[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.  Association Between Disease Severity and Age of Onset
Association Between Disease Severity and Age of Onset

A, In the UK cohort, the Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI) score was inversely correlated with age of onset (r = −0.18, P = .01). Regression lines are plotted with their 95% CIs (gray areas). B, In the Northern European sample, age of onset was significantly lower among patients with moderate-to-severe disease. Data are presented as median (interquartile range). P < .05 per Mann-Whitney test. PPPASI measures severity with scores from 0 (no sign of disease) to 72 (very severe disease).

Figure 2.  Disease Severity Scores in Women and Men
Disease Severity Scores in Women and Men

A, In the UK cohort, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI) scores were significantly higher in women than men. Data are presented as median (interquartile range). P < .01 per Mann-Whitney test. B, In the Northern European sample, the proportion of individuals with moderate to severe disease was significantly elevated in women compared with men. P < .05 per Fisher exact test. Physician Global Assessment (PGA) measures severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). PPPASI measures severity with scores from 0 (no sign of disease) to 72 (very severe disease). PPP indicates palmoplantar pustulosis.

Figure 3.  Disease Severity Scores in Current, Former, and Never Smokers
Disease Severity Scores in Current, Former, and Never Smokers

A, In the UK cohort, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI) scores are highest in current smokers, intermediate in former smokers and lowest in never smokers. Data are presented as median (interquartile range). P < .01 per Kruskal-Wallis test. B, In the Northern European sample, the proportion of individuals with moderate to severe disease was elevated in current and former smokers compared with never smokers. Physician Global Assessment (PGA) measures severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). PPPASI measures severity with scores from 0 (no sign of disease) to 72 (very severe disease). PPP indicates palmoplantar pustulosis.

