Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70–90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.

Background: The incidence of severe immune-related hepatitis (irHepatitis) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 under combination therapy with ipilimumab and nivolumab ranges from 15% to 20%. Current clinical guidelines recommend initiating treatment with systemic corticosteroids, followed by second-line immunosuppressants such as mycophenolate mofetil. In contrast, the use of the tumor necrosis factor-α antibody infliximab—commonly administered for other immune-related adverse events such as colitis—is generally not recommended for irHepatitis. A recent single-center study, however, reported the use of infliximab for steroid-refractory irHepatitis in 10 patients without signs of infliximab-associated hepatotoxicity and overall favorable efficacy. This multicenter retrospective analysis aimed to evaluate the safety and efficacy of infliximab in patients with steroid-refractory irHepatitis. Methods: A total of 28 patients with advanced cutaneous melanoma and irHepatitis during immune checkpoint inhibitor (ICI) therapy were included from five university hospitals in Germany and one in Belgium. Of these, 27 patients were in American Joint Committee on Cancer stage IV (8th edition). Results: All patients received ipilimumab plus nivolumab. The Eastern Cooperative Oncology Group performance status was 0 in 75.0% of patients, and nearly all (27/28) developed severe irHepatitis of CTCAE grade 3 or 4 (V.5.0). The median time to onset of irHepatitis was 46 days after first ICI administration. 96.4% of patients were initially treated with systemic corticosteroids. The median interval between onset of irHepatitis and the first dose of infliximab was 23 days. Infliximab was administered intravenously at a dose of 5 mg/kg. 22 patients received one dose, while 6 patients received two doses. In 82.1% of patients, corticosteroids were tapered to less than 5 mg prednisolone equivalent within a median period of 75 days. Clinical remission for irHepatitis (≤CTCAE grade 1) was achieved in 92.9% of patients and was reached after a median time of 21 days following the first infliximab administration. During a median follow-up of 349 days, no deaths or drug-induced liver injury attributable to infliximab were observed. Conclusion: In this retrospective analysis, infliximab appeared to be effective and safe for the treatment of steroid-refractory irHepatitis, with no evidence of hepatotoxicity.

Background: Immune checkpoint inhibitor-induced immune-related adverse events (irAEs) can be steroid-refractory (sr) or steroid-dependent (sd), requiring second-line therapy. Evidence guiding optimal management of sr/sd-irAEs while preserving antitumor efficacy is scarce. This study compared extracorporeal photopheresis (ECP) with systemic immunosuppressants (IS) for treatment of sr/sd-irAEs. Methods: This prospective two-arm study included 46 patients (23 ECP, 23 IS) with 12 distinct types of irAEs across 6 tumor entities, all classified as steroid-refractory or steroid-dependent. Toxicities affected the gastrointestinal tract, skin, lung, musculoskeletal system, and serosal membranes, with up to seven prior irAE treatment lines. Patients received six cycles of ECP or investigator’s choice IS over 12 weeks. Longitudinal assessments included clinical irAE outcomes, quality of life (QoL), and tumor response. ECP was more frequently used in patients with multi-toxicity (39% vs 9%; p=0.02) and multi-resistance to prior second-line immunosuppression (39% vs 17%; p=0.19). Results: At week 12, ECP showed a lower cumulative corticosteroid exposure (395 mg vs 1,260 mg prednisolone equivalent; p=0.03), significantly improved QoL (p=0.01), and a numerically higher irAE response rate without statistical significance compared with IS (94% vs 81%; p=0.85). In advanced cutaneous melanoma, ECP was associated with superior overall survival (15 vs 10 months; p=0.02), and longer progression-free survival (9 vs 3 months; p=0.01). No significant safety concerns were observed with ECP; one fatality in the IS group was infection-related. Conclusions: ECP demonstrated clinical outcomes comparable to IS in sr/sd-irAEs, with significantly lower cumulative corticosteroid exposure and improved QoL. Furthermore, ECP was associated with a favorable safety profile and showed no evidence of compromised antitumor activity. A multicenter trial is planned for further investigation. Trial registration number: NCT05700565 .