Palmoplantar pustulosis (PPP) is a rare chronic inflammatory skin disease characterized by recurrent and/or persistent sterile pustules on the palms and/or soles [1]. The management of PPP is frequently challenging due to the limited understanding of its exact pathogenesis and response to conventional treatments is often unpredictable and inadequate [2]. Recently, there has been an increased interest in exploring the use of Janus kinase 1 (JAK-1) inhibitors, with several studies reporting promising outcomes in patients treated with tofacitinib, a broad-acting JAK-1 inhibitor [3]. We sought to evaluate the efficacy of more selective JAK-1 inhibitors as well as tyrosine kinase 2 (TYK-2) inhibitors for PPP.
We conducted a retrospective review of 10 patients with PPP who were successfully treated with JAK-1 inhibitors and/or TYK-2 inhibitors following failure to respond to conventional treatments. The patients’ baseline demographics and clinical characteristics are summarized in Table 1. 60% of patients were treated with JAK-1 inhibitors and 40% were treated with a TYK-2 inhibitor. The particular treatments used and outcomes at week 16 are detailed in Table 2. 100% of patients, regardless of the agent or dosage administered, reported marked improvement in their condition with semi- or complete clearance of lesions with no adverse events reported.
Table 1
Clinical and demographic characteristics of patients at baseline prior to initiating treatment
Table 2
Description of treatments administered and outcomes
Elevated concentrations of various inflammatory molecules, including IL-8, IL-1a, IL-1b, IL-17, and IL-23, have been observed in biopsies of individuals with PPP. Additionally, higher serum levels of TNF-a, IL-17, IFN-a and IFN-g have been identified in affected patients when compared to healthy individuals [4]. However, biologic agents found to be effective for plaque psoriasis, like IL-17 and IL-23 inhibitors, and for generalized pustular psoriasis (GPP), like IL-36 and IL-1 inhibitors, all display inconsistent efficacy in PPP, suggesting different underlying disease mechanisms [2]. Of particular interest are IFN-g, mediated by JAK-1 and JAK-2, and IFN-a, mediated by JAK-1 and TYK-2 [5]. Also, IL-19 has been reported to be the most elevated cytokine in patients with PPP and may play a role in its pathogenesis. Interestingly, IL-19 is also mediated via JAK-1/TYK-2 [4]. Consequently, reducing IFN-g levels via JAK-1 inhibition (by abrocitinib or upadacitinib), reducing IFN-a levels via TYK-2 inhibition (by deucravacitinib), or reducing IL-19 levels via JAK-1 and/or TYK-2 inhibition (by abrocitinib, upadacitinib, or deucravacitinib) may provide an explanation for the marked improvement observed in our study [5].
Similar results have been reported in a review of 16 cases reporting on outcomes following treatment with tofacitinib. However, the promising outcomes highlighted in the studies are not generalizable to more targeted therapies, as tofacitinib is a broad-acting JAK-1 inhibitor [3]. Thus, our study provides compelling evidence for the efficacy of more selective JAK-1 and TYK-2 inhibitors in the treatment of PPP, especially in cases refractory to conventional treatments.
Future controlled studies evaluating the use of selective JAK-1 and TYK-2 inhibitors in PPP are warranted to help develop a better understanding of what drugs yield the best outcomes, which in turn will provide further insight into the condition’s pathogenesis and guide clinicians towards more effective treatment strategies for patients with PPP.