Table.  Features of Study Cohorts
Features of Study Cohorts
1.
Mahil  SK, Barker  JN, Capon  F. Pustular forms of psoriasis related to autoinflammation. In: Hashkes  P, Laxer  R, Simon  A, eds.  Textbook of Autoinflammation. Switzerland: Springer Nature; 2019:471-484. doi:10.1007/978-3-319-98605-0_26
2.
Twelves  S, Mostafa  A, Dand  N,  et al.  Clinical and genetic differences between pustular psoriasis subtypes.   J Allergy Clin Immunol. 2019;143(3):1021-1026. doi:10.1016/j.jaci.2018.06.038 PubMedGoogle ScholarCrossref
3.
Wilsmann-Theis  D, Jacobi  A, Frambach  Y,  et al.  Palmoplantar pustulosis—a cross-sectional analysis in Germany.   Dermatol Online J. 2017;23(4):13030/qt0h15613d.PubMedGoogle Scholar
4.
Kharawala  S, Golembesky  AK, Bohn  RL, Esser  D.  The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review.   Expert Rev Clin Immunol. 2020;16(3):239-252. doi:10.1080/1744666X.2019.1708193 PubMedGoogle ScholarCrossref
5.
Naldi  L, Chatenoud  L, Linder  D,  et al.  Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study.   J Invest Dermatol. 2005;125(1):61-67. doi:10.1111/j.0022-202X.2005.23681.x PubMedGoogle ScholarCrossref
6.
Naldi  L, Peli  L, Parazzini  F.  Association of early-stage psoriasis with smoking and male alcohol consumption: evidence from an Italian case-control study.   Arch Dermatol. 1999;135(12):1479-1484. doi:10.1001/archderm.135.12.1479 PubMedGoogle ScholarCrossref
7.
Navarini  AA, Burden  AD, Capon  F,  et al; ERASPEN Network.  European consensus statement on phenotypes of pustular psoriasis.   J Eur Acad Dermatol Venereol. 2017;31(11):1792-1799. doi:10.1111/jdv.14386PubMedGoogle ScholarCrossref
8.
Trattner  H, Blüml  S, Steiner  I, Plut  U, Radakovic  S, Tanew  A.  Quality of life and comorbidities in palmoplantar pustulosis—a cross-sectional study on 102 patients.   J Eur Acad Dermatol Venereol. 2017;31(10):1681-1685. doi:10.1111/jdv.14187 PubMedGoogle ScholarCrossref
9.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
10.
Cornelius  V, Wilson  R, Cro  S,  et al.  A small population, randomised, placebo-controlled trial to determine the efficacy of anakinra in the treatment of pustular psoriasis: study protocol for the APRICOT trial.   Trials. 2018;19(1):465. doi:10.1186/s13063-018-2841-yPubMedGoogle ScholarCrossref
11.
APRICOT. PLUM: pustular psoriasis, elucidating underlying mechanisms. Accessed August 10, 2020. http://apricot-trial.com/plum/
12.
Brunasso  AM, Puntoni  M, Aberer  W, Delfino  C, Fancelli  L, Massone  C.  Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study.   Br J Dermatol. 2013;168(6):1243-1251. doi:10.1111/bjd.12223 PubMedGoogle ScholarCrossref
13.
Bhushan  M, Burden  AD, McElhone  K, James  R, Vanhoutte  FP, Griffiths  CE.  Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.   Br J Dermatol. 2001;145(4):546-553. doi:10.1046/j.1365-2133.2001.04411.x PubMedGoogle ScholarCrossref
14.
Terui  T, Kobayashi  S, Okubo  Y, Murakami  M, Hirose  K, Kubo  H.  Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial.   JAMA Dermatol. 2018;154(3):309-316. doi:10.1001/jamadermatol.2017.5937 PubMedGoogle ScholarCrossref
16.
WHO Global Health Observatory Data Repository. Published 2013. Accessed April 3, 2020. https://www.who.int/gho/countries/en/
17.
Andersen  YMF, Augustin  M, Petersen  J,  et al.  Characteristics and prevalence of plaque psoriasis in patients with palmoplantar pustulosis.   Br J Dermatol. 2019;181(5):976-982. doi:10.1111/bjd.17832 PubMedGoogle ScholarCrossref
18.
Burden  AD, Kemmett  D.  The spectrum of nail involvement in palmoplantar pustulosis.   Br J Dermatol. 1996;134(6):1079-1082. doi:10.1111/j.1365-2133.1996.tb07946.x PubMedGoogle ScholarCrossref
19.
Ogdie  A, Langan  S, Love  T,  et al.  Prevalence and treatment patterns of psoriatic arthritis in the UK.   Rheumatology (Oxford). 2013;52(3):568-575. doi:10.1093/rheumatology/kes324 PubMedGoogle ScholarCrossref
20.
Coimbra  S, Catarino  C, Santos-Silva  A.  The triad psoriasis-obesity-adipokine profile.   J Eur Acad Dermatol Venereol. 2016;30(11):1876-1885.PubMedGoogle Scholar
21.
Iskandar  IY, Ashcroft  DM, Warren  RB,  et al.  Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register.   Br J Dermatol. 2015;173(2):510-518. doi:10.1111/bjd.13908 PubMedGoogle ScholarCrossref
22.
Timotijević  ZS, Trajković  G, Jankovic  J,  et al.  How frequently does palmoplantar psoriasis affect the palms and/or soles? a systematic review and meta-analysis.   Postepy Dermatol Alergol. 2019;36(5):595-603. doi:10.5114/ada.2019.89508 PubMedGoogle ScholarCrossref
23.
Burden  AD, Kirby  B. Psoriasis and related disorders. In: Griffiths  CEM, Barker  JN, Bleiker  T, Chalmers  RJ, Creamer  D, eds.  Rook’s Textbook of Dermatology. Chichester: Wiley-Blackwell; 2016.
24.
Michaëlsson  G, Gustafsson  K, Hagforsen  E.  The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking.   J Am Acad Dermatol. 2006;54(4):737-738. doi:10.1016/j.jaad.2005.07.024 PubMedGoogle ScholarCrossref
25.
Mrowietz  U, van de Kerkhof  PC.  Management of palmoplantar pustulosis: do we need to change?   Br J Dermatol. 2011;164(5):942-946. doi:10.1111/j.1365-2133.2011.10233.x PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    We Should Know More Clinical and Demographic Factors Related to Palmoplantar Pustulosis
    Liu KeShuai, Graduate student | Beijing University of Chinese Medicine
    Letter to the Editor:
    In an observational, cross-sectional study of two cohorts, Benzian-Olsson N. and colleagues1 observed that there was an connection between the severe palmoplantar pustulosis and female, smoker, low age of disease onset respectively. Their observation highlighted the importance of quitting smoking and the necessity of further studies for palmoplantar pustulosis patients’ demographic factors. However, we have two major methodological concerns.
    Firstly, there are statistically significant differences in smoking habits between males and females. Oktem, A. and colleagues’ study2 showed a higher average number
    of cigarettes in male patients. In this study, participants were divided into three groups including the current smokers, the former smokers, and the never smokers. The authors concluded that smoking aggravated the disease, which followed our clinical experiences and previous studies.2,3 We suggest that the authors compare the severity of the disease between smokers and non-smokers in males and females respectively. This method can not only exclude gender factors and reflect the real impact of smoking on the disease, but also explore whether smoking has the same impact on male and female patients.
    Secondly, there was a large age span for participants, which may interfered with the study results as a confounding factor. Wilsmann-Theis D. and colleagues’ study4 showed that the age at onset of palmoplantar pustulosis was most frequently between 40 and 49, followed by the age range of 50 to 59. Another study showed the median age at onset of the disease is 48.5 Considering the number of subjects is too small to represent the population under 20-year-old, we suggest that all patients be divided into four groups according to age to find whether there are differences in disease severity between them. Besides, the influence of the disease duration for palmoplantar pustulosis shouldn’t be neglected. Maybe the authors should try to explore the co-relationship between the disease duration and the severity of the disease.
    In closing, the study made by Benzian-Olsson N. and his colleagues emphasized the influences of demographic factors on palmoplantar pustulosis, and they urged patients to quit smoking. Meanwhile, they proposed the needs for pilot studies concerning demographic factors.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Views 1,619
    Citations 0
    Original Investigation
    September 16, 2020

    Association of Clinical and Demographic Factors With the Severity of Palmoplantar Pustulosis

