Clinical and genetic differences between pustular psoriasis subtypes - 17/08/18

Doi : 10.1016/j.jaci.2018.06.038

Sophie Twelves, MRes ^a, Alshimaa Mostafa, MD ^b,^c, Nick Dand, PhD ^a, Elias Burri, MBBS ^b, Katalin Farkas, PhD ^d, Rosemary Wilson, BA ^e, Hywel L. Cooper, BM ^f, Alan D. Irvine, MD, DSc ^g, Hazel H. Oon, MD ^h, Külli Kingo, MD, PhD ⁱ, Sulev Köks, PhD ^j, Ulrich Mrowietz, MD ^k, Luis Puig, MD, PhD ^l, Nick Reynolds, MD ^m, Eugene Sern-Ting Tan, MBBS ^h, Adrian Tanew, MD ⁿ, Kaspar Torz, MD ^k, Hannes Trattner, MD ⁿ, Mark Valentine, MD ^o, Shyamal Wahie, MD ^p, Richard B. Warren, MB ChB, PhD ^q, Andrew Wright, MB ChB ^r, Zsuzsa Bata-Csörgő, MD ^s, Marta Szell, DSc ^t, Christopher E.M. Griffiths, MD ^q, A. David Burden, MD ^u, Siew-Eng Choon, MBBS ^v, Catherine H. Smith, MD ^e, Jonathan N. Barker, MD ^e,^⁎^{∗
These authors contributed equally to this work.} , Alexander A. Navarini, MD, PhD ^b,^{∗
These authors contributed equally to this work.}, Francesca Capon, PhD ^a,^{∗
These authors contributed equally to this work.}
^a Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, United Kingdom
^b Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
^c Department of Dermatology, Beni Suef University, Beni Suef, Egypt
^d Department of Medical Genetics, University of Szeged, Szeged, Hungary
^e St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom
^f Portsmouth Dermatology Unit, Portsmouth Hospitals Trust, Portsmouth, United Kingdom
^g Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, and Clinical Medicine, Trinity College Dublin, Dublin, Ireland
^h Department of Dermatology, National Skin Centre, Singapore
ⁱ Department of Dermatology, University of Tartu, and the Clinic of Dermatology, Tartu University Hospital, Tartu, Estonia
^j Department of Pathophysiology, University of Tartu, Tartu, Estonia
^k Psoriasis Center at the Department of Dermatology, University Medical Center, Schleswig-Holstein, Campus Kiel, Kiel, Germany
^l Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^m Institute of Cellular Medicine, Medical School, Newcastle University and the Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
ⁿ Department of Dermatology, Medical University of Vienna, Vienna, Austria
^o Division of Dermatology, University of Washington School of Medicine, Seattle, Wash
^p University Hospital of North Durham and Darlington Memorial Hospital, Darlington, United Kingdom
^q Dermatology Centre, Salford Royal Hospital, University of Manchester and the Academic Health Science Centre, Manchester, United Kingdom
^r St Lukes Hospital, Bradford, and the Centre for Skin Science, University of Bradford, Bradford, United Kingdom
^s MTA-SZTE Dermatological Research Group, Szeged, and the Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
^t MTA-SZTE Dermatological Research Group, Szeged, and the Department of Medical Genetics, University of Szeged, Szeged, Hungary
^u Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom
^v Department of Dermatology, Hospital Sultanah Aminah, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Johor Bahru, Selangor, Malaysia

^∗Corresponding author: Jonathan N. Barker, MD, St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, 9th floor Tower Wing Guy's Hospital, London SE1 9RT, United Kingdom.St John's Institute of DermatologySchool of Basic and Medical BiosciencesKing's College London9th floor Tower Wing Guy's HospitalLondonSE1 9RTUnited Kingdom

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Abstract

Background

The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations.

Objective

We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort.

Methods

We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases.

Results

Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10⁻⁵). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10⁻¹⁵). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10⁻¹⁴ and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003).

Conclusions

The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.

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Graphical abstract

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Key words : Generalized pustular psoriasis, palmoplantar pustulosis, acrodermatitis continua of Hallopeau, IL36RN, AP1S3, genotype-phenotype correlation

Abbreviations used : ACH, ERASPEN, GPP, PPP, PV

Plan

Methods

Patient ascertainment

Mutation screening

Statistics

Results

Age of onset and PV concurrence rates vary significantly among disease subtypes

PPP is the form of pustular psoriasis most influenced by sex and smoking status

Definition of a patient subset for genetic analysis

Frequency of IL36RN mutations differentiates PPP from ACH and GPP

CARD14 mutations are observed in only a small minority of cases

AP1S3 mutations occur with comparable frequency across disease types

Discussion

Supported by the Department of Health through the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and comprehensive Biomedical Research Centre awards to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust (guysbrc-2012-1) and to the NIHR-Newcastle Biomedical Research Centre. This work was funded by a Medical Research Council (MRC) Stratified Medicine award (MR/L011808/1; to J.N.B., F.C., and C.H.S.) and by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (grant EME 13/50/17 to C.H.S., F.C., J.N.B., C.E.M.G., and N.R.). N.R. is also supported by the Newcastle MRC/EPSRC Molecular Pathology Node. S.T. is supported by the King's Bioscience Institute and the Guy's and St Thomas' Charity Prize PhD Programme in Biomedical and Translational Science. The European Rare and Severe Psoriasis Expert Network is funded by a PPRC grant from the European Association of Dermatology and Venereology (EADV; to A.A.N. and J.N.B.). The views expressed in this publication are those of the authors and not necessarily those of the MRC, NHS, NIHR, or Department of Health.