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the buttocks, axillae, and groins and evolved in crops. Besides these nodules, physical examination revealed bridged scars, but no interconnecting tracts. Histologic examination of a skin biopsy and cultures ruled out Crohn disease and an opportunistic infection, respectively. The diagnosis was HS grade II according to the Hurley classification. A 6-month course of oxacillin (2 g/day), followed by a combination of rifampicin (600 mg/day) with clindamycin (600 mg/day) for 9 months were ineffective (Fig 1). In February 2012, Cs was replaced with tacrolimus (2 mg/day) based on the hypothesis of a deleterious effect of Cs on pilosebaceous apparatus and of a potential efficacy of tacrolimus as suggested in another report.2 In November 2012, all inflammatory lesions had disappeared (Fig 2). To our knowledge, this patient is the first case of HS appearing in the setting of organ transplantation. Although a fortuitous association cannot be excluded, considering the patient’s age, the clinical scenario speaks in favor of an iatrogenic origin of HS. Indeed, rare cases of iatrogenic HS have been reported.3 Even if several Cs-responsive cases of HS exist,4 Cs is known to induce hyperplasia of the pilosebaceous apparatus.5 Isotretinoin may also have played an aggravating role. This patient is similar to one suffering from HS for more than 20 years, in whom treatment with Cs had been ineffective.2 He was cured at the age of 40 years, a few months after kidney transplantation, while receiving tacrolimus and mycophenolate mofetil as immunosuppressive treatment. We recently observed another case of HS that appeared within 2 years after transplantation, for which we suggested a switch from Cs to tacrolimus. Although tacrolimus and Cs exert very similar immunosuppressive effects, the former proved more effective than the latter against HS in these cases. This may be due to the fact that tacrolimus exerts fewer effects on the pilosebaceous apparatus. This observation suggests that patients in whom HS develops while on Cs should be switched to tacrolimus. Emilie Ducroux, MD,a Maria Andrea Ocampo, MD,a Jean Kanitakis, MD,a Emmanuel Morelon, MD, PhD,b Denis Jullien, MD, PhD,a Michel Faure, MD, PhD,a and Sylvie Euvrard, MDa Department of Dermatologya and Nephrology and Transplantation,b Edouard Herriot Hospital Group, Hospices Civils de Lyon, Lyon, France Funding sources: None.
Conflict of interests: None declared. Correspondence to: Emilie Ducroux, MD, Department of Dermatology, Edouard Herriot Hospital Group, 5 Place d’Arsonval, 69437 Lyon cedex 03, France E-mail: [email protected] REFERENCES 1. Jemec GB. Hidradenitis suppurativa. N Engl J Med 2012;366:158-64. 2. Arnadottir M, Jonsson E, Jonsson J. Inactivity of hidradenitis suppurativa after renal transplantation. Transplantation 2006; 82:849. 3. Ma L, Dominguez AR, Collins GR, Kia KF, Cockerell CJ. Hidradenitis suppurativa, eruptive melanocytic nevi, and keratosis pilaris-like eruption in a patient treated with vemurafenib. Arch Dermatol 2012;148:1428-9. 4. Blok JL, van Hattem S, Jonkman MF, Horvath B. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol 2013;168:243-52. 5. Leyral C, Beylot-Barry M, Vergier B, Begueret H, Dromer C, Doutre MS, et al. Cyclosporine-induced follicular eruption. Ann Dermatol Venereol 2008;135:58-62. http://dx.doi.org/10.1016/j.jaad.2014.06.031
Ipilimumab-associated Sweet syndrome in a melanoma patient To the Editor: We read with interest the recently published letter ‘‘Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma,’’1 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
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Fig 1. Sweet syndrome. Erythematous and edematous papules and plaques were noted over the trunk, legs, arms, and dorsal hands, some with a pseudovesicular appearance. Views of pseudovesicular lesions on the dorsal hand.