    Author Affiliations
    • 1Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    • 2Health Data Research UK, London, United Kingdom
    • 3Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
    • 4Humanitas Clinical and Research Center, IRCCS, Milan, Italy
    • 5Department of Biomedical Sciences, Humanitas University, Milan, Italy
    • 6Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    • 7Portsmouth Dermatology Unit, Portsmouth Hospitals Trust, Portsmouth, United Kingdom
    • 8Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, United Kingdom
    • 9St John's Institute of Dermatology, King's College London, London, United Kingdom
    • 10Dermatology Centre, National Institute for Health Research Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom
    • 11Dermatology Clinic, Tartu University Hospital, Department of Dermatology, University of Tartu, Tartu, Estonia
    • 12Centre for Molecular Medicine and Innovative Therapeutics, Murdoch and Perron Institute for Neurological and Translational Science, Murdoch University, Nedlands, Western Australia, Australia
    • 13National Amyloidosis Centre, University College London, Royal Free Campus, London, United Kingdom
    • 14The Psoriasis Association, Northampton, United Kingdom
    • 15Psoriasis Center at the Department of Dermatology, University Medical Center, Schleswig-Holstein, Campus Kiel, Kiel, Germany
    • 16Department of Dermatology, Royal Liverpool Hospitals, Liverpool, United Kingdom
    • 17Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
    • 18Department of Dermatology and National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
    • 19Department of Dermatology, Medical University of Vienna, Austria
    • 20Department of Dermatology, University Hospital of North Durham, Durham
    • 21The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
    • 22Department of Dermatology, St Lukes Hospital, Bradford, United Kingdom
    • 23Department of Dermatology & Allergy, University Hospital of Basel, Basel, Switzerland
    JAMA Dermatol. Published online September 16, 2020. doi:10.1001/jamadermatol.2020.3275
    Key Points

    Question  Are clinical and demographic factors associated with the severity of palmoplantar pustulosis?

    Findings  In a cross-sectional study of 203 patients in the UK, the Palmoplantar Pustulosis Psoriasis Area Severity Index score was significantly higher in women compared with men and in current smokers vs former and never smokers. Both of these findings were replicated in an independently ascertained, Northern European cohort including 159 patients.

    Meaning  The findings of this study suggest that smoking cessation interventions may be beneficial in patients with palmoplantar pustulosis and should be investigated in clinical studies.

    Abstract

    Importance  Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied.

    Objective  To examine the factors associated with PPP severity.

    Design, Setting, and Participants  An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020.

    Main Outcomes and Measures  Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe).

    Results  Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = −0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14).

    Conclusions and Relevance  The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.

    Introduction

    Palmoplantar pustulosis (PPP) is an uncommon pustular eruption affecting the palms and/or soles. It is observed in approximately 1:2000 individuals of European descent and 1:800 individuals of East Asian descent.1 The disease typically manifests in adulthood, with a median age of onset older than 45 years reported in most studies.2 Palmoplantar pustulosis shows a marked sex bias, with women accounting for 60% to 90% of affected individuals.2,3 The disease is also characterized by an association with cigarette smoking, with up to 90% of patients self-identifying as smokers at the time of diagnosis.2,4-6

    The disease manifests with the eruption of sterile, neutrophil-filled pustules on the palms and soles. The lesions, which can occur on a background of normal or inflamed skin, are persistent (>3 months), painful, and disabling, and can be accompanied by fissures, pruritus, and a burning sensation.7 Comorbidities are also common, as affected individuals are at increased risk of psoriasis vulgaris, psoriatic arthritis, and autoimmune thyroid disease.8

    While PPP can profoundly impact quality of life, the factors underlying variable disease severity have not been investigated. The rarity of the condition has hindered the ascertainment and characterization of adequately powered data sets. In this context, the objective of our study was 2-fold: to evaluate the features of PPP in 2 independent patient cohorts and to examine whether PPP severity is influenced by sex and smoking status—the 2 most well-established risk factors for the disease.1 Given that symptoms typically manifest in adulthood, we also sought to examine whether the presentation of PPP is more severe in early-onset cases.

    Methods
    Patients

    This study was carried out in accordance with the principles of the Declaration of Helsinki9 and with the approval of the participating institutions’ ethics committees. The present study was approved by London Bridge Research ethics committee (London, UK) and Kantonale Ethikkommission (Zurich, Switzerland). All patients granted their informed consent in writing; participants did not receive financial compensation. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. The present study was conducted from October 1, 2014, to March 15, 2020.

    The UK resource included 203 unrelated and prospectively ascertained patients. Forty-two patients were recruited between 2016 and 2019 through Anakinra in Pustular Psoriasis, Response in a Controlled Trial (APRICOT).10 The remaining 161 patients were enrolled between 2016 and 2020 through the sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (PLUM).11 A total of 23 dermatology centers located across the UK were involved in the recruitment.

    The Northern Europe resource included 193 unrelated patients. Affected individuals were mostly enrolled between 2014 and 2017 through 3 centers affiliated with the European Rare and Severe Psoriasis Expert Network (ERASPEN). These centers were in the dermatology departments of the Medical University of Vienna, Austria (n = 100), Tartu University, Estonia (n = 57), and University Medical Centre Schleswig-Holstein, Campus Kiel, Germany (n = 31). The remaining 5 patients were recruited outside the main reference centers by clinicians who provided individual cases to the ERASPEN Consortium.

