Tyrosine Kinase 2 Inhibition for Refractory Pityriasis Rubra Pilaris in Two Cases

Pityriasis rubra pilaris (PRP) is a rare, chronic, immune-mediated papulosquamous dermatosis characterized by keratotic follicular papules, coalescing orange-red scaly plaques with distinctive “islands of sparing,” and palmoplantar keratoderma. Clinical presentation ranges from limited involvement of extensor surfaces to generalized erythroderma, which can be associated with skin tightness, ectropion, pruritus, burning, and pain [1]. Current systemic approaches include retinoids, immunosuppressants, and biologics targeting tumor necrosis factor-α, interleukin (IL)-17, and IL-12/23, with partial efficacy [2]. We report two individual cases of PRP that responded well to tyrosine kinase 2 (TYK2) inhibitor deucravacitinib after failure of IL-17A blockers. Patient 1 was a woman in her 60s who presented with a 3-week history of keratotic, follicular papules coalescing into salmon-red plaques on the head, face, trunk, and extremities with scattered islands of sparing, covered by thick silvery-white scales and accompanied by palmoplantar keratoderma (Figure 1A). Clinical presentation was consistent with type I PRP. Skin biopsy showed hyperkeratosis with focal parakeratosis in a checkerboard pattern and elongation of the rete ridge. Due to the patient's high body mass index (28.4) and potential for acitretin-related metabolic adverse effects, she declined classical systemic therapies. IL-17A blocker vunakizumab, 240 mg every 2 weeks, was initially administered. However, after 1 month, continued expansion of skin lesions was observed, accompanied by worsened pruritus (Psoriasis Area and Severity Index (PASI) of 19.4 to 25, numeric rating scale (NRS) score for usual itch over the past week of 5 to 7, and Dermatology Life Quality Index (DLQI) of 9 to 14; Figure 1B). Deucravacitinib, 6 mg once daily, was subsequently started. After 3 months, she reported near-complete cutaneous clearance (PASI of 1.8, NRS of 0, DLQI of 1; Figure 1C). Patient 2 was a 17-year-old man with a 7-month history of hyperkeratotic follicular-based papules, scaling erythematous plaques with areas of sparing on the trunk and extremities, along with palmoplantar keratoderma (Figure 2A). He also had a history of neurofibromatosis type 1. Clinical presentation and skin biopsy confirmed type III PRP. Prior acitretin therapy for 2 months was discontinued due to inadequate efficacy. Vunakizumab, 240 mg, was administered at Weeks 0, 2, 4, and then every 4 weeks. After 4 months of treatment, residual plaques remained on the chest and knees (Figure 2B). Two months after switching to deucravacitinib, he reported more than 90% improvement (PASI of 7.8 to 0.4, NRS of 3 to 0, DLQI of 6 to 1; Figure 2C). Although evidence suggests a potential role for the IL-23/T helper 17 (Th17) axis in PRP [3], the precise molecular mechanisms driving its pathogenesis remain unclear. This knowledge gap is reflected in the variable treatment responses observed among patients. Deucravacitinib, an oral and selective TYK2 inhibitor, targets cytokine signaling pathways involving IL-12, IL-23, type I interferons, and IL-10 [4]. By enhancing the phenotype, epigenetic stability, and function of regulatory T cells (Tregs) while simultaneously preventing the differentiation of naïve CD4+ T cells and Tregs into Th1 and Th17 cells [5], TYK2 inhibition promotes reprogramming of immune homeostasis, which may contribute to durable remission in PRP. Moreover, deucravacitinib binds to the regulatory pseudokinase domain of TYK2, rather than the conserved catalytic domain targeted by Janus kinase 1/2/3 inhibitors [4]. This unique mechanism of action may underlie its favorable safety profile, as observed in these two cases. To our knowledge, this is the first report on the use of deucravacitinib for PRP. These cases provide valuable insights into the pathogenesis of PRP and indicate that deucravacitinib may represent a promising and well-tolerated oral treatment option for patients with refractory PRP. Further studies in large cohorts are warranted to confirm its efficacy for PRP and explore underlying mechanisms. The authors have nothing to report. The patients in this manuscript have given written informed consent to the publication of case details. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.