Upadacitinib Efficacy in Palmoplantar Pustulosis

Photo Credit: Dorin Puha

Upadacitinib efficacy and safety in treating palmoplantar pustulosis (PPP) revealed rapid and sustained pustule clearance with an acceptable safety profile. The researchers also introduced a novel mouse model to further advance PPP research by providing insights into disease mechanisms and potential treatment targets.

Palmoplantar pustulosis is a chronic, inflammatory condition affecting the palms and soles, often resistant to treatment. The study, presented by Yuling Shi, MD, PhD, Shanghai Skin Disease Hospital and Tongji University School of Medicine, Shanghai, China, enrolled 79 participants who were randomized to receive either upadacitinib (15 mg/day) or acitretin (20 mg/day).¹ The primary end point was complete pustule clearance at week 2, while secondary end points included pustule count reduction, PPP Area and Severity Index (PPPASI) responses, and Dermatology Life Quality Index (DLQI) improvement over 4 weeks.

At week 2, complete pustule clearance was observed in 41.9% of the upadacitinib group compared with 10.5% in the acitretin group (P=0.003). By week 4, clearance rates increased to 87.1% for upadacitinib versus 31.6% for acitretin (P<0.001). Upadacitinib also led to significantly higher PPPASI-75 and PPPASI-90 response rates at weeks 2 and 4 and greater improvements in DLQI scores. All participants in the upadacitinib group achieved a pustular count of fewer than 30 by week 2, maintaining this through week 4. All primary and secondary end points were met.

Regarding safety, upadacitinib demonstrated a favorable profile. Common adverse events included acne (19.4%) and headache (12.9%), whereas acitretin was associated with a higher frequency of skin-related side effects, dyslipidemia, and laboratory-detected elevated liver enzymes.

The research team decided to further investigate a potential etiology of PPP: the role of METTL3, an RNA methyltransferase involved in post-transcriptional gene regulation. To this end, they developed a murine model for PPP by inducing Mettl3 deletion in keratinocytes, leading to spontaneous sterile inflammation localized to the palmar-plantar regions. Transcriptomic analysis revealed a significant overlap between differentially expressed genes in this model and human PPP lesions. Furthermore, in vitro human cell culture models indicated that depleting METTL3 regulates immune response of primary keratinocytes. Collectively, the preclinical models provide insights into disease mechanisms and potential treatment targets by involving METTL3 function. Dr. Shi answered a question from the audience, “No, we have not yet tried to treat the mice with upadacitinib, but that is certainly our next step!”

Medical writing support was provided by Dr. Rachel Giles.
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