    Pustular psoriasis was always diagnosed by a dermatologist, based on clinical examination and/or the ERASPEN consensus criteria.7 The observation of sterile, macroscopically visible pustules on palms or soles was the main inclusion criterion. Conversely, the presence of pustules restricted to the edges of psoriatic plaques represented an exclusion criterion. Individuals with concomitant generalized pustular psoriasis or concomitant acrodermatitis continua of Hallopeau were also excluded from the study, given that lesions affecting nails or nonacral skin are deemed incompatible with a diagnosis of PPP.12

    Clinical information and key demographics were collated using a standardized case report form, shared by all centers. In the UK cohort, disease severity was measured using the Palmoplantar Pustulosis Area Severity Index (PPPASI)13 and the Dermatology Life Quality Index (DLQI) (eFigure 1 in the Supplement). The PPPASI measures severity of the disease with scores from 0 (no sign of disease) to 72 (very severe disease). The DLQI measures quality of life with scores ranging from 0 to 30, with higher scores indicating greater impairment. In the Northern European cohort, patients were assessed with the Physician Global Assessment (PGA), which has been shown to correlate with the PPPASI.14 The individuals who recorded clinical data and measured disease severity (reporting dermatologists or trained research nurses) were blinded to the study objectives.

    Statistical Analysis

    Given that different scoring systems were used in the UK and Northern European cohorts, the 2 data sets were analyzed separately. The quantitative PPPASI and DLQI measures obtained in the UK cohort were analyzed using the Mann-Whitney test for binary variables, such as sex, or the Kruskal-Wallis test for categorical variables, such as smoking status. The correlation between PPPASI or DLQI findings and age at onset was assessed using the Spearman rank correlation coefficient. To account for the confounding effects of therapeutic intervention, statistical significance was confirmed by regression analysis. The PPPASI and DLQI values were normalized (square root transformation) and analyzed vs sex, age of onset, or smoking status, using treatment as a covariate.

    To maximize statistical power, the categorical PGA scores recorded in the Northern European data set were dichotomized into clear to mild (including PGA-0 [clear], PGA-1 [almost clear], and PGA-2 [mild]) and moderate to severe (including PGA-3 [moderate] and PGA-4 [severe]). The 2 groups were then compared using the Fisher exact test. Given that the purpose of the PGA analysis was to replicate results showing statistical significance in the UK cohort, P values were computed based on a 1-tailed distribution. As the number of individuals receiving systemic treatment was relatively small (n = 25 from the Medical University of Vienna and 9 from Tartu University), the confounding effect of therapeutic intervention was addressed by excluding these cases from downstream analyses.

    Individuals for whom information on smoking status or age at onset was missing (Table) were excluded from the relevant analyses. All statistical tests were implemented in R, version 3.6.1 (R Project for Statistical Computing). P values <.05 were considered statistically significant.

    Results
    Patient Cohorts

    The features of the UK and Northern European cohorts are summarized in the Table. Among the 203 UK patients (43 men [21%]; 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years). The Northern European cohort comprised 193 patients (32 men [17%]; 161 women [83%]; median age at onset, 45 [IQR, 33-54] years). Of these, 159 patients were available for analysis (25 men [16%]; 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years). All patients were of European descent. The percentage of women (>75%), median age of onset (≥45 years), and prevalence of current and former smokers (>80%) were comparable in the 2 data sets. Prominent nail involvement was observed in both study populations, with more than 30% of patients presenting with at least 1 of the following: pustules involving the nail apparatus, subungual hyperkeratosis, permanent nail loss, and nonpustular nail dystrophy.

    Concurrent psoriasis vulgaris was observed in substantial numbers of study participants (66/203 [33%] UK patients and 22/193 [11%] Northern European cases), while psoriatic arthritis was reported in fewer patients from both cohorts (20/203 [10%] UK cases and 17/193 [9%] Northern European individuals).

    Autoimmune thyroid disease was reported in several affected individuals from both data sets (14 of 203 [7%] of UK cases and 25 of 193 [13%] of Northern European patients). The prevalence of obesity (60 of 150 [40%] in the UK data set and 51 of 193 [26%] in the Northern European sample) was comparable to that observed among the overall population of British (36%),15 German (25%),16 and Estonian (21%)16 adults. In keeping with this observation, no correlation between the body mass index of patients with PPP and their PPPASI was noted (Spearman r = 0.03, P = .61).

    While different scoring systems were used in the 2 cohorts, both included a substantial proportion of individuals with severe PPP, reflecting ascertainment in hospital settings. Specifically, 84 of 203 UK patients (41%) had a PPPASI score greater than 10 and 73 of 193 of their Northern European counterparts (38%) had a PGA score greater than or equal to 3 (Table).

    Disease Severity

    Among UK patients, age at onset was inversely correlated with the PPPASI score (r = −0.18, P = .01) (Figure 1A), although not with DLQI score (r = −0.08, P = .21). The association with the PPPASI score remained significant when the confounding effect of systemic treatment was taken into account by linear regression (P = .04) (eTable in the Supplement). In keeping with these findings, the analysis of the Northern European cohort revealed that the median age at onset was lower in patients with moderate to severe PGA (41 [IQR, 30.5-52] years) compared with those with clear to mild PGA (46.5 [IQR, 35.0-55.0] years) (P = .04) (Figure 1B). Thus, severe PPP appeared to be associated with early disease onset.

