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.
| Original language | English |
|---|---|
| Pages (from-to) | 1021-1026 |
| Number of pages | 6 |
| Journal | The Journal of Allergy and Clinical Immunology |
| Volume | 143 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2019 |
Keywords
- acrodermatitis continua of Hallopeau
- AP1S3
- Generalized pustular psoriasis
- genotype-phenotype correlation
- IL36RN
- palmoplantar pustulosis
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
Clinical and genetic differences between pustular psoriasis subtypes. / Twelves, Sophie; Mostafa, Alshimaa; Dand, Nick et al.
In: The Journal of Allergy and Clinical Immunology, Vol. 143, No. 3, 03.2019, p. 1021-1026.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Clinical and genetic differences between pustular psoriasis subtypes
AU - Twelves, Sophie
AU - Mostafa, Alshimaa
AU - Dand, Nick
AU - Burri, Elias
AU - Farkas, Katalin
AU - Wilson, Rosemary
AU - Cooper, Hywel L.
AU - Irvine, Alan D.
AU - Oon, Hazel H.
AU - Kingo, Külli
AU - Köks, Sulev
AU - Mrowietz, Ulrich
AU - Puig, Luis
AU - Reynolds, Nick
AU - Tan, Eugene Sern Ting
AU - Tanew, Adrian
AU - Torz, Kaspar
AU - Trattner, Hannes
AU - Valentine, Mark
AU - Wahie, Shyamal
AU - Warren, Richard B.
AU - Wright, Andrew
AU - Bata-Csörgő, Zsuzsa
AU - Szell, Marta
AU - Griffiths, Christopher E.M.
AU - Burden, A. David
AU - Choon, Siew Eng
AU - Smith, Catherine H.
AU - Barker, Jonathan N.
AU - Navarini, Alexander A.
AU - Capon, Francesca
N1 - Funding Information: The purpose of our study was to robustly define clinical and genetic features of pustular psoriasis by investigating a patient cohort of unprecedented size. Initially, we sought to define the presentation of the various clinical variants through a rigorous statistical analysis of key phenotypic features. This work, which builds on the definition of consensus diagnostic criteria by ERASPEN, 1 underscores the importance of collaborative efforts in the analysis of rare diseases. Here a common case report form was used in all prospectively recruited cases, enabling standardized patient phenotyping and robust data collection. The participation of multiple centers also allowed us to monitor the effects of ascertainment bias and show that key patients’ demographics were comparable across the various data sets. Our analysis demonstrated novel and significant differences between disease subtypes. Specifically, it showed that PPP is associated with patients’ demographics (very high prevalence of female subjects and smokers), clinical (low rates of PV) and genetic features (low prevalence of IL36RN mutations) that are clearly distinct from those observed in ACH and GPP. Given that abnormal IL-36 signaling has now been implicated in the pathogenesis of plaque psoriasis, 22 it is tempting to speculate that these observations might be correlated with each other and that the decreased prevalence of PV in PPP might be linked to the low frequency of deleterious IL36RN alleles in this patient group. We also found that IL36RN mutations are associated with an earlier age of onset across all variants of pustular psoriasis. This validates the results we obtained originally in patients with GPP 4 and indicates that IL36RN should be prioritized for mutation screening when patients have disease symptoms before the age of 30 years (40 years in the case of ACH/PPP). Given that biologics that counter the effect of IL36RN mutations by blocking IL-36 signaling are now under development, 23 such targeted screening could have important implications for patient management. Our study showed that IL36RN mutations are the most frequent genetic abnormality observed in pustular psoriasis. In fact, deleterious AP1S3 alleles were found in only 7% to 10% of patients, and CARD14 variants were observed in a very small number of affected subjects. Importantly, our analysis demonstrated that known genes account only for a minority of disease cases. This is especially the case in patients with PPP, in whom the combined frequency of AP1S3 and IL36RN mutations is less than 10%. Therefore additional studies will be needed to illuminate the genetic landscape of this condition, facilitate its diagnosis, and better understand the correlation between genotype and clinical phenotype. Although the discovery of novel genetic determinants has thus far been hindered by the rarity and heterogeneous nature of the disease, the ascertainment and rigorous phenotyping of our clinical resource lays a robust foundation for future gene identification studies. Clinical implications The association between IL36RN mutations and early-onset pustular psoriasis defines a patient group that should be prioritized for IL36RN screening and might benefit from