Successful Treatment of Post‐Transplant Generalized Pustular Psoriasis With Apremilast

A 55-year-old woman with a medical history of type 1 diabetes mellitus (diagnosed at age 16), colorectal cancer (age 54), and psoriasis vulgaris underwent simultaneous living-donor pancreas-kidney transplantation at the age of 47. Postoperatively, she was maintained on tacrolimus (3 mg/day), mycophenolate mofetil (1 g/day), and methylprednisolone (4 mg/day). During routine post-transplant follow-up, she presented to our dermatology department with erythematous lesions on the trunk (Figure 1a). A skin biopsy confirmed a diagnosis of psoriasis vulgaris (Figure 1b). Two years after the transplantation, she developed generalized fatigue and presented with erythematous, scaly plaques accompanied by small pustules on the trunk and extremities (Figure 1c,e). A repeat skin biopsy revealed subcorneal pustules and spongiform pustules of Kogoj (Figure 1d), confirming a diagnosis of generalized pustular psoriasis (GPP). The Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score at that time was 13.2 points. Given her comorbidities and history of malignancy, biologic agents, which could add immunosuppressive burden, were considered high risk. Thus, apremilast, a PDE4 inhibitor, was chosen. After 8 months, the patient showed marked improvement (Figure 1f,g) with a GPPASI score of 1.2. After temporary discontinuation due to diarrhea, lesions recurred and the score rose to 4.8 (Figure 1h). The mechanism by which psoriasis vulgaris transitions to GPP remains unclear [1]. However, it is possible that long-term immunosuppression with tacrolimus, mycophenolate mofetil, and corticosteroids contributed to a disruption of innate immune responses [2-4]. GPP is known to be associated with genetic alterations, particularly in the IL-36 pathway [1]. Nevertheless, in this case, no pathogenic variants were identified in either IL36RN or CARD14. Chronic immunomodulation may have altered cytokine networks and promoted aberrant IL-36 signaling, leading to neutrophil-dominated inflammation [1]. Although no pathogenic variants in IL36RN or CARD14 were identified, further mechanistic studies are warranted to clarify how chronic immunosuppression might lead to dysregulation of the IL-36 pathway. Immunohistochemical analysis revealed PDE4A labeling in keratinocytes, dermal fibroblasts, and neutrophils in GPP lesions, whereas only minimal staining was detected in normal skin from healthy individuals as controls (Figure 1i,j). These findings suggest that enhanced PDE4A immunoreactivity may be associated with the inflammatory response in this transition. Neutrophils are key effector cells in GPP, and their PDE4A expression supports the hypothesis that PDE4A-mediated signaling contributes to the development and maintenance of neutrophilic inflammation [5]. During long-term immunosuppression after pancreas-kidney transplantation, the altered immune environment may have further increased PDE4A expression or activity, contributing to progression to a more severe pustular phenotype. Apremilast, a PDE4 inhibitor, exerts anti-inflammatory effects by suppressing pro-inflammatory cytokines, including TNF-α and IL-23 [5]. However, evidence supporting its efficacy in GPP, particularly in immunosuppressed individuals, remains limited [2-4]. To our knowledge, there have been no prior reports of GPP after simultaneous pancreas–kidney transplantation successfully treated with apremilast. The marked clinical response may indicate a role for the PDE4-dependent inflammatory pathway in the pathogenesis of GPP and highlights apremilast as a potentially effective and safe systemic therapeutic option for managing psoriasis in immunocompromised settings. The grant number is JP24K11462 (Grant-in-Aid for Scientific Research (C)). https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-24K11462/. Written informed consent was obtained from the patient. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.