    In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) compared with men (4.0 [IQR, 1.0-11.7]) (P = .01) (Figure 2A). The same applied to the median DLQI (women: 10.5 [IQR, 4.3-17] vs men: 4 [IQR, 1-9]; P = 8.2 × 10−5) (eFigure 2 in the Supplement). Both associations were confirmed when systemic treatment was included in a linear regression model (P = .03 for PPPASI, P < .001 for DLQI) (eTable in the Supplement). In agreement with these observations, analysis of the Northern European data set revealed that moderate to severe PPP was more prevalent among women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03) (Figure 2B). Thus, PPP severity appeared to be associated with the sex of the patients in both the UK and Northern European study populations.

    Among the UK patients, the median PPPASI score was highest in current smokers (10.7 [IQR, 4.2-17.5]), intermediate in former smokers (7 [IQR, 2.0-14.4]), and lowest among nonsmokers (2.2 [IQR, 1-6]) (P = .003) (Figure 3A). Comparable findings were obtained when the median DLQI scores were analyzed (current smokers: 10 [IQR, 4.8-16.3] vs former smokers: 9 [IQR, 3-17] vs nonsmokers: 5 [IQR, 1-10.8]) (P = .04) (eFigure 3 in the Supplement). Both associations could be replicated when the effects of systemic treatment were incorporated into a linear model (P = .005 for PPPASI, P = .04 for DLQI) (eTable in the Supplement). The percentage of current smokers (men: 18/43 [42%] and women: 72/160 [45%]) and former smokers (men: 19/43 [44%] and women: 69/160 [43%]) was comparable in the 2 sexes. Moreover, multivariable regression modeling found no evidence that the effect of smoking differed by sex (data available from the authors).

    While the analysis of the smaller Northern European data set did not yield statistically significant results, we observed a similar trend toward increased disease severity in smokers. Moderate to severe PPP was more frequent among current and former smokers (51 of 130 [39%]) than nonsmokers (6 of 24 [25%]) (P = .14) (Figure 3B).

    Discussion

    To our knowledge, this is the first systematic study of the factors associated with PPP severity. This study builds on previous work from our network, which enabled the definition of consensus diagnostic criteria for PPP7 and suggested that the disease is genetically different from other forms of pustular psoriasis.2

    Our investigation noted key epidemiologic features of PPP, such as the late age of onset and sex bias (male-female ratios were >1:3.5 in both cohorts). Psoriasis vulgaris concurrence, which is frequently reported in PPP, was also observed in the 2 data sets. While the prevalence of psoriasis vulgaris in the 2 cohorts was consistent with published estimates (14%-61%),17 the number of individuals with both PPP and psoriasis vulgaris was too small for subgroup analyses, and the use of different scoring systems prevented us from merging the UK and Northern European data sets. Conversely, the study of the entire resource highlighted aspects of PPP that, to our knowledge, had not been systematically investigated before.

    We observed nail involvement in approximately one-third of affected individuals. Subungual pustulation was reported in a similar fraction of cases in a small UK study,18 suggesting that nail abnormalities are a consistent feature of PPP.

    We also report substantial comorbidity with psoriatic arthritis, which was present in both cohorts at a frequency greater than 9%. This percentage exceeds the prevalence of the disease in the general population (0.1%-0.3%).19

    Obesity was relatively uncommon, affecting only one-third of all study participants. This level contrasts with findings obtained in psoriasis vulgaris studies, where the association with obesity is well established20 and up to 42% of individuals with severe disease have a body mass index greater than 30.21

    Overall, these findings suggest that PPP is part of the psoriasis spectrum because the substantial comorbidity with psoriasis vulgaris and psoriatic arthritis points to shared pathogenic pathways. At the same time, the distinctive demographics of PPP suggest the involvement of risk factors that are specific to this disease. For example, the female bias that characterizes PPP is not observed in palmoplantar psoriasis.22 Likewise, psoriasis vulgaris affects both sexes equally23 and occurred with comparable frequency in the male (15/28 [35%]) and female (51/160 [32%]) patients examined in this study (P = .72).

    Our analysis of PPPASI and PGA scores suggests that PPP severity is higher in women vs men. Further experimental studies will be required to dissect the causes of this phenomenon. These sources may involve genetic modifiers or hormonal imbalances that could be targeted for disease treatment.

    Our study also noted an association between cigarette smoking and disease severity that was statistically significant in the UK cohort (P < .01), where PPPASI values were highest in smokers, intermediate in former smokers, and lowest in nonsmokers. This observation suggests a clinically relevant dosage effect that may be validated and refined by analyzing pack-year data in further patient resources.

    Smoking cessation is sometimes applied to the management of PPP and was found to be beneficial in a pilot study.24,25 In this context, our findings suggest that smoking cessation should be systematically investigated in adequately powered trials.

    Limitations

    This study has limitations. The setting was exclusively based in secondary and tertiary referral centers, where the proportion of patients with severe PPP and the burden of comorbid disease may be higher than in other settings. Thus, the potential for ascertainment bias limits the generalizability of our findings.