Fig 2. Sweet 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: 340.)
tapered over 6 weeks with resolution of his skin lesions. He was not re-treated with ipilimumab. Ipilimumab has been associated with immunerelated inflammatory toxic effects in 80% of patients, including enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.2 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).2
NOVEMBER 2014
More specific reports of adverse dermatologic effects range from milder entities, such as vitiligo and alopecia, to more severe conditions including StevensJohnson syndrome and toxic epidermal necrolysis.2,3 The histopathologic characteristics of ipilimumabrelated dermatitis are not yet well-characterized. The few existing reports describe an interface dermatitis (composed of predominately CD81 T cells), perivascular inflammation, and increased mucin deposition in the papillary and reticular dermis, similar to cutaneous lupus erythematosus.4 Outside of the report by Kyllo et al,1 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).4 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.5 As ipilimumab treatment for melanoma becomes more widespread, it is important for clinicians to be aware of the potential for development of SS. Rachel Gormley, MD,a Karolyn Wanat, MD,c Rosalie Elenitsas, MD,a Julia Giles, RN,b Suzanne McGettigan, MSN, CRNP, AOCN,b Lynn Schuchter, MD,b and Junko Takeshita, MD, PhDa Department of Dermatologya and Department of Medicine, Hematology Oncology Division,b University of Pennsylvania School of Medicine, Philadelphia; Department of Dermatology,c University of Iowa, Carver College of Medicine, Iowa City Funding sources: None. Disclosure: Dr Elenitsas is associated with Lippincott Williams & Wilkins. Dr Schuchter receives Bristol Myers Squibb support for clinical trials. The other authors declared no conflicts of interest.
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Correspondence to: Rachel Gormley, MD, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Maloney Building, Philadelphia, PA 19104 E-mail: [email protected] REFERENCES 1. Kyllo RL, Parker MK, Rosman I, Musiek AC. Ipilimumabassociated Sweet syndrome in a patient with high-risk melanoma. J Am Acad Dermatol 2014;70:e85-6. 2. Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011;9:277-86. 3. Weber J, Thompson JA, 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;15:5591-8. 4. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, 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(8):3005-10. 5. Sanchez Conejo-Mir J, Perez Bernal A, Camacho F. [Acute neutrophilic febrile dermatosis (Sweet syndrome) associated with melanoma]. Med Cutan Ibero Lat Am 1990; 18:155-8.
Fig 1. Disseminated cutaneous leishmaniasis in patient with S ezary syndrome. Erythematous papulonodules on the trunk.
http://dx.doi.org/10.1016/j.jaad.2014.06.042
Disseminated cutaneous leishmaniasis in a patient with S ezary syndrome To the Editor: A 66-year-old Caucasian man was diagnosed with S ezary syndrome (SS) in 2007. After chlorambucil, prednisone, and bexarotene treatment, only a partial response was achieved. In May 2012, he was hospitalized with necrotizing pneumonia. He presented with typical features of SS: erythroderma, pruritus, and enlarged lymph nodes. Laboratory studies showed total leukocytes 8.2 3 109/L (normal range: 4-11 3 109/L), 84.5% neutrophils, and 8.2% lymphocytes, of which 35% were S ezary cells. Increased lactate dehydrogenase, 520 U/L (normal range: 250-450 U/L), was also seen. The patient had numerous asymptomatic hyperpigmented macules on his trunk and limbs, which appeared over the previous 6 months. Histopathologic examination of lesions showed acanthosis, epidermotropism, and a mild perivascular atypical lymphoid infiltrate in the upper dermis. Lymphocytes were hyperchromatic, with indented cerebriform nuclei, and expressed CD2, CD3, CD4, and CD5, with partial loss of CD7. Five months later, the patient was readmitted with fever, malaise, and progression of skin lesions. Cutaneous examination revealed numerous widespread erythematous papules and nodules (Fig 1). A
Fig 2. Disseminated cutaneous leishmaniasis in patient with S ezary syndrome. Large numbers of Leishmania amastigotes within the macrophages (arrows). (Hematoxylin and eosin; original magnification: 3640.)
