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

doi:10.1016/j.jaci.2018.11.038

Journal of Allergy and Clinical Immunology

Volume 143, Issue 6, June 2019, Pages 2120-2130

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/j.jaci.2018.11.038 Get rights and content

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.

Section snippets

Patient population

The study was conducted in accordance with the 2008 Declaration of Helsinki and in the spirit of the 1996 International Conference on Harmonisation in Good Clinical Practice. Ethical approval for this study was granted by The South East London REC 2 Ethics Committee (11/H0802/7). Written informed consent was obtained from all subjects before enrollment.

All participants are adults (>16 years) enrolled in the Biomarkers of Systemic Treatment Outcomes in Psoriasis (BSTOP) study (//www.kcl.ac.uk/lsm/research/divisions/gmm/departments/dermatology/Research/stru/groups/bstop/index.aspx

A prospective observational data resource facilitating predictive genetic biomarker identification in psoriasis

To assess the ability of HLA-C*06:02 to predict different rates of response to adalimumab and ustekinumab, we considered 3320 patients enrolled in the BSTOP study and BADBIR for whom genotype data were available (see the main Methods section). Of these patients, 53.4% were HLA-C*06:02 positive (carrying ≥1 copy of the allele), with 46.6% being HLA-C*06:02 negative. After applying eligibility criteria to ensure that valid baseline and response PASI scores were available, 1326 participants were

Discussion

This study constitutes the largest investigation to date into the pharmacogenetics of biologic response in patients with psoriasis and is the first to use jointly generated clinical and genetic data on different drugs to identify a predictive biomarker with potential clinical utility. We report that the HLA-C*06:02 allele effectively stratifies patients with psoriasis into groups with different profiles of response to the 2 most frequently prescribed biologics: adalimumab and ustekinumab.

References (44)

R. Parisi et al.
Global epidemiology of psoriasis: a systematic review of incidence and prevalence
J Invest Dermatol
(2013)
J.F. Fowler et al.
The impact of psoriasis on health care costs and patient work loss
J Am Acad Dermatol
(2008)
E. Generali et al.
Lessons learned from twins in autoimmune and chronic inflammatory diseases
J Autoimmun
(2017)
A. Menter et al.
Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial
J Am Acad Dermatol
(2008)
C.L. Leonardi et al.
Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)
Lancet
(2008)
J.E. Gudjonsson et al.
Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients—an analysis of 1019 HLA-C- and HLA-B-typed patients
J Invest Dermatol
(2006)
K. Li et al.
HLA-C*06:02 allele and response to IL-12/23 inhibition: results from the ustekinumab phase 3 psoriasis program
J Invest Dermatol
(2016)
S. Purcell et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am J Hum Genet
(2007)
C.E.M. Griffiths et al.
Establishing an academic-industrial stratified medicine consortium: psoriasis stratification to optimize relevant therapy
J Invest Dermatol
(2015)
R.B. Warren et al.
Differential drug survival of biologic therapies for the treatment of psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)
J Invest Dermatol
(2015)

T. Henseler et al.

Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris

J Am Acad Dermatol

(1985)

Global Report on Psoriasis

K.D. Wuepper et al.

Psoriasis vulgaris: a genetic approach

J Invest Dermatol

(1990)

L.C. Tsoi et al.

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Nat Commun

(2017)

N. Dand et al.

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Hum Mol Genet

(2017)

S.K. Mahil et al.

Update on psoriasis immunopathogenesis and targeted immunotherapy

Semin Immunopathol

(2016)

C.H. Smith et al.

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

Br J Dermatol

(2017)

K.F. Baker et al.

Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?

