A Case of Erythema Multiforme Major Developed after Sequential Use of Two Immune Checkpoint Inhibitors, Nivolumab and Ipilimumab, for Advanced Melanoma: Possible Implication of Synergistic and/or Complementary Immunomodulatory Effects

Abstract

Immune checkpoint inhibitors, such as ipilimumab and nivolumab, reverse the imbalance of antitumor self-tolerance and enhance T-cell responses. Currently, ipilimumab and nivolumab have a reported therapeutic impact on unresectable or metastatic melanomas; however, they also induce immune-related adverse events (irAEs). Ipilimumab-induced cutaneous irAEs are mostly low grade and manageable, although all-grade rash may occur in approximately 45% of all patients. We here report the case of a young woman with erythema multiforme major, which developed after sequential use of these 2 immune checkpoint inhibitors for advanced melanoma of the scalp. Initially, she received 12 cycles of nivolumab monotherapy followed by ipilimumab. A week later, multiple erythematous papulo-erythemas appeared on almost her entire body, with high-grade fever, mucosal involvements, and dyspnea. Immunohistochemistry using the lesioned skin revealed lymphocytic infiltration predominantly positive for CD8, contrasting with those for CD4 and Foxp3. Ipilimumab was stopped but she continued to receive empirical antibiotics; additionally, she was treated with intravenous steroid pulse therapy and immunoglobulin, followed by oral prednisolone. Her symptoms subsided rapidly, allowing a restart of nivolumab monotherapy alone. In our case, the long-standing preceding nivolumab monotherapy may synergistically and/or complementary have contributed to – in combination with the later administration of ipilimumab – recover antigen-responsive T-cell immunity, which is similar to the concept of immune reconstitution inflammatory syndrome, resulting in the establishment of an underlying immunopathology of erythema multiforme and life-threatening airway obstruction.

Oral immune‐related adverse events associated with PD‐1 inhibitor therapy: A case series

“…A number of studies have reported the association of PD‐1 inhibitors with oral lichenoid reactions (Schaberg et al, ; Shi et al, ; Sibaud et al, ), SJS (Saw et al, ), toxic epidermal necrolysis (TEN) (Nayar et al, ), bullous pemphigoid (Jour et al, ), EM (Utsunomiya et al, ), and sicca syndrome (Cappelli et al, ; Teyssonneau, Cousin, & Italiano, ; Warner et al, ). Nevertheless, further characterization of oral lesions and management outcomes warrants study.…”

“…Shi et al reported four out of twenty patients (20%) required temporary discontinuation of PD‐1 inhibitor nivolumab due to cutaneous irAEs, but all patients were able to resume therapy with some form of topical or systemic corticosteroid. Patients who developed autoimmune vesiculobullous disorders, EM, SJS, and TEN were all discontinued from PD‐1 inhibitor therapy (Jour et al, ; Nayar et al, ; Salati et al, ; Saw et al, ; Utsunomiya et al, ).…”

“…Although the use of PD‐1 inhibitors in oncology continues to grow at a rapid rate, there have been scarce descriptions of oral irAEs (Tang et al, ). Thus far, oral irAEs have been shown to include lichenoid reactions, vesiculobullous disorders, erythema multiforme (EM), and Steven–Johnson syndrome (SJS) (Goldinger et al, ; Nayar, Briscoe, & Fernandez Penas, ; Salati et al, ; Saw, Lee, & Ng, ; Schaberg et al, ; Shi et al, ; Sibaud et al, ; Utsunomiya et al, ). Moreover, the association between oral irAEs and the discontinuation of PD‐1 inhibitor therapy and their management strategies and outcomes have not been well‐documented.…”

Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

“…Utsunomiya et al . reported a patient retreated with nivolumab after grade 4 erythema multiforme major . However, they did not recommend retreatment after grade 4 dermatologic toxicities according to NCCN and ESMO guidelines.…”

“…Intravenous immunoglobulin (IVIg) has been used with corticosteroid in patients with immunotherapy‐related erythema multiforme major, myasthenia gravis, Guillain‐Barré syndrome, encephalopathy, peripheral neuropathy, scleroderma, ocular myositis, pancytopenia, and neutropenia . Most irAEs showed improvement, while myasthenia gravis, Guillain‐Barré syndrome, and necrotizing encephalopathy worsened in some patients.…”