuck

AU - Evans, Ian

AU - Mason, Kayleigh J.

AU - Alsharqi, Ali

AU - Becher, Gabrielle

AU - Burden, A. David

AU - Goodwin, Richard G.

AU - McKenna, Kevin

AU - Murphy, Ruth

AU - Perera, Gayathri K.

AU - Rotarescu, Radu

AU - Wahie, Shyamal

AU - Wright, Andrew

AU - Reynolds, Nick J.

AU - Warren, Richard B.

AU - Griffiths, Christopher E.M.

AU - Smith, Catherine H.

AU - Simpson, Michael A.

AU - Barker, Jonathan N.

PY - 2019/6

Y1 - 2019/6

N2 - BackgroundBiologic 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.ObjectiveWe 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-α) and ustekinumab (anti–IL-12/23).MethodsThis 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.ResultsHLA-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 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 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 × 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.ConclusionThis large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

AB - BackgroundBiologic 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.ObjectiveWe 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-α) and ustekinumab (anti–IL-12/23).MethodsThis 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.ResultsHLA-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 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 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 × 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.ConclusionThis large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

KW - psoriasis

KW - psoriatic arthritis

KW - biologic therapy

KW - genetics

KW - pharmacogenetics

KW - treatment response

KW - HLA

KW - adalimumab

KW - ustekinumab

KW - skin disease

U2 - 10.1016/j.jaci.2018.11.038

DO - 10.1016/j.jaci.2018.11.038

M3 - Article

SN - 0091-6749

VL - 143

SP - 2120

EP - 2130

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this