Ann Rheum Dis

(2018)

C. Kromer et al.

Biologicals and small molecules in psoriasis: a systematic review of economic evaluations

PLoS One

(2018)

L.C. Tsoi et al.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Nat Genet

(2012)

A. Strange et al.

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Nat Genet

(2010)

L. Chen et al.

HLA-Cw6 and psoriasis

Br J Dermatol

(2018)

Cited by (103)

Integrated proteomics and genomics analysis of paradoxical eczema in psoriasis patients treated with biologics
2023, Journal of Allergy and Clinical Immunology
Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis.
We sought to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated.
This study used the Olink Target 96 Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide polymorphisms used to create polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls.
STAMBP expression was lower in cases at T1 than in controls (log-fold change: −0.44; adjusted P = .022); no other proteins reached statistical significance at equivalent time points. Eleven gene sets including cytokine and chemokine pathways were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema (adjusted P = .046).
The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene-set level and is detectable before onset of the phenotype. This signature could be genetically determined.
Molecular bases of comorbidities: present and future perspectives
2023, Trends in Genetics
Co-occurrence of diseases decreases patient quality of life, complicates treatment choices, and increases mortality. Analyses of electronic health records present a complex scenario of comorbidity relationships that vary by age, sex, and cohort under study. The study of similarities between diseases using ‘omics data, such as genes altered in diseases, gene expression, proteome, and microbiome, are fundamental to uncovering the origin of, and potential treatment for, comorbidities. Recent studies have produced a first generation of genetic interpretations for as much as 46% of the comorbidities described in large cohorts. Integrating different sources of molecular information and using artificial intelligence (AI) methods are promising approaches for the study of comorbidities. They may help to improve the treatment of comorbidities, including the potential repositioning of drugs.
Biomarkers and biologics related with psoriasis and psoriatic arthritis
2023, International Immunopharmacology
Over the past half century, psoriasis is considered as an immune-mediated inflammatory skin disease with the combined hallmarks of autoimmunity and autoinflammation, according to growing volumes of clinical and experimental findings. There is currently no cure for psoriasis, current treatment strategies focus on symptom control, disease minimization, and patient’s quality of life enhancement. To meet these challenges, it keeps imperative to discover potential biomarkers, so that not only can they be used for the prediction and monitoring of psoriasis disease in clinic, but also can provide novel therapeutic targets or treatment strategies for psoriasis sufferers. This review systematically demonstrates the research progress of psoriasis-related biomarkers and elaborates their related mechanisms in the pathological development of psoriasis and psoriatic arthritis. In addition, we summarize the development of biologic therapies for psoriasis and psoriatic arthritis in order to drive the broader discussion of psoriasis as an autoimmune-mediated inflammatory skin disease.
Atopic Polygenic Risk Score Is Associated with Paradoxical Eczema Developing in Patients with Psoriasis Treated with Biologics
2023, Journal of Investigative Dermatology
Biologic therapies for psoriasis can cause paradoxical eczema. The role of genetic factors in its pathogenesis is unknown. To identify risk variants, we conducted a GWAS of 3,212 patients with psoriasis, of whom 88 developed paradoxical eczema. Two lead SNPs reached genome-wide significance (P ≤ 5 × 10⁻⁸) for association with paradoxical eczema: rs192705221 (near UNC5B, P = 9.52 × 10⁻¹⁰) and rs72925168 (within SLC1A2, P = 1.66 × 10⁻⁹). Genome-wide significant SNPs from published GWAS were used to generate polygenic risk scores (PRSs) for atopic eczema, general atopic disease, or a combination, which were tested for association with paradoxical eczema. Improvement over a clinical risk model was assessed by the area under the curve. All three atopy polygenic risk scores were associated with paradoxical eczema (P < 0.05); polygenic risk score for a combination of atopic eczema and general atopic disease had the strongest association (OR = 1.83, 95% CI = 1.17−2.84, P = 0.0078). Including atopic polygenic risk scores in the multivariable model, which included age, sex, atopic background, and psoriatic arthritis history, increased the area under the curve from 0.671 to 0.681−0.686. Atopic genetic burden is associated with paradoxical eczema occurring in biologic-treated patients with psoriasis, indicating shared underlying mechanisms. Incorporating genetic risk may improve treatment outcome prediction models for psoriasis.
Long-term Temporal Stability of Peripheral Blood DNA Methylation Profiles in Patients With Inflammatory Bowel Disease
2023, Cellular and Molecular Gastroenterology and Hepatology
There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBLs) as biomarkers of susceptibility, progression, and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterized. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array.
We followed a cohort of 46 adult patients with IBD (36 Crohn’s disease [CD], 10 ulcerative colitis [UC]; median age, 44 years; interquartile range [IQR] 27–56 years; 50% female) that received standard care follow-up at the Amsterdam University Medical Centers. Paired PBL samples were collected at 2 time points with a median of 7 years (range, 2–9 years) in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively.
Around 60% of all EPIC array loci presented poor intra-individual stability (ICC <0.50); 78.114 (≈9%) showed good (ICC, 0.75–0.89), and 41.274 (≈5%) showed excellent (ICC ≥0.90) stability, between both measured time points. Focusing on previously identified consistently differentially methylated positions indicated that 22 CD-, 11 UC-, and 24 IBD-associated loci demonstrated high stability (ICC ≥0.75) over time; of these, we observed a marked stability of CpG loci associated to the HLA genes.
Our data provide insight into the long-term stability of the PBL DNA methylome within an IBD context, facilitating the selection of biologically relevant and robust IBD-associated epigenetic biomarkers with increased potential for independent validation. These data also have potential implications in understanding disease pathogenesis.
The Role of Aminopeptidase ERAP1 in Human Pathology—A Review
2024, Current Issues in Molecular Biology

