Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma

Abstract

To the Editor: Ipilimumab is a biologic anticancer therapy used in the treatment of advanced melanoma. Ipilimumab's antitumor effect stems from CTLA-4 blockade, which results in the nonspecific activation of T cells. Rash is a common side effect of ipilimumab, with all-grade rash occurring in approximately 25% of patients and high-grade rash in 2.4%.1Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis [published online January 25, 2013]. J Am Acad Dermatol doi: 10.1016/j.jaad.2012.12.963.Google Scholar Cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and DRESS have been reported after ipilimumab exposure.2Voskens C.J. Goldinger S.M. Loquai C. Robert C. Kaehler K.C. Berking C. et al.The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.PLoS One. 2013; 8: e53745Crossref PubMed Scopus (352) Google Scholar, 3Weber J.S. Kahler K.C. Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab.J Clin Oncol. 2012; 30: 2691-2697Crossref PubMed Scopus (1061) Google Scholar We present what, to our knowledge, is the first reported case of Sweet syndrome associated with ipilimumab therapy. The patient was a 70-year-old white woman with a history of stage IIIB nodular melanoma. Six months before admission, she underwent wide local excision and lymphadenectomy with no evidence of residual disease. Because of her high risk for recurrence, she elected to enroll in a clinical trial for adjuvant chemotherapy and was randomized to receive infusions of high-dose ipilimumab (10 mg/kg) every 3 weeks. Nineteen days after receiving her fourth ipilimumab infusion, she presented to the hospital with a painful rash (Fig 1) and fever, with temperature of 38.4°C. Cutaneous examination revealed multiple erythematous and tender papules and nodules on her face and upper extremities, as well as pseudovesicular lesions on the lips and oral mucosa. Multiple skin biopsies showed similar histopathologic features of a diffuse dermal neutrophilic infiltrate with cellular debris but no fibrinoid changes of vasculitis (Fig 2). Special stains were negative for microorganisms (fungal, bacterial, acid-fast). The clinical and histopathologic findings were consistent with a diagnosis of Sweet syndrome. She was treated with high-dose intravenous corticosteroids (1.8 mg/kg prednisone equivalent) and dapsone with dramatic clinical improvement. A slow taper of corticosteroids was initiated after 2 weeks of treatment with no resulting rebound.Fig 2Skin biopsy from the arm with a dense dermal neutrophilic infiltrate with cellular debris. Hematoxylin-eosin stain; original magnifications: ×2; inset, ×20.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This case appears to meet criteria for drug-induced Sweet syndrome (DISS), given the abrupt onset of a typical rash, associated fever, features of neutrophilic dermatosis on histopathology, an appropriate temporal relationship with the suspected drug, and the dramatic resolution after systemic corticosteroid therapy. To our knowledge, ipilimumab-induced Sweet syndrome has not been previously reported in the medical literature.1Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis [published online January 25, 2013]. J Am Acad Dermatol doi: 10.1016/j.jaad.2012.12.963.Google Scholar, 2Voskens C.J. Goldinger S.M. Loquai C. Robert C. Kaehler K.C. Berking C. et al.The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.PLoS One. 2013; 8: e53745Crossref PubMed Scopus (352) Google Scholar, 3Weber J.S. Kahler K.C. Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab.J Clin Oncol. 2012; 30: 2691-2697Crossref PubMed Scopus (1061) Google Scholar The development of DISS in a patient receiving immunostimulatory therapy is particularly interesting given the relative paucity of knowledge regarding the pathophysiologic mechanism underlying Sweet syndrome. Historically, Sweet syndrome has been thought of as a hypersensitivity reaction; however, cytokine dysregulation has also been implicated.4Thompson D.F. Montarella K.E. Drug-induced Sweet's syndrome.Ann Pharmacother. 2007; 41: 801-811Crossref Scopus (73) Google Scholar Given the relative novelty of ipilimumab use, it remains to be seen whether CTLA-4 blockade results in an increased risk for DISS over other immune stimulatory therapies.