Therapeutic Approaches to Painful Palmoplantar Keratoderma and Pachyonychia Congenita

Conclusions

• Painful palmoplantar epidermal differentiation disorders have a highly heterogeneous pathogenesis, so treatment should be individualized rather than one-size-fits-all.
• Symptom-directed care such as offloading, barrier repair, wound care, and pain control can substantially improve function and quality of life.
• Capsaicin and botulinum toxin can reduce pain in selected patients, but clinical benefits may be more modest than histologic improvements alone would suggest.
• Disease-modifying approaches that target the underlying molecular pathway, including siRNA, mTOR inhibition, EGFR/TRPV3 blockade, statins, and tapinarof, show real therapeutic promise.
• Combination therapy often appears more effective than single-agent treatment because multiple pathogenic mechanisms contribute to the disease.
• Some repurposed drugs work best when paired with adjunctive therapies, such as keratolytics, to enhance clinical response.
• Topical and localized delivery methods are crucial because many of these treatments are painful, impractical, or limited by systemic toxicity.
• The FDA’s more flexible master-protocol framework could make development of personalized RNA-based therapies for ultra-rare keratin disorders more feasible.
• Clinical trial outcomes show that biologic or molecular improvement does not always translate directly into patient-centered benefit, so meaningful endpoints must reflect symptoms and function.
• Overall, the field is moving toward precision, pathway-based, and combination strategies to optimize outcomes for patients with painful PPK and related pEDDs.