- María Julia Cura, MD
- Expert Insights, Research, Treatment
A Disease with Marked Geographic Variation
According to the ERASPEN consensus, palmoplantar pustulosis (PPP) is classified as a variant of pustular psoriasis and is characterized by sterile, macroscopically visible pustules affecting the palms and/or soles that persist for more than three months. The disease may occur with or without concomitant psoriasis vulgaris.1
Epidemiological data reveal marked geographic variation in PPP prevalence, with a substantially higher burden in Japan compared with the United States. Estimates indicate approximately 90 cases per 100,000 population in Japan versus 6–9 per 100,000 in the United States, likely reflecting a combination of genetic, environmental, and healthcare-related factors.2
A Persistent Unmet Need
An important aspect to consider is that PPP affects high-impact sites and is associated with greater impairment in quality of life compared with plaque psoriasis.3 Consistently, real-world data demonstrate poor adherence and limited treatment persistence with biologic therapies, likely reflecting suboptimal efficacy and only modest durability, even among interleukin inhibitors.4
Both clinical trials and real-world evidence have been similarly discouraging. Apremilast, etanercept, guselkumab, imsidolimab, and ustekinumab failed to demonstrate significant superiority over placebo in achieving a clear or almost clear Pustulosis Physician Global Assessment response (PPPGA 0/1).5
In a randomized controlled trial, secukinumab failed to meet a robust primary endpoint at week 16, showing only modest improvement over placebo and a limited clinical response.6
Consistent with these findings, most patients treated with deucravacitinib showed no response, and spesolimab did not demonstrate superiority over placebo in PPP.7,8
The Acrosyringium as the Inflammatory Epicenter and a Paradigm Shift
In this psoriasis phenotype, the intraepidermal sweat duct (acrosyringium) has been proposed as the primary inflammatory site, in which both innate and adaptive immune mechanisms are involved. Biopsy studies have demonstrated increased expression of IL-8, IL-1α, IL-1β, IL-17A, IL-17C, IL-17D, IL-17F, IL-22, IL-23A, and the IL-23 receptor. In addition, overexpression of IL-17, IL-8, and IL-36γ has been detected within the acrosyringia.9
However, this classical Th17/IL-23-centered model does not fully account for the limited clinical efficacy of biologic therapies targeting these pathways. More recent evidence supports a more complex and dynamic immune landscape in PPP, characterized by upregulation of Th2-associated pathways, resembling those observed in atopic dermatitis, a condition for which marked clinical responses to dupilumab have been reported in small case series.10 These observations are corroborated by genome-wide association data identifying genetic susceptibility loci implicating Th2-mediated immune responses and demonstrating a significant genetic correlation between PPP and Th2-driven diseases. Moreover, Mendelian randomization analyses provide evidence supporting a causal role of cigarette smoking in PPP pathogenesis 11
In parallel, single-cell and spatial transcriptomic studies have identified a hybrid regulatory Th17 population (regTh17), characterized by co-expression of regulatory markers such as FOXP3, CTLA4, and TIGIT, and by the preferential production of IL-17F and IL-26 rather than IL-17A. These cells display marked plasticity along the Th17–Treg continuum, interact closely with IL-36γ-expressing keratinocytes, and may sustain a pathogenic IL-17F/IL-26–IL-36 inflammatory loop.12 Collectively, these findings support a stage-dependent and highly plastic Th17-driven immune response in PPP, with shifting Th17/Th2, Th17/Th1, and regulatory signatures over time. This dynamic profile distinguishes PPP from plaque psoriasis and underscores the need for therapeutic strategies beyond isolated IL-23/IL-17 blockade 13
Which Target Should We Choose?