    Different measures of disease severity were used in the UK (DLQI and PPPASI) and Northern European cohorts (PGA). Although these scales are widely used in clinical practice, our results suggest that the categorical nature of the PGA tool affected the statistical power of the Northern European cohort and limited our ability to apply correlation-based methods. Thus, quantitative measurements, such as the PPPASI, or even more-sensitive methods, such as machine-learning–based pustule counts, should be considered the standard for studies of PPP severity.

    Conclusions

    The findings from this cross-sectional study note the benefits of multicenter collaboration and standardized data collection in the analysis of rare skin diseases. The study also suggests that PPP symptoms are particularly severe in patients with early-onset disease, women, and current smokers. The association between the severity of the disease and smoking will need to be replicated in further data sets; however, the increased severity suggests that smoking cessation interventions may benefit the treatment of PPP.

    Back to top
    Article Information

    Accepted for Publication: June 19, 2020.

    Published Online: September 16, 2020. doi:10.1001/jamadermatol.2020.3275

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Benzian-Olsson N et al. JAMA Dermatology.

    Corresponding Author: Catherine H. Smith, MD, St John’s Institute of Dermatology, King’s College London, London SE1 9RT, United Kingdom (catherine.smith@kcl.ac.uk).

    Author Contributions: Ms Benzian-Olsson and Dr Capon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Benzian-Olsson, Chaloner, Cornelius, Griffiths, Koks, McAteer, Barker, Smith, Capon.

    Acquisition, analysis, or interpretation of data: Benzian-Olsson, Dand, Chaloner, Bata-Csorgo, Borroni, Burden, Cooper, Cro, Dasandi, Griffiths, Kingo, Koks, Lachmann, Meynell, Mrowietz, Parslew, Patel, Pink, Reynolds, Tanew, Torz, Trattner, Wahie, Warren, Wright, Barker, Navarini, Smith, Capon.

    Drafting of the manuscript: Benzian-Olsson, Dand, Chaloner, Kingo, Barker, Smith, Capon.

    Critical revision of the manuscript for important intellectual content: Benzian-Olsson, Dand, Bata-Csorgo, Borroni, Burden, Cooper, Cornelius, Cro, Dasandi, Griffiths, Koks, Lachmann, McAteer, Meynell, Mrowietz, Parslew, Patel, Pink, Reynolds, Tanew, Torz, Trattner, Wahie, Warren, Wright, Barker, Navarini, Smith.

    Statistical analysis: Benzian-Olsson, Dand, Chaloner, Patel.

    Obtained funding: Cornelius, Griffiths, Koks, Smith, Capon.

    Administrative, technical, or material support: Benzian-Olsson, Dand, Chaloner, Bata-Csorgo, Borroni, Burden, Cooper, Dasandi, Koks, Lachmann, McAteer, Meynell, Mrowietz, Parslew, Patel, Pink, Tanew, Torz, Wright, Navarini.

    Supervision: Koks, Pink, Warren, Barker, Smith, Capon.

    Conflict of Interest Disclosures: Dr Borroni reported receiving grants from Celgene Research Award and personal fees from AbbVie outside the submitted work. Dr Burden reported receiving personal fees from Boehringer Ingelheim, Novartis, Celgene, Janssen, AbbVie, and Almirall outside the submitted work. Dr Cro reported receiving grants from the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation during the conduct of the study. Dr Griffiths reported receiving grants from the Medical Research Council (MRC) NIHR during the conduct of the study. Dr Koks reported receiving grants from Estonian Research Council and grants from H2020 ERAchair during the conduct of the study and Prion Ltd, a member of the board and shareholder of the company. Dr McAteer reported receiving grants from AbbVie, Almirral, Amgen, Celgene, Eli Lilly, Janssen, LEO Pharma, UCB, and Thornton and Ross Derma outside the submitted work. Dr Patel reported receiving grants from Efficacy and Mechanism Evaluation (EME) Programme during the conduct of the study. Dr Pink reported receiving personal fees from AbbVie, Lilly, Sanofi, Leo Pharma, Novartis, Almirall, UCB, Janssen, and La Roche-Posay outside the submitted work. Dr Reynolds reported receiving lecture fees from AbbVie (to Newcastle University), payment for medical advisory board meeting and lectures fees from Almirall (to Newcastle University), contributing to a clinical trial from AnaptysBio (to Newcastle upon Tyne Hospital), lecture fees from Celgene to Newcastle University), lecture fees from Janssen (to Newcastle University), grants and serving as a paid member of a medical advisory board from Novartis, and lecture fees from UCB Pharma Ltd (to Newcastle University) outside the submitted work. Dr Wahie reported receiving nonfinancial support from Janssen, AbbVie, Novartis, and Almirall outside the submitted work. Dr Navarini reported receiving grants from EADV during the conduct of the study; grants and personal fees from AbbVie; personal fees from Almirall, Amgen, Eli Lilly, Galderma, Leo Pharma, Novartis, Sanofi, UCB, and Biomed; grants and personal fees from Boehringer Ingelheim; and nonfinancial support from Janssen-Cilag outside the submitted work. Dr Smith reported receiving grants from National Institute for Health Research and nonfinancial support from SOBI during the conduct of the study; grants from Medical Research Council, grants from Boehringer Ingelheim GmbH, grants from Innovative Medicines Initiative Horizon 2020, and grants from Medical Research Council outside the submitted work; and serving as an unpaid guideline committee member for UK and European guidelines for psoriasis, including pustular psoriasis. Dr Capon reported receiving grants from the European Academy of Dermatology and Venereology and MRC/NIHR during the conduct of the study; and grants from Boehringer-Ingelheim and personal fees from AnaptysBio outside the submitted work. No other disclosures were reported.