skin biopsy showed a dense lymphohistiocytic infiltrate in the upper and middle dermis with intracellular microorganisms suggestive of Leishmania amastigotes (Fig 2). Disseminated cutaneous leishmaniasis was diagnosed and confirmed by positive polymerase chain reaction for Leishmania infantum. Bone marrow aspirate was negative for Leishmania. Liposomal amphotericin B (4 mg/kg/day intravenously) was given for 10 days without clinical improvement, so treatment was switched to meglumine antimonate (20 mg/kg/day intravenously). After the first dose, the patient’s condition worsened; fever and flare of cutaneous lesions developed. Jarisch-Herxheimer reaction was diagnosed and the
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VOLUME 71, NUMBER 5
the buttocks, axillae, and groins and evolved in crops. Besides these nodules, physical examination revealed bridged scars, but no interconnecting tracts. Histologic examination of a skin biopsy and cultures ruled out Crohn disease and an opportunistic infection, respectively. The diagnosis was HS grade II according to the Hurley classification. A 6-month course of oxacillin (2 g/day), followed by a combination of rifampicin (600 mg/day) with clindamycin (600 mg/day) for 9 months were ineffective (Fig 1). In February 2012, Cs was replaced with tacrolimus (2 mg/day) based on the hypothesis of a deleterious effect of Cs on pilosebaceous apparatus and of a potential efficacy of tacrolimus as suggested in another report.2 In November 2012, all inflammatory lesions had disappeared (Fig 2). To our knowledge, this patient is the first case of HS appearing in the setting of organ transplantation. Although a fortuitous association cannot be excluded, considering the patient’s age, the clinical scenario speaks in favor of an iatrogenic origin of HS. Indeed, rare cases of iatrogenic HS have been reported.3 Even if several Cs-responsive cases of HS exist,4 Cs is known to induce hyperplasia of the pilosebaceous apparatus.5 Isotretinoin may also have played an aggravating role. This patient is similar to one suffering from HS for more than 20 years, in whom treatment with Cs had been ineffective.2 He was cured at the age of 40 years, a few months after kidney transplantation, while receiving tacrolimus and mycophenolate mofetil as immunosuppressive treatment. We recently observed another case of HS that appeared within 2 years after transplantation, for which we suggested a switch from Cs to tacrolimus. Although tacrolimus and Cs exert very similar immunosuppressive effects, the former proved more effective than the latter against HS in these cases. This may be due to the fact that tacrolimus exerts fewer effects on the pilosebaceous apparatus. This observation suggests that patients in whom HS develops while on Cs should be switched to tacrolimus. Emilie Ducroux, MD,a Maria Andrea Ocampo, MD,a Jean Kanitakis, MD,a Emmanuel Morelon, MD, PhD,b Denis Jullien, MD, PhD,a Michel Faure, MD, PhD,a and Sylvie Euvrard, MDa Department of Dermatologya and Nephrology and Transplantation,b Edouard Herriot Hospital Group, Hospices Civils de Lyon, Lyon, France Funding sources: None.
Conflict of interests: None declared. Correspondence to: Emilie Ducroux, MD, Department of Dermatology, Edouard Herriot Hospital Group, 5 Place d’Arsonval, 69437 Lyon cedex 03, France E-mail: [email protected] REFERENCES 1. Jemec GB. Hidradenitis suppurativa. N Engl J Med 2012;366:158-64. 2. Arnadottir M, Jonsson E, Jonsson J. Inactivity of hidradenitis suppurativa after renal transplantation. Transplantation 2006; 82:849. 3. Ma L, Dominguez AR, Collins GR, Kia KF, Cockerell CJ. Hidradenitis suppurativa, eruptive melanocytic nevi, and keratosis pilaris-like eruption in a patient treated with vemurafenib. Arch Dermatol 2012;148:1428-9. 4. Blok JL, van Hattem S, Jonkman MF, Horvath B. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol 2013;168:243-52. 5. Leyral C, Beylot-Barry M, Vergier B, Begueret H, Dromer C, Doutre MS, et al. Cyclosporine-induced follicular eruption. Ann Dermatol Venereol 2008;135:58-62. http://dx.doi.org/10.1016/j.jaad.2014.06.031
Ipilimumab-associated Sweet syndrome in a melanoma patient To the Editor: We read with interest the recently published letter ‘‘Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma,’’1 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
J AM ACAD DERMATOL
e212 Letters
Fig 1. Sweet syndrome. Erythematous and edematous papules and plaques were noted over the trunk, legs, arms, and dorsal hands, some with a pseudovesicular appearance. Views of pseudovesicular lesions on the dorsal hand.
