- María Julia Cura, MD
- Diagnosis, Expert Insights, Quality of Life, Treatment
José-Manuel Carrascosa Carrillo, MD, PhD
University Hospital Germans Trias í Pujol; Autonomous University of Barcelona
Badalona, Spain
IPC Councilor
Palmoplantar pustulosis (PPP) remains one of the most challenging inflammatory diseases encountered in dermatology practice. Although traditionally classified within the psoriasis spectrum, growing clinical and molecular evidence suggests that PPP may represent a distinct disease with its own pathogenic mechanisms and therapeutic challenges. According to the European Rare and Severe Psoriasis Expert Network (ERASPEN) consensus, PPP is defined as a form of pustular psoriasis characterized by sterile pustules affecting the palms and/or soles for more than three months, with or without concomitant psoriasis vulgaris.1
Despite the limited body surface area involved, PPP carries a substantial disease burden. Because lesions occur in high-impact areas such as the hands and feet, patients frequently experience pain, difficulty walking, impaired manual activities, and significant limitations in work and daily life.2 Real-world registry data have shown that PPP may even have a greater impact on quality of life than plaque psoriasis.3
For Dr. José-Manuel Carrascosa, who has extensive clinical experience managing patients with this condition, PPP represents one of the most challenging inflammatory dermatoses encountered in routine practice.
“Historically, we have tended to classify it simply as another variant of psoriasis,” he explains. “However, today there are solid arguments, even beyond the phenotype, to consider it a different entity.”
Rethinking PPP as a Distinct Disease
One of the main reasons to reconsider PPP as a separate entity comes from emerging genetic and molecular data. According to Dr. Carrascosa, PPP does not consistently share the same genetic background typically associated with psoriasis vulgaris.
“Some of the classic psoriasis susceptibility genes are not present in PPP,” he notes. Instead, newer genomic analyses suggest that alternative inflammatory pathways may play an important role.
Among these, the involvement of type 2 immune responses has generated considerable interest. “One of the most interesting findings,” he says, “is the identification of TH2-response pathways and genetic correlations with diseases that are classically mediated by Th2 immunity, such as atopic dermatitis or ulcerative colitis.”
These observations are consistent with recent genetic studies demonstrating associations between PPP and Th2-mediated diseases, as well as evidence suggesting a causal role for cigarette smoking in disease pathogenesis.4 For Dr. Carrascosa, these findings reinforce the view that PPP should not simply be regarded as another variant within the psoriasis spectrum.
A Heterogeneous and Complex Inflammatory Disease
Beyond genetics, immunologic studies also suggest that PPP may involve a more complex inflammatory architecture than previously assumed. While psoriasis vulgaris is strongly driven by the IL-23/Th17 axis, PPP appears to involve several overlapping pathways.
“When we analyze the disease transcriptomically,” Dr. Carrascosa explains, “we see not only Th17 activation but also very strong innate immune activation and this TH2 phenotype.”
This coexistence of multiple inflammatory pathways may help explain why PPP often responds poorly to therapies that are highly effective in plaque psoriasis. In his view, PPP likely represents a heterogeneous inflammatory phenotype, with different pathways dominating in different patients.
“It is very possible that within this mixed phenotype, there are patients in whom one pathway predominates over another,” he says. Unfortunately, clinicians currently lack reliable biomarkers to identify these subgroups or guide therapeutic selection.
Diagnosis in Clinical Practice
Despite the growing mechanistic complexity of PPP, diagnosis remains largely clinical. Dr. Carrascosa notes that a skin biopsy rarely provides decisive information.
“In all my years of practice, I have performed very few biopsies for palmoplantar pustulosis,” he says. “And when I have done them, they rarely showed anything different from what I expected clinically.”
When diagnostic uncertainty exists, he believes infectious causes should often be considered first. “If I have doubts about the diagnosis, it is often more useful to perform a bacterial or fungal culture than a biopsy.”
Histopathology may show mixed inflammatory patterns, including neutrophils, eosinophils, and psoriasiform changes, but these findings are not always specific enough to clarify the diagnosis. Additionally, biopsy procedures in palmoplantar skin can be painful and technically challenging for patients.
Setting Expectations: A Difficult Disease to Treat
For Dr. Carrascosa, one of the most important steps in managing PPP is setting realistic expectations early in the treatment process.
