Ipilimumab-associated Sweet syndrome in a melanoma patient
Authors: Rachel Gormley, Karolyn Wanat, Rosalie Elenitsas, Julia Giles, Suzanne McGettigan, Lynn Schuchter, Junko Takeshita
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: We read with interest the recently published letter "Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma,"1Kyllo R.L. Parker M.K. Rosman I. Musiek A.C. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma.J Am Acad Dermatol. 2014; 70: e85-e86Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar in that we had a patient with a very similar presentation. A 57-year-old man with stage IIIC (T4b, N3, cM0) melanoma was enrolled in a phase 3 randomized study of adjuvant ipilimumab. Eleven days after his first infusion of ipilimumab, he presented to his oncologist with an itchy rash. He was on no other new medications and denied fever, diarrhea, myalgias, or other systemic symptoms.The patient subsequently presented to the dermatology service 6 weeks after his first dose of ipilimumab with widespread erythematous, edematous papules and plaques, some with pseudovesicular appearance, and scattered pustules on the face, trunk, arms, and dorsal hands (Fig 1). At the time of evaluation, there was no evidence of melanoma progression. Complete blood count was within normal limits without peripheral neutrophilia. Skin biopsies were performed and demonstrated prominent papillary dermal edema with extensive neutrophilic infiltrate extending to the subcutaneous tissue with scattered eosinophils and plasma cells (Fig 2). The histopathologic features were consistent with Sweet syndrome (SS). The patient was treated with oral prednisone, initial dose of 60 mg daily, with rapid improvement. Prednisone was subsequently tapered over 6 weeks with resolution of his skin lesions. He was not re-treated with ipilimumab.Fig 2Sweet syndrome. Histopathology demonstrated spongiosis and prominent papillary dermal edema with a predominantly neutrophilic infiltrate. The inflammatory infiltrate also consisted of many eosinophils with scattered lymphocytes and histiocytes. Periodic−acid Schiff and acid-fast bacilli stains were negative for organisms (not shown). (Hematoxylin and eosin stain; original magnification: ×40.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Ipilimumab has been associated with immune-related inflammatory toxic effects in 80% of patients, including enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google Scholar Ipilimumab-related dermatitis is generally observed within 3 to 4 weeks of starting therapy, often reported as a "maculopapular rash" (47% to 68% of patients).2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google ScholarMore specific reports of adverse dermatologic effects range from milder entities, such as vitiligo and alopecia, to more severe conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis.2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google Scholar, 3Weber J. Thompson J.A. Hamid O. Minor D. Amin A. Ron I. et al.A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma.Clin Cancer Res. 2009; 15: 5591-5598Crossref PubMed Scopus (448) Google Scholar The histopathologic characteristics of ipilimumab-related dermatitis are not yet well-characterized. The few existing reports describe an interface dermatitis (composed of predominately CD8+ T cells), perivascular inflammation, and increased mucin deposition in the papillary and reticular dermis, similar to cutaneous lupus erythematosus.4Hodi F.S. Butler M. Oble D.A. Seiden M.V. Haluska F.G. Kruse A. et al.Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.Proc Natl Acad Sci U S A. 2008; 105: 3005-3010Crossref PubMed Scopus (537) Google ScholarOutside of the report by Kyllo et al,1Kyllo R.L. Parker M.K. Rosman I. Musiek A.C. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma.J Am Acad Dermatol. 2014; 70: e85-e86Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar there was a case of SS in association with ipilimumab observed in a study patient being treated for metastatic ovarian cancer who was receiving ipilimumab as part of a sequential immunotherapy protocol involving vaccination with autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF).4Hodi F.S. Butler M. Oble D.A. Seiden M.V. Haluska F.G. Kruse A. et al.Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.Proc Natl Acad Sci U S A. 2008; 105: 3005-3010Crossref PubMed Scopus (537) Google Scholar However, in this case it is difficult to definitively determine the individual contributions of the patient's solid ovarian malignancy, vaccination with subsequent GM-CSF production, and/or ipilimumab treatment to development of SS.We present another case of SS in a patient with melanoma, temporally related to ipilimumab treatment, which strengthens the potential association. Although difficult to know whether SS occurred as a paraneoplastic phenomenon triggered by the patient's underlying melanoma, as has been once previously reported in the Spanish literature, the timing and onset of SS 11 days after his first dose of ipilimumab, lack of tumor progression, and improvement off the medication suggest ipilimumab as the trigger.5Sanchez Conejo-Mir J. Perez Bernal A. Camacho F. [Acute neutrophilic febrile dermatosis (Sweet syndrome) associated with melanoma].Med Cutan Ibero Lat Am. 1990; 18: 155-158PubMed Google Scholar As ipilimumab treatment for melanoma becomes more widespread, it is important for clinicians to be aware of the potential for development of SS. To the Editor: We read with interest the recently published letter "Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma,"1Kyllo R.L. Parker M.K. Rosman I. Musiek A.C. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma.J Am Acad Dermatol. 2014; 70: e85-e86Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar in that we had a patient with a very similar presentation. A 57-year-old man with stage IIIC (T4b, N3, cM0) melanoma was enrolled in a phase 3 randomized study of adjuvant ipilimumab. Eleven days after his first infusion of ipilimumab, he presented to his oncologist with an itchy rash. He was on no other new medications and denied fever, diarrhea, myalgias, or other systemic symptoms. The patient subsequently presented to the dermatology service 6 weeks after his first dose of ipilimumab with widespread erythematous, edematous papules and plaques, some with pseudovesicular appearance, and scattered pustules on the face, trunk, arms, and dorsal hands (Fig 1). At the time of evaluation, there was no evidence of melanoma progression. Complete blood count was within normal limits without peripheral neutrophilia. Skin biopsies were performed and demonstrated prominent papillary dermal edema with extensive neutrophilic infiltrate extending to the subcutaneous tissue with scattered eosinophils and plasma cells (Fig 2). The histopathologic features were consistent with Sweet syndrome (SS). The patient was treated with oral prednisone, initial dose of 60 mg daily, with rapid improvement. Prednisone was subsequently tapered over 6 weeks with resolution of his skin lesions. He was not re-treated with ipilimumab. Ipilimumab has been associated with immune-related inflammatory toxic effects in 80% of patients, including enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google Scholar Ipilimumab-related dermatitis is generally observed within 3 to 4 weeks of starting therapy, often reported as a "maculopapular rash" (47% to 68% of patients).2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google Scholar More specific reports of adverse dermatologic effects range from milder entities, such as vitiligo and alopecia, to more severe conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis.2Kahler K.C. Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma.J Dtsch Dermatol Ges. 2011; 9: 277-286PubMed Google Scholar, 3Weber J. Thompson J.A. Hamid O. Minor D. Amin A. Ron I. et al.A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma.Clin Cancer Res. 2009; 15: 5591-5598Crossref PubMed Scopus (448) Google Scholar The histopathologic characteristics of ipilimumab-related dermatitis are not yet well-characterized. The few existing reports describe an interface dermatitis (composed of predominately CD8+ T cells), perivascular inflammation, and increased mucin deposition in the papillary and reticular dermis, similar to cutaneous lupus erythematosus.4Hodi F.S. Butler M. Oble D.A. Seiden M.V. Haluska F.G. Kruse A. et al.Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.Proc Natl Acad Sci U S A. 2008; 105: 3005-3010Crossref PubMed Scopus (537) Google Scholar Outside of the report by Kyllo et al,1Kyllo R.L. Parker M.K. Rosman I. Musiek A.C. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma.J Am Acad Dermatol. 2014; 70: e85-e86Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar there was a case of SS in association with ipilimumab observed in a study patient being treated for metastatic ovarian cancer who was receiving ipilimumab as part of a sequential immunotherapy protocol involving vaccination with autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF).4Hodi F.S. Butler M. Oble D.A. Seiden M.V. Haluska F.G. Kruse A. et al.Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.Proc Natl Acad Sci U S A. 2008; 105: 3005-3010Crossref PubMed Scopus (537) Google Scholar However, in this case it is difficult to definitively determine the individual contributions of the patient's solid ovarian malignancy, vaccination with subsequent GM-CSF production, and/or ipilimumab treatment to development of SS. We present another case of SS in a patient with melanoma, temporally related to ipilimumab treatment, which strengthens the potential association. Although difficult to know whether SS occurred as a paraneoplastic phenomenon triggered by the patient's underlying melanoma, as has been once previously reported in the Spanish literature, the timing and onset of SS 11 days after his first dose of ipilimumab, lack of tumor progression, and improvement off the medication suggest ipilimumab as the trigger.5Sanchez Conejo-Mir J. Perez Bernal A. Camacho F. [Acute neutrophilic febrile dermatosis (Sweet syndrome) associated with melanoma].Med Cutan Ibero Lat Am. 1990; 18: 155-158PubMed Google Scholar As ipilimumab treatment for melanoma becomes more widespread, it is important for clinicians to be aware of the potential for development of SS.