Eosinophilic fasciitis after immune checkpoint inhibition: Case report with mechanistic considerations

Checkpoint inhibitors selectively block the main negative regulators of immune responses, especially cytotoxic T lymphocytes (CTLA-1) and programmed cell death 1 (PD-1) or its ligand (PD-L1), and are among the new cancer therapies.1 Adverse autoimmune manifestations can occur owing to the mechanism of persistent T-cell activation against tumor cells and the dysregulation of tissue homeostasis, with arthritis and myositis being the main conditions requiring rheumatological support from oncologists.2 In addition, a growing number of rare clinical conditions with poorly understood etiopathogeneses have been associated with the use of checkpoint inhibitors.2, 3 Although this raises safety concerns, such events can provide valuable insights into disease mechanisms. Here, we report a rare case of eosinophilic fasciitis (EF) following therapy with the immune checkpoint inhibitor pembrolizumab, an anti-PD-1 antibody. Furthermore, we discuss the potential mechanistic considerations linking the immune effects of this drug class to EF pathogenesis. A 49-year-old male patient with no previous comorbidities and a history of dorsal cutaneous melanoma with a positive sentinel lymph node underwent surgical resection of the lesion and adjuvant treatment with the immune checkpoint inhibitor pembrolizumab at a fixed dose of 200 mg every 21 days for four cycles. The patient developed eosinophilia in the peripheral blood (initially 4.67 × 10⁹/L of eosinophils, evolving to eosinophilia of 8.1 × 10⁹/L), myalgia, and fatigue, as well as skin thickening on the forearms, characterizing Groove's sign, during treatment (Figure 1). The patient was screened for connective tissue disease, with negative antibodies and normal inflammatory test results. Magnetic resonance imaging of the musculoskeletal system of the forearms revealed prominent thickening of the fascia (Figure 1). In view of these findings, the diagnosis of EF was made, and it was possible to suspend adjuvant therapy with a checkpoint inhibitor due to the remission of melanoma after surgical resection. Prednisone (1 mg/kg daily) and methotrexate (MTX) 20 mg/week were administered. The patient showed significant improvement, with a notable drop in blood eosinophils (serum eosinophils 0.8 × 10⁹/L and a reduction in myalgia. There was no progression of the skin thickening, maintaining a good response to the instituted therapy and gradually reducing corticosteroid therapy. The patient remains in remission from cancer, with no need for new therapy, and is being monitored by rheumatology to control adverse reactions. The present case, along with previous reports linking immune checkpoint inhibitors to EF,2-4 suggests a possible interplay between two immune pathways already implicated in the pharmacodynamics of this drug class: interleukin (IL)-5-driven eosinophil expansion and CD8+ T cell activation.1, 2, 5 We hypothesized that these pathways might operate in parallel: the first axis, in which eosinophils recruited via IL-5 signaling contribute to early inflammation and fibrogenesis, and the second axis, in which CD8+ T cells drive fibrosis through cytotoxic mechanisms and fibroblast activation. This conceptual model can help frame future research on checkpoint inhibitor-related idiopathic EF. Importantly, this hypothetical construct requires validation by mechanistic and immunophenotypic studies using larger patient cohorts. Alternative explanations such as genetic susceptibility, subclinical autoimmunity, and environmental triggers must also be considered. Observations from immune checkpoint inhibitor-associated events may serve as valuable “windows” into disease pathogenesis, and in rare immune-mediated disorders such as EF, immune-related adverse events can offer unique opportunities to explore underlying biology.1-3 Hanna C. A. dos Santos, Gabriela B. Nicolela, and Alisson Pugliesi jointly contributed to the conception, writing, and revision of this manuscript. Andreza Vertuan, Laís R. G. B. Venâncio, and Ana P. del Rio contributed to the data acquisition, writing, and final revision. All authors have read and approved this version of the manuscript. The authors would like to thank the medical and nursing staff of the Hospital de Clínicas, University of Campinas (UNICAMP), for their support in the management of this case. The authors have no funding to report. The authors declare no conflicts of interest. The patient provided written informed consent for the publication of this case report, in accordance with institutional guidelines and ethical standards. The data supporting the findings of this study are available from the corresponding author upon reasonable request.