Although much remains unknown about the pathophysiology of PPP, growing immunologic insights suggest critical therapeutic implications. Nevertheless, evidence from randomized clinical trials remains limited, with most data originating from small studies or case series. In contrast to other IL-17–targeted therapies, brodalumab, an inhibitor of the IL-17 receptor A, demonstrated clinical efficacy in a randomized clinical trial conducted in Japanese patients with PPP, leading to its regulatory approval in Japan as the first IL-17 pathway-targeted therapy specifically indicated for this condition.14
This observation is likely attributable to receptor blockade inhibiting the activity of multiple IL-17 subclasses. In this context, bimekizumab, which simultaneously inhibits IL-17A and IL-17F, has shown encouraging results, with a case series reporting complete clearance in 17 of 21 patients within one to four months.15
Additionally, Janus kinase (JAK) inhibitors represent a promising therapeutic approach, as they may concurrently modulate Th17- and Th2-driven pathways, as illustrated by reports of patients with PPP successfully treated with upadacitinib.16
The Clinical Dilemma: PPP with Psoriatic Arthritis
As in other psoriasis phenotypes, PPP may be associated with psoriatic arthritis as a comorbidity. It would therefore be pertinent to investigate whether the Th17 plasticity described in the skin also plays a significant role in the development of joint disease.
JAK inhibitors and bimekizumab have been approved for the treatment of psoriatic arthritis since 2021 and 2024, respectively. However, the role of dupilumab in this clinical context remains uncertain, particularly in patients with concomitant PPP and psoriatic arthritis.
Where Do We Go from Here?
The unmet need in the treatment of psoriasis is evident to dermatologists and patients who suffer long-term from its impact. Further surveys on the impact on quality of life, mental health, and, in particular, on daily activities in private life and at work are needed to justify the need to provide highly effective treatments for patients with palmoplantar psoriasis.
Significant knowledge gaps continue to hamper a comprehensive understanding of PPP pathophysiology, particularly regarding disease-aggravating factors, making it challenging for dermatologists to achieve effective, durable disease control in many patients. Recent evidence that targeting the IL-17 receptor or IL-17A, together with IL-17F, results in substantial improvement in the majority of patients in small studies is encouraging and warrants more robust studies.14,15 Also, the small case series showing that dupilumab can be effective, and the positive reports on upadacitinib, require more large-scale clinical trials to advance the treatment of pustulosis palmoplantaris. 10,16
However, for the patient of today, it is important, in anticipation of these clinical trials, to conduct real-world efficacy and safety analyses, capturing treatment outcomes in registries for these promising treatments. With the availability of the broader anti-IL17 treatments (brodalumab and bimekizumab) and Th2-focused treatments in a learning healthcare environment, dermatologists should pioneer new treatment opportunities, paving the way for highly efficient clinical trial programs.
Dermatologists will need expert-driven treatment recommendations to support rapid communication and optimize management strategies and long-term follow-up for patients living with palmoplantar pustulosis, for which no fully satisfactory therapeutic solution currently exists.
Based on recent research insights, novel therapies targeting distinct pathogenic pathways identified through recent advances are likely to emerge in the coming years. Accordingly, the development of IL-17F or IL-26 inhibitors, along with clinical trials evaluating biologic therapies currently used in atopic dermatitis for use in PPP, appears to be a plausible next step.
References
- European Consensus Statement on Phenotypes of Pustular Psoriasis. Navarini AA, Burden AD, Capon F, et al. J Eur Acad Dermatol Venereol. 2017;31(11):1792–1799. doi:10.1111/jdv.14386.
- The Epidemiology of Palmoplantar Pustulosis: An Analysis of Multiple Health Insurance Claims and Electronic Health Records Databases. Ramcharran D, Strober B, Gordon K, et al. Adv Ther. 2023;40(11):5090–5101. doi:10.1007/s12325-023-02669-w.
- Palmoplantar Pustulosis Has a Greater Disease Burden Than Plaque Psoriasis: Real-World Evidence from the CorEvitas Psoriasis Registry. Lebwohl MG, Medeiros RA, Mackey RH, et al. J Psoriasis Psoriatic Arthritis. 2023;8(2):56–65. doi:10.1177/24755303221146990.