Fig 2. Sweet 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: 340.)
tapered over 6 weeks with resolution of his skin lesions. He was not re-treated with ipilimumab. Ipilimumab has been associated with immunerelated inflammatory toxic effects in 80% of patients, including enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.2 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).2
NOVEMBER 2014
More specific reports of adverse dermatologic effects range from milder entities, such as vitiligo and alopecia, to more severe conditions including StevensJohnson syndrome and toxic epidermal necrolysis.2,3 The histopathologic characteristics of ipilimumabrelated dermatitis are not yet well-characterized. The few existing reports describe an interface dermatitis (composed of predominately CD81 T cells), perivascular inflammation, and increased mucin deposition in the papillary and reticular dermis, similar to cutaneous lupus erythematosus.4 Outside of the report by Kyllo et al,1 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).4 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.5 As ipilimumab treatment for melanoma becomes more widespread, it is important for clinicians to be aware of the potential for development of SS. Rachel Gormley, MD,a Karolyn Wanat, MD,c Rosalie Elenitsas, MD,a Julia Giles, RN,b Suzanne McGettigan, MSN, CRNP, AOCN,b Lynn Schuchter, MD,b and Junko Takeshita, MD, PhDa Department of Dermatologya and Department of Medicine, Hematology Oncology Division,b University of Pennsylvania School of Medicine, Philadelphia; Department of Dermatology,c University of Iowa, Carver College of Medicine, Iowa City Funding sources: None. Disclosure: Dr Elenitsas is associated with Lippincott Williams & Wilkins. Dr Schuchter receives Bristol Myers Squibb support for clinical trials. The other authors declared no conflicts of interest.
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Letters e213
Correspondence to: Rachel Gormley, MD, Department of Dermatology, Hospital of the University of Pennsylvania, 3600 Spruce St, 2 Maloney Building, Philadelphia, PA 19104 E-mail: [email protected] REFERENCES 1. Kyllo RL, Parker MK, Rosman I, Musiek AC. Ipilimumabassociated Sweet syndrome in a patient with high-risk melanoma. J Am Acad Dermatol 2014;70:e85-6. 2. Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011;9:277-86. 3. Weber J, Thompson JA, 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;15:5591-8. 4. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, 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(8):3005-10. 5. Sanchez Conejo-Mir J, Perez Bernal A, Camacho F. [Acute neutrophilic febrile dermatosis (Sweet syndrome) associated with melanoma]. Med Cutan Ibero Lat Am 1990; 18:155-8.
Fig 1. Disseminated cutaneous leishmaniasis in patient with S ezary syndrome. Erythematous papulonodules on the trunk.
http://dx.doi.org/10.1016/j.jaad.2014.06.042
Disseminated cutaneous leishmaniasis in a patient with S ezary syndrome To the Editor: A 66-year-old Caucasian man was diagnosed with S ezary syndrome (SS) in 2007. After chlorambucil, prednisone, and bexarotene treatment, only a partial response was achieved. In May 2012, he was hospitalized with necrotizing pneumonia. He presented with typical features of SS: erythroderma, pruritus, and enlarged lymph nodes. Laboratory studies showed total leukocytes 8.2 3 109/L (normal range: 4-11 3 109/L), 84.5% neutrophils, and 8.2% lymphocytes, of which 35% were S ezary cells. Increased lactate dehydrogenase, 520 U/L (normal range: 250-450 U/L), was also seen. The patient had numerous asymptomatic hyperpigmented macules on his trunk and limbs, which appeared over the previous 6 months. Histopathologic examination of lesions showed acanthosis, epidermotropism, and a mild perivascular atypical lymphoid infiltrate in the upper dermis. Lymphocytes were hyperchromatic, with indented cerebriform nuclei, and expressed CD2, CD3, CD4, and CD5, with partial loss of CD7. Five months later, the patient was readmitted with fever, malaise, and progression of skin lesions. Cutaneous examination revealed numerous widespread erythematous papules and nodules (Fig 1). A
Fig 2. Disseminated cutaneous leishmaniasis in patient with S ezary syndrome. Large numbers of Leishmania amastigotes within the macrophages (arrows). (Hematoxylin and eosin; original magnification: 3640.)
skin biopsy showed a dense lymphohistiocytic infiltrate in the upper and middle dermis with intracellular microorganisms suggestive of Leishmania amastigotes (Fig 2). Disseminated cutaneous leishmaniasis was diagnosed and confirmed by positive polymerase chain reaction for Leishmania infantum. Bone marrow aspirate was negative for Leishmania. Liposomal amphotericin B (4 mg/kg/day intravenously) was given for 10 days without clinical improvement, so treatment was switched to meglumine antimonate (20 mg/kg/day intravenously). After the first dose, the patient’s condition worsened; fever and flare of cutaneous lesions developed. Jarisch-Herxheimer reaction was diagnosed and the