    Funding/Support: Support for the study was received from the Department of Health via the 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). Support was also received from the Newcastle NIHR Biomedical Research Centre. The APRICOT trial and the PLUM study were funded by the EME Programme, an MRC and NIHR partnership (grant EME 13/50/17 to Drs Smith, Capon, Barker, and Griffiths). This work was supported by the European Academy of Dermatology and Venereology (grant PPRC-2018-25 to Drs Barker, Capon, and Navarini, and grant PPRC-2012-11 to Drs Navarini and Barker). Ms Benzian-Olsson was funded by an NIHR predoctoral fellowship (grant NIHR300473). Dr Dand was funded by Health Data Research UK (MR/S003126/1). Dr Griffiths was funded in part by the NIHR Manchester Biomedical Research Centre and is an NIHR Emeritus Senior Investigator. Dr Reynolds is an NIHR Senior Investigator and receives support from the Newcastle MRC/EPSRC Molecular Pathology Node and the Newcastle NIHR Medtech and In Vitro Diagnostic Co-operative. Dr Warren is supported by the Manchester NIHR Biomedical Research Centre.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Membership of the PLUM and APRICOT Study Team: The following members of the PLUM and APRICOT study team contributed to this work: Mahmud Ali, Worthing Hospital; Nisha Arujuna, Kingston Hospital; Suzannah August, Poole Hospital; David Baudry, Guy’s Hospital, London; A. David Burden, Glasgow Western Infirmary; Hywel Cooper, St Marys Hospital, Portsmouth; Victoria Cornelius, Imperial College London; Suzie Cro, Imperial College London; Giles Dunnill, University Hospitals Bristol; Christopher Griffiths, University of Manchester; John Ingram, University Hospital of Wales; Helen Lachmann, Royal Free Hospital, London; Effie Ladoyanni, Russell’s Hall Hospital, Dudley; Nick Levell, Norfolk & Norwich University Hospital; Areti Makrygeorgou, West Glasgow Ambulatory Care Hospital; Helen McAteer, The Psoriasis Association, Northampton; John McKenna, Leicester Royal Infirmary; Freya Meynell, Guy’s Hospital, London; Richard Parslew, Royal Liverpool; Prakash Patel, Guy’s Hospital, London; Andrew Pink, Guy’s Hospital, London; Angela Pushparajah, Guy’s Hospital, London; Nick Reynolds, Newcastle Hospitals; Catherine Smith, Guy’s Hospital, London; Shyamal Wahie, University Hospital of North Durham and Darlington Memorial Hospital; Richard Warren, Salford Royal Infirmary; Rosemary Wilson, Guy’s Hospital, London; Andrew Wright, St Lukes Hospital, Bradford.

    Membership of the ERASPEN Study Team: The following members of the ERASPEN study team contributed to this work: Zsuzsa Bata-Csorgo, University of Szeged; Riccardo Borroni, Humanitas University, Milan; Ulrich Mrowietz, University Medical Centre Schleswig-Holstein, Campus Kiel, Germany; Raquel Rivera, Hospital Universitario 12 Octubre; Noemi Eiris Salvado, Complejo Asistencial Universitario de Leon; Hannes Trattner, Spezialambulanz für Psoriasis, Vienna.

    Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the MRC, NHS, NIHR, or the Department of Health.