- Biologic Treatment Adherence and Persistence in Patients with Palmoplantar Pustulosis: A Real-World, Claims-Based Study. Feldman SR, Gao R, Bohn RL, et al. Adv Ther. 2025;42(4):1994–2002. doi:10.1007/s12325-025-03122-w.
- Small-Molecule Inhibitors and Biologics for Palmoplantar Psoriasis and Palmoplantar Pustulosis: A Systematic Review and Network Meta-Analysis. Huang IH, Wu PC, Chiu HY, et al. Am J Clin Dermatol. 2024;25(3):347–358. doi:10.1007/s40257-024-00849-0.
- Secukinumab for Moderate-to-Severe Palmoplantar Pustular Psoriasis: Results of the 2PRECISE Study. Mrowietz U, Bachelez H, Burden AD, et al. J Am Acad Dermatol. 2019;80(5):1344–1352. doi:10.1016/j.jaad.2019.01.066.
- Exploring the Effect of Deucravacitinib in Patients with Palmoplantar Pustular Psoriasis. De Luca DA, Papara C, Hawro T, et al. J Dermatolog Treat. 2024;35(1):2399220. doi:10.1080/09546634.2024.2399220.
- Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study. Burden AD, Bissonnette R, Navarini AA, et al. Dermatol Ther (Heidelb). 2023;13(10):2279–2297. doi:10.1007/s13555-023-01002-1.
- Recent Advances in Palmoplantar Pustulosis. Brunasso AMG, Massone C, et al. Fac Rev. 2021;10:62. doi:10.12703/r/10-62.
- Efficacy of Dupilumab in Palmoplantar Pustulosis Treatment Highlights the Role of Th2 Inflammation. Zheng YX, Chen XB, Wang ZY, et al. Allergy. 2024;79(5):1361–1364. doi:10.1111/all 16019.
- A Genome-Wide Meta-Analysis of Palmoplantar Pustulosis Implicates TH2 Responses and Cigarette Smoking in Disease Pathogenesis. Hernandez-Cordero A, Thomas L, Smail A, et al. J Allergy Clin Immunol. 2024;154(3):657–665.e9. doi:10.1016/j.jaci.2024.05.015.
- Th17 Cells with Regulatory Phenotype Are the Main IL-17F and IL-26 Producers in Palmoplantar Pustulosis. Do TH, Bogle R, Zhang H, et al. JCI Insight. 2025;10(18):e193038. doi:10.1172/jci.insight.193038.
- Palmoplantar Pustulosis as an Immune-Mediated Inflammatory Disease with a Possible Relevance of Th17 Cell Plasticity: A Narrative Review. Terui T, Murakami M, Okubo Y, et al. Dermatol Ther (Heidelb). 2025;15(4):797–810. doi:10.1007/s13555-025-01382-6.
- Efficacy and Safety of Brodalumab, an Anti-Interleukin-17 Receptor A Monoclonal Antibody, for Palmoplantar Pustulosis: 16-Week Results of a Randomized Clinical Trial. Okubo Y, Kobayashi S, Murakami M, et al. Am J Clin Dermatol. 2024;25(5):837–847. doi:10.1007/s40257-024-00876-x.
- Treatment of Severe Palmoplantar Pustular Psoriasis with Bimekizumab. Passeron T, Perrot JL, Jullien D, et al. JAMA Dermatol. 2024;160(2):199–203. doi:10.1001/jamadermatol. 2023.
- Palmoplantar Pustulosis with Psoriatic Arthritis Ineffective to Interleukin-17 Inhibitors: Two Patients Successfully Treated with Upadacitinib. Zhang ZY, Mi WY, Wang YY, et al. J Dermatolog Treat. 2023;34(1):2280508. doi:10.1080/09546634.2023.2280508.