“These patients usually respond worse than we would expect,” he says. “It is a real therapeutic challenge.” In many cases, treatment requires a process of trial and adjustment.
“I usually tell patients from the beginning that we do not have a treatment that can guarantee a fully satisfactory response,” he explains.
A Pragmatic Treatment Strategy
In his clinical practice, Dr. Carrascosa typically begins treatment with potent topical corticosteroids, sometimes applied under occlusion.
“Although it may seem simple, topical corticosteroids can sometimes work,” he notes. While complete remission with topical therapy alone is uncommon, meaningful reductions in lesion severity and symptoms can often be achieved.
If topical therapy proves insufficient, phototherapy, particularly PUVA, may represent the next step when available. Dr. Carrascosa frequently combines PUVA with low-dose acitretin, which he believes may have a synergistic therapeutic effect.
Oral acitretin alone can also be effective in selected cases, while methotrexate remains one of his preferred systemic options.
“Even relatively low doses such as 10 or 12.5 mg weekly can sometimes work quite well,” he explains.
Cyclosporine may also produce good responses in certain patients, although long-term use is often limited by toxicity and drug interactions.
According to Dr. Carrascosa, the relative effectiveness of these broader systemic agents may reflect the complex inflammatory nature of PPP. “Palmoplantar pustulosis is a very transversal disease,” he explains. “Drugs that affect several inflammatory circuits simultaneously may therefore be useful.”
Biologic Therapies: Unpredictable Responses
When biologic therapy becomes necessary, outcomes are often less predictable than in plaque psoriasis.
“If I had to summarize my experience,” Dr. Carrascosa says, “I would say that in palmoplantar pustulosis almost everything can be effective….or can go wrong.”
In his experience, anti-TNF agents and IL-12/23 inhibitors have generally produced disappointing results, and he has occasionally observed paradoxical worsening with anti-TNF therapy.
His best responses, although still inconsistent, have been seen with IL-17 and IL-23 inhibitors. Interestingly, he also notes that apremilast can sometimes perform better than expected in patients with PPP.
Clinical trials support the difficulty of treating this condition, as several systemic and biologic therapies have failed to demonstrate clear superiority over placebo in PPP populations.5
Measuring Response in Localized Disease
Another important challenge lies in how treatment response should be evaluated. Dr. Carrascosa cautions against relying too heavily on traditional psoriasis outcome metrics.
“In localized forms such as palmoplantar disease,” he explains, “either the patient responds or does not respond.”
Because palms and soles represent high-impact areas, improvements that appear meaningful numerically may still leave patients with substantial functional impairment.
For this reason, he often evaluates patients using PPPASI or physician global assessment (PGA), while placing greater emphasis on patient-reported quality of life and functional improvement.
Drug Survival and Future Directions
Treatment responses in PPP can also be unstable over time. According to Dr. Carrascosa, patients may initially respond well but later lose control of the disease.
“Some patients respond very well initially,” he explains, “but suddenly they stop responding and worsen.”
Looking toward future therapeutic strategies, he believes that drugs capable of modulating multiple inflammatory pathways may offer the greatest promise.
“If I had to choose the class of drugs that gives me the most expectations right now,” he says, “it would probably be oral JAK inhibitors.”
Based on his experience with upadacitinib in patients with PPP and concomitant psoriatic arthritis, including cases refractory to multiple biologics, these agents may be particularly useful because they act across several inflammatory pathways simultaneously.6
Recognizing PPP as a Disease Worth Studying
Ultimately, Dr. Carrascosa believes that the most important step forward is simply recognizing PPP as a disease that deserves focused investigation.
“The fact that we have stopped to look at it specifically means that we are on the right path, ” he says.
Advances in transcriptomic and mechanistic research are beginning to shed light on the complex biology underlying PPP. With a deeper understanding of these pathways, future research may finally lead to therapies capable of addressing the unique inflammatory landscape of this challenging disease.
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.
- Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council. Strober B, Ryan C, van de Kerkhof P, et al. J Am Acad Dermatol. 2020;82(1):117-122. doi: 10.1016/j.jaad.2019.08.026.
- 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.
- 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.
- 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.
- 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 Dermatol Treat. 2023;34(1):2280508. doi:10.1080/09546634.2023.2280508.
