Generalized pustular psoriasis induced by an intraductal pancreatic tumour producing <scp>IL</scp> ‐36γ: A case report

We report a case of generalized pustular psoriasis (GPP) associated with an interleukin-36γ (IL-36γ)–producing intraductal papillary mucinous carcinoma (IPMC) of the pancreas. In this case, IL-36γ expression within tumour cells suggested that tumour-derived IL-36γ potentially contributed to disease development. The patient was a 63-year-old woman with no personal or family history of psoriasis. She was admitted for investigation of a pancreatic tumour and received an antibiotic. A few weeks later, she developed erythema on the trunk with malaise. A drug eruption was suspected and prednisolone 20 mg/day was started; however, the eruption rapidly progressed, and generalized erythema with numerous non-follicular pustules appeared (Figure 1a), prompting referral to our department. Laboratory tests showed a temperature of 37.8°C, leukocytosis (15,700/μL; neutrophils 81.9%), elevated C-reactive protein (12.3 mg/dL) and a GPPASI score of 41.6. A drug-induced lymphocyte stimulation test for the antibiotic was negative, and the clinical and histopathological features were more consistent with GPP than acute generalized exanthematous pustulosis. The findings fulfilled the ERASPEN consensus clinicopathological criteria for GPP,1 and GPP was diagnosed. Direct immunofluorescence was not performed, so IgA pemphigus cannot be excluded, but was considered unlikely. Prednisolone was increased to 30 mg/day and etretinate 20 mg/day was added, resulting in improvement of the eruption (Figure 1c). With informed consent and approval from the institutional ethics committee (approval no. HG20-049), targeted Sanger sequencing of IL36RN, CARD14, MPO, AP1S3, SERPINA1, SERPINA3 and BTN3A3 was performed, but no pathogenic variants were identified. Imaging revealed an intraductal pancreatic lesion (Figure 1d,e), and total pancreatectomy was carried out; histopathology confirmed IPMC (Figure 1f). Prednisolone was tapered to 8 mg/day, and no recurrence of GPP was observed over 4 months, after which the patient died of progressive malignancy. GPP is thought to be driven predominantly by dysregulation of the IL-36 pathway.2 In some patients, IL36RN mutations lead to deficiency of the IL-36 receptor antagonist,3, 4 and IL-36 signalling can shape tumour-associated inflammation and promote pro-tumorigenic phenotypes in several cancers.5, 6 Cutaneous manifestations associated with granulocyte colony-stimulating factor–producing tumours are well recognized,7, 8 but the potential for IL-36γ–producing tumours to induce pustular skin disease is less widely appreciated. To investigate the relationship between the tumour and GPP, immunohistochemical staining with an anti–IL-36γ antibody (ab156783; Abcam, UK) showed cytoplasmic positivity in tumour cells (Figure 1g). RNAscope in situ hybridization using the RNAscope Red detection kit (Advanced Cell Diagnostics, CA, USA) performed according to previously published methods and approved under an opt-out policy by the ethics committee (approval no. HM24-292) demonstrated IL-36γ mRNA expression within tumour cells (Figure 1h), indicating that the IPMC was producing IL-36γ. Taken together, the absence of pathogenic variants in IL36RN and related genes and the lack of GPP recurrence after tumour resection suggest that tumour-derived IL-36γ contributed to pathogenesis. An IL-36 receptor–blocking antibody has shown efficacy in GPP,9, 10 supporting the importance of this pathway. We did not use an IL-36 receptor inhibitor because current Japanese guidance generally discourages biologic therapy in patients with active malignancy, and treatment with prednisolone plus etretinate was chosen instead. As a single case report, this study cannot prove causality between tumour-derived IL-36γ and GPP, and no serum samples were stored before or after surgery, precluding retrospective measurement of IL-36γ. Nevertheless, the tumoural IL-36γ expression, the temporal association between tumour resection and GPP remission, and sustained postoperative remission together support the possibility that an IL-36γ–producing tumour acted as a paraneoplastic trigger for GPP. Clinicians should be aware that IL-36γ–producing tumours may elicit pustular skin disease and that underlying malignancy should be considered, particularly in patients with late-onset pustular eruptions. This research was supported by KAKENHI, grant/award number 24K11462 to KS and KAKENHI, grant/award number 22K16292 to SW. All authors declare no conflicts of interest. Genetic testing was conducted with written informed consent obtained during the patient's lifetime under the approval of the institutional ethics committee of Fujita Health University (approval no. HG20-049). RNAscope analysis was approved under the opt-out policy by the same committee (approval no. HM24-292). For genetic testing, written informed consent was obtained during the patient's lifetime. For RNAscope analysis, verbal consent was obtained from the patient during her lifetime. However, consent from the patient's next of kin could not be obtained despite reasonable efforts, and the analysis was therefore conducted under the opt-out policy approved by the institutional ethics committee (approval no. HM24-292). All data have been fully anonymized, and no identifiable personal information is included in the report. The patient in this manuscript has given written informed consent to publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.