Flagellate Shiitake Mushroom Reaction With Histologic Features of Acute Generalized Exanthematous Pustulosis

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Flagellate Shiitake Mushroom Reaction With Histologic Features of Acute Generalized Exanthematous Pustulosis
Author(s)
Richard J. Browning, MD
Ramin Fathi, MD
Mahsa A. Smith, MD
Theodore Alkousakis, MD

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

FIGURE 1. Linear, whiplike, red, crisscrossed patches on the lower legs consistent with flagellate dermatitis.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

FIGURE 2. Bright red erythematous patch showing the location of biopsied pustule.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

FIGURE 3. A shave biopsy of the right medial thigh showed spongiotic dermatitis with neutrophilic-predominant subcorneal pustule formation and frequent eosinophils. The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (H&E, original magnification ×10).

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

References
  1. Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
  2. Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
  3. Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
  4. Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
  5. Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
  6. Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
  7. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
  8. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
  9. Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
  10. Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
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Dr. Browning is from Presbyterian St. Luke’s Medical Center, Denver, Colorado. Drs. Fathi, Smith, and Alkousakis are from the Department of Dermatology, University of Colorado Denver School of Medicine, Aurora.

The authors report no conflict of interest.

Correspondence: Richard J. Browning, MD, UCHealth Medical Group, 100 Cook St, Denver, CO 80203 ([email protected]).

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Author(s)
Richard J. Browning, MD
Ramin Fathi, MD
Mahsa A. Smith, MD
Theodore Alkousakis, MD
Author(s)
Richard J. Browning, MD
Ramin Fathi, MD
Mahsa A. Smith, MD
Theodore Alkousakis, MD
Author and Disclosure Information

Dr. Browning is from Presbyterian St. Luke’s Medical Center, Denver, Colorado. Drs. Fathi, Smith, and Alkousakis are from the Department of Dermatology, University of Colorado Denver School of Medicine, Aurora.

The authors report no conflict of interest.

Correspondence: Richard J. Browning, MD, UCHealth Medical Group, 100 Cook St, Denver, CO 80203 ([email protected]).

Author and Disclosure Information

Dr. Browning is from Presbyterian St. Luke’s Medical Center, Denver, Colorado. Drs. Fathi, Smith, and Alkousakis are from the Department of Dermatology, University of Colorado Denver School of Medicine, Aurora.

The authors report no conflict of interest.

Correspondence: Richard J. Browning, MD, UCHealth Medical Group, 100 Cook St, Denver, CO 80203 ([email protected]).

Article PDF
CT108003008_e.PDF
Article PDF
CT108003008_e.PDF

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

FIGURE 1. Linear, whiplike, red, crisscrossed patches on the lower legs consistent with flagellate dermatitis.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

FIGURE 2. Bright red erythematous patch showing the location of biopsied pustule.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

FIGURE 3. A shave biopsy of the right medial thigh showed spongiotic dermatitis with neutrophilic-predominant subcorneal pustule formation and frequent eosinophils. The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (H&E, original magnification ×10).

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

To the Editor:

A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.

Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.

FIGURE 1. Linear, whiplike, red, crisscrossed patches on the lower legs consistent with flagellate dermatitis.

A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.

FIGURE 2. Bright red erythematous patch showing the location of biopsied pustule.

The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.

FIGURE 3. A shave biopsy of the right medial thigh showed spongiotic dermatitis with neutrophilic-predominant subcorneal pustule formation and frequent eosinophils. The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (H&E, original magnification ×10).

Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2

Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.

We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.

References
  1. Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
  2. Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
  3. Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
  4. Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
  5. Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
  6. Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
  7. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
  8. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
  9. Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
  10. Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
References
  1. Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
  2. Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
  3. Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
  4. Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
  5. Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
  6. Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
  7. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
  8. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
  9. Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
  10. Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
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Flagellate Shiitake Mushroom Reaction With Histologic Features of Acute Generalized Exanthematous Pustulosis
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  • Ingestion of shiitake mushrooms and bleomycin is associated with flagellate dermatitis.
  • Acute generalized exanthematous pustulosis (AGEP) is a rare condition associated with certain drug ingestion.
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Remote-Onset Alopecia Areata Attributed to Ipilimumab

Article Type
Article
Changed
Tue, 01/07/2020 - 10:45
Author(s)
David R. Pearson, MD
Karl Lewis, MD
Theodore Alkousakis, MD

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.4 Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25+CD4+ regulatory T cells (Tregs), where it plays a role in immune tolerance.5 Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).6

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,7-10 with 3-year survival rates ranging from 20.8% to 46.5%.10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.12 The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.13 Immune-related adverse effects occur in 64.2% of patients,14 with severe or life-threatening irAEs in 17.8% of patients.14 Rates of irAEs appear dose dependent but consistent across increased doses.15 Cutaneous irAEs occur in more than 47% of patients16 and commonly manifest as pruritus with or without a diffuse morbilliform rash,10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Well-circumscribed, nonscarring alopecia (6 cm) on the right occipital scalp consistent with alopecia areata.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.24

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.27 More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,28 and Megiorni et al29 identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.



Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,12 less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

References
  1. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328:267-270.
  2. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev. 2008;223:143-155.
  3. Buchbinder E, Hodi FS. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J Clin Invest. 2015;125:3377-3383.
  4. Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162:5813-5820.
  5. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-310.
  6. Carroll JM, McElwee KJ, E King L, et al. Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol. 2002;119:392-402.
  7. Weber J, Thompson JA, Hamid O, 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;15:5591-5598.
  8. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
  9. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  10. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  11. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-530.
  12. Yervoy (ipilimumab)[package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019.
  13. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864-872.
  14. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma [abstract]. J Clin Oncol. 2011;29(suppl):8583.
  15. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
  16. Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277-286.
  17. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 2006;142:166-172.
  18. Voskens CJ, Goldinger SM, Loquai 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:E537545.
  19. Assi H, Wilson KS. Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Curr Oncol. 2013;20:E165-E169.
  20. Zarbo A, Belum VR, Sibaud V, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol. 2017;176:1649-1652.
  21. Lakhmiri M, Cavelier-Balloy B, Lacoste C, et al. Nivolumab-induced alopecia areata: a reversible factor of good prognosis? JAAD Case Rep. 2018;4:761-765.
  22. Tan E, Tay YK, Goh CL, et al. The pattern and profile of alopecia areata in Singapore–a study of 219 Asians. Int J Dermatol. 2002;41:748-753.
  23. Goh C, Finkel M, Christos PJ, et al. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol. 2006;20:1055-1060.
  24. Mirzoyev SA, Schrum AG, Davis MD, et al. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol. 2014;134:1141-1142.
  25. Zöller M, McElwee KJ, Engel P, et al. Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata. J Invest Dermatol. 2002;118:983-992.
  26. Zöller M, McElwee KJ, Vitacolonna M, et al. The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells. Exp Dermatol. 2004;13:435-444.
  27. Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466:113-117.
  28. John KK, Brockschmidt FF, Redler S, et al. Genetic variants in CTLA4 are strongly associated with alopecia areata. J Invest Dermatol. 2011;131:1169-1172.
  29. Megiorni F, Mora B, Maxia C, et al. Cytotoxic T-lymphocyte antigen 4 (CTLA4) +49AG and CT60 gene polymorphisms in alopecia areata: a case-control association study in the Italian population. Arch Dermatol Res. 2013;305:665-670
Article PDF
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Author and Disclosure Information

Dr. Pearson is from the Department of Dermatology, University of Minnesota School of Medicine, Minneapolis. Dr. Lewis is from the Division of