    References
    1.
    Mahil  SK, Barker  JN, Capon  F. Pustular forms of psoriasis related to autoinflammation. In: Hashkes  P, Laxer  R, Simon  A, eds.  Textbook of Autoinflammation. Switzerland: Springer Nature; 2019:471-484. doi:10.1007/978-3-319-98605-0_26
    2.
    Twelves  S, Mostafa  A, Dand  N,  et al.  Clinical and genetic differences between pustular psoriasis subtypes.   J Allergy Clin Immunol. 2019;143(3):1021-1026. doi:10.1016/j.jaci.2018.06.038 PubMedGoogle ScholarCrossref
    3.
    Wilsmann-Theis  D, Jacobi  A, Frambach  Y,  et al.  Palmoplantar pustulosis—a cross-sectional analysis in Germany.   Dermatol Online J. 2017;23(4):13030/qt0h15613d.PubMedGoogle Scholar
    4.
    Kharawala  S, Golembesky  AK, Bohn  RL, Esser  D.  The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review.   Expert Rev Clin Immunol. 2020;16(3):239-252. doi:10.1080/1744666X.2019.1708193 PubMedGoogle ScholarCrossref
    5.
    Naldi  L, Chatenoud  L, Linder  D,  et al.  Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study.   J Invest Dermatol. 2005;125(1):61-67. doi:10.1111/j.0022-202X.2005.23681.x PubMedGoogle ScholarCrossref
    6.
    Naldi  L, Peli  L, Parazzini  F.  Association of early-stage psoriasis with smoking and male alcohol consumption: evidence from an Italian case-control study.   Arch Dermatol. 1999;135(12):1479-1484. doi:10.1001/archderm.135.12.1479 PubMedGoogle ScholarCrossref
    7.
    Navarini  AA, Burden  AD, Capon  F,  et al; ERASPEN Network.  European consensus statement on phenotypes of pustular psoriasis.   J Eur Acad Dermatol Venereol. 2017;31(11):1792-1799. doi:10.1111/jdv.14386PubMedGoogle ScholarCrossref
    8.
    Trattner  H, Blüml  S, Steiner  I, Plut  U, Radakovic  S, Tanew  A.  Quality of life and comorbidities in palmoplantar pustulosis—a cross-sectional study on 102 patients.   J Eur Acad Dermatol Venereol. 2017;31(10):1681-1685. doi:10.1111/jdv.14187 PubMedGoogle ScholarCrossref
    9.
    World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
    10.
    Cornelius  V, Wilson  R, Cro  S,  et al.  A small population, randomised, placebo-controlled trial to determine the efficacy of anakinra in the treatment of pustular psoriasis: study protocol for the APRICOT trial.   Trials. 2018;19(1):465. doi:10.1186/s13063-018-2841-yPubMedGoogle ScholarCrossref
    11.
    APRICOT. PLUM: pustular psoriasis, elucidating underlying mechanisms. Accessed August 10, 2020. http://apricot-trial.com/plum/
    12.
    Brunasso  AM, Puntoni  M, Aberer  W, Delfino  C, Fancelli  L, Massone  C.  Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study.   Br J Dermatol. 2013;168(6):1243-1251. doi:10.1111/bjd.12223 PubMedGoogle ScholarCrossref
    13.
    Bhushan  M, Burden  AD, McElhone  K, James  R, Vanhoutte  FP, Griffiths  CE.  Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.   Br J Dermatol. 2001;145(4):546-553. doi:10.1046/j.1365-2133.2001.04411.x PubMedGoogle ScholarCrossref
    14.
    Terui  T, Kobayashi  S, Okubo  Y, Murakami  M, Hirose  K, Kubo  H.  Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial.   JAMA Dermatol. 2018;154(3):309-316. doi:10.1001/jamadermatol.2017.5937 PubMedGoogle ScholarCrossref
    16.
    WHO Global Health Observatory Data Repository. Published 2013. Accessed April 3, 2020. https://www.who.int/gho/countries/en/
    17.
    Andersen  YMF, Augustin  M, Petersen  J,  et al.  Characteristics and prevalence of plaque psoriasis in patients with palmoplantar pustulosis.   Br J Dermatol. 2019;181(5):976-982. doi:10.1111/bjd.17832 PubMedGoogle ScholarCrossref
    18.
    Burden  AD, Kemmett  D.  The spectrum of nail involvement in palmoplantar pustulosis.   Br J Dermatol. 1996;134(6):1079-1082. doi:10.1111/j.1365-2133.1996.tb07946.x PubMedGoogle ScholarCrossref
    19.
    Ogdie  A, Langan  S, Love  T,  et al.  Prevalence and treatment patterns of psoriatic arthritis in the UK.   Rheumatology (Oxford). 2013;52(3):568-575. doi:10.1093/rheumatology/kes324 PubMedGoogle ScholarCrossref
    20.
    Coimbra  S, Catarino  C, Santos-Silva  A.  The triad psoriasis-obesity-adipokine profile.   J Eur Acad Dermatol Venereol. 2016;30(11):1876-1885.PubMedGoogle Scholar
    21.
    Iskandar  IY, Ashcroft  DM, Warren  RB,  et al.  Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register.   Br J Dermatol. 2015;173(2):510-518. doi:10.1111/bjd.13908 PubMedGoogle ScholarCrossref
    22.
    Timotijević  ZS, Trajković  G, Jankovic  J,  et al.  How frequently does palmoplantar psoriasis affect the palms and/or soles? a systematic review and meta-analysis.   Postepy Dermatol Alergol. 2019;36(5):595-603. doi:10.5114/ada.2019.89508 PubMedGoogle ScholarCrossref
    23.
    Burden  AD, Kirby  B. Psoriasis and related disorders. In: Griffiths  CEM, Barker  JN, Bleiker  T, Chalmers  RJ, Creamer  D, eds.  Rook’s Textbook of Dermatology. Chichester: Wiley-Blackwell; 2016.
    24.
    Michaëlsson  G, Gustafsson  K, Hagforsen  E.  The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking.   J Am Acad Dermatol. 2006;54(4):737-738. doi:10.1016/j.jaad.2005.07.024 PubMedGoogle ScholarCrossref
    25.
    Mrowietz  U, van de Kerkhof  PC.  Management of palmoplantar pustulosis: do we need to change?   Br J Dermatol. 2011;164(5):942-946. doi:10.1111/j.1365-2133.2011.10233.x PubMedGoogle ScholarCrossref
    ×