the development of IL-36 inhibitors. We thank the Psoriasis Association for their continued support with patient recruitment. We also thank the following PLUM and APRICOT investigators for their contribution to patient ascertainment: Mahmud Ali (Worthing Hospital, Worthing, United Kingdom), Suzannah August (Poole Hospital, Poole, United Kingdom), Herve Bachelez (AP-HP Saint-Louis Hospital, Paris, France), Anthony Bewley (Whipps Cross University Hospital, London, United Kingdom), John Ingram (Cardiff University, Cardiff, United Kingdom), Susan Kelly (The Royal Shrewsbury Hospital, Shrewsbury, United Kingdom), Mohsen Korshid (Basildon Hospital, Basildon, United Kingdom), Effie Ladoyanni (Russell's Hall Hospital, Dudley, United Kingdom), and John McKenna (Leicester Royal Infirmary, Leicester, United Kingdom). We also thank the following external collaborators, who contributed to patient recruitment outside of the main reference centers: Ivona Aksentijevich (National Institutes of Health, Bethesda, Md), Sibel Dogan (Hacettepe University, Ankara, Turkey), Carlos Ferrándiz (Germans Trias i Pujol Hospital, Barcelona, Spain), Eduardo Fonseca (Complejo Hospitalario Juan Canalejo, Badalona, Spain), Joanna E. Gach (University Hospitals Coventry and Warwickshire, United Kingdom), Maja Mockenhaupt (University of Freiburg, Freiburg, Germany), Jason Pinner (Royal Prince Alfred Hospital, Sidney, Australia), Christa Prins (Geneva University Hospital, Switzerland), Annamarie Ranki (Helsinki University Central Hospital, Helsinki, Finland), Raquel Rivera (Hospital Universitario 12 de Octubre, Madrid, Spain), Marieke M Seyger (Radboud University Medical Center, Nijmegen, The Netherlands), Pere Soler-Palacin (Vall d'Hebron Research Institute, Barcelona, Spain), Eoin R. Storan (Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland), Virginia Sybert (University of Washington, Seattle, Wash), Raül Tortosa (Vall d'Hebron Hospital Research Institute, Barcelona, Spain), and Helen S. Young (the University of Manchester, Manchester, United Kingdom). Funding Information: We thank the Psoriasis Association for their continued support with patient recruitment. We also thank the following PLUM and APRICOT investigators for their contribution to patient ascertainment: Mahmud Ali (Worthing Hospital, Worthing, United Kingdom), Suzannah August (Poole Hospital, Poole, United Kingdom), Herve Bachelez (AP-HP Saint-Louis Hospital, Paris, France), Anthony Bewley (Whipps Cross University Hospital, London, United Kingdom), John Ingram (Cardiff University, Cardiff, United Kingdom), Susan Kelly (The Royal Shrewsbury Hospital, Shrewsbury, United Kingdom), Mohsen Korshid (Basildon Hospital, Basildon, United Kingdom), Effie Ladoyanni (Russell's Hall Hospital, Dudley, United Kingdom), and John McKenna (Leicester Royal Infirmary, Leicester, United Kingdom). We also thank the following external collaborators, who contributed to patient recruitment outside of the main reference centers: Ivona Aksentijevich (National Institutes of Health, Bethesda, Md), Sibel Dogan (Hacettepe University, Ankara, Turkey), Carlos Ferr?ndiz (Germans Trias i Pujol Hospital, Barcelona, Spain), Eduardo Fonseca (Complejo Hospitalario Juan Canalejo, Badalona, Spain), Joanna E. Gach (University Hospitals Coventry and Warwickshire, United Kingdom), Maja Mockenhaupt (University of Freiburg, Freiburg, Germany), Jason Pinner (Royal Prince Alfred Hospital, Sidney, Australia), Christa Prins (Geneva University Hospital, Switzerland), Annamarie Ranki (Helsinki University Central Hospital, Helsinki, Finland), Raquel Rivera (Hospital Universitario 12 de Octubre, Madrid, Spain), Marieke M Seyger (Radboud University Medical Center, Nijmegen, The Netherlands), Pere Soler-Palacin (Vall d'Hebron Research Institute, Barcelona, Spain), Eoin R. Storan (Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland), Virginia Sybert (University of Washington, Seattle, Wash), Ra?l Tortosa (Vall d'Hebron Hospital Research Institute, Barcelona, Spain), and Helen S. Young (the University of Manchester, Manchester, United Kingdom). 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. Publisher Copyright: © 2018 The Authors Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
KW - acrodermatitis continua of Hallopeau
KW - AP1S3
KW - Generalized pustular psoriasis
KW - genotype-phenotype correlation
KW - IL36RN
KW - palmoplantar pustulosis
UR - http://www.scopus.com/inward/record.url?scp=85051522281&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2018.06.038
DO - 10.1016/j.jaci.2018.06.038
M3 - Article
C2 - 30036598
AN - SCOPUS:85051522281
VL - 143
SP - 1021
EP - 1026
JO - The Journal of Allergy and Clinical Immunology
JF - The Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 3
ER -