View all citing articles on Scopus

: Supported by PSORT, which is in turn funded by a Medical Research Council (MRC) Stratified Medicine award (MR/L011808/1). The Psoriasis Association (RG2/10), the NIHR Biomedical Research Centre at King's College London/Guy's and St Thomas' NHS Foundation Trust, the Newcastle NIHR Biomedical Research Centre, and the NIHR Manchester Biomedical Research Centre. The British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) is coordinated by the University of Manchester. BADBIR is funded by the British Association of Dermatologists (BAD). The BAD receives income from Janssen Cilag, AbbVie, Novartis, Samsung Bioepis, Eli Lilly, Celgene, Almirall, and Hexal AG for providing pharmacovigilance services. This income finances a separate contract between the BAD and the University of Manchester who coordinate BADBIR. All decisions concerning analysis, interpretation, and publication are made independently of any industrial contribution. N.D. was partly supported by Health Data Research UK (MR/S003126/1), which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council; Economic and Social Research Council; Department of Health & Social Care (England); Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Health and Social Care Research and Development Division (Welsh Government); Public Health Agency (Northern Ireland); British Heart Foundation; and Wellcome. N.J.R.'s laboratory is funded in part by the Newcastle NIHR Biomedical Research Centre, the Newcastle NIHR Medtech, and the In Vitro Diagnostic Co-operative and the Newcastle MRC/EPSRC Molecular Pathology Node.

: Disclosure of potential conflict of interest: M.A.S. has a contract of service with Genomics. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work as co-senior authors.

^‡: The members of the BADBIR study group (excluding individually named authors of this work) are Marilyn Benham, Sagair Hussain, Brian Kirby, Linda Lawson, Kathleen McElhone, Anthony Ormerod, and Caroline Owen.

^§: The members of the PSORT consortium (excluding individually named authors of this work) are Michael R. Barnes, Paola Di Meglio, Richard Emsley, Andrea Evans, Katherine Payne, and Deborah Stocken.

View full text

Atopic dermatitis and inflammatory skin diseaseHLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis

Background

Objective

Methods

Results

Conclusion

Section snippets

Patient population

A prospective observational data resource facilitating predictive genetic biomarker identification in psoriasis

Discussion

J Invest Dermatol

J Am Acad Dermatol

J Autoimmun

J Am Acad Dermatol

Lancet

J Invest Dermatol

J Invest Dermatol

Am J Hum Genet

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

Global Report on Psoriasis

Psoriasis vulgaris: a genetic approach

J Invest Dermatol

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Nat Commun

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Hum Mol Genet

Update on psoriasis immunopathogenesis and targeted immunotherapy

Semin Immunopathol

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

Br J Dermatol

Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?

Ann Rheum Dis

Biologicals and small molecules in psoriasis: a systematic review of economic evaluations

PLoS One

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Nat Genet

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Nat Genet

HLA-Cw6 and psoriasis

Br J Dermatol

Atopic dermatitis and inflammatory skin disease
HLA-C06:02* genotype is a predictive biomarker of biologic treatment response in psoriasis