Plain Language Summary: JAK inhibitors for the treatment of palmoplantar pustulosis: a narrative review

Palmoplantar pustulosis (PPP) is a chronic, inflammatory skin disease characterized by sterile pustules on the palms and/or soles. These lesions often fissure, causing significant pain, functional impairment and reduced quality of life. The disease predominantly affects women in middle age and is strongly associated with smoking. PPP is challenging to treat as it often responds poorly to conventional treatments, including topical corticosteroids, phototherapy and even many biologics used for psoriasis.

Understanding the pathogenesis

Recent research has revealed that the pathogenesis of PPP is more complex than previously thought. While the TH17–IL-36 axis was considered the primary driver, newer transcriptomic studies have shown a surprising upregulation of TH2-related genes in PPP lesions. This suggests a mixed TH17/TH2 immune profile, which may explain the limited efficacy of therapies that only target a single pathway.

JAKis for the treatment of PPP

Janus kinase inhibitors (JAKis) are a class of small-molecule agents that interrupt intracellular signalling mediated by the JAK–STAT pathway. This pathway is a central hub for multiple cytokines involved in PPP, including those from both the TH17 and TH2 pathways. By blocking this central pathway, JAKis offer a broad effect when modulating the immune system potentially providing a more effective and durable response than targeted biologics.

JAKis for PPP treatments are:

• Tofacitinib (JAK1/JAK3 inhibitor): Several case reports and series demonstrate consistent clinical efficacy, with several patients achieving complete or near-complete remission after failing multiple prior systemic and biologic therapies.

• Upadacitinib (selective JAK1 inhibitor): This agent has shown promising results in a broader patient population, including those with refractory disease. Studies highlight significant reductions in disease severity and quality of life improvements with a potentially more favourable safety profile due to its selectivity.

• Baricitinib (JAK1/JAK2 inhibitor): Case reports indicate rapid clinical improvement, especially in patients with coexisting immune-mediated conditions like rheumatoid arthritis or atopic dermatitis, supporting the shared immunopathogenic mechanism.

• Deucravacitinib (selective TYK2 inhibitor): A phase IV clinical trial is under way to evaluate the efficacy of this highly targeted agent in PPP. Its results will be crucial in determining whether a more selective approach is as effective as broader JAK inhibition.

Clinical implications and future directions

The available evidence, primarily from case reports and small studies, suggests that JAKis are a valuable addition to the drugs available for the treatment of PPP, particularly for patients with severe, treatment-refractory disease. Their ability to target multiple inflammatory pathways simultaneously appears to be a key factor in their success.

However, robust, long-term safety data for JAKis in people with PPP are limited. Clinicians must weigh the potential benefits against the risks of immunosuppression, including infection, thromboembolism and malignancy. Larger, randomized controlled trials are urgently needed to confirm these preliminary findings, establish longterm safety and determine the optimal role of JAKis within existing treatment algorithms for PPP.

Article available at: https://doi.org/10.7573/dic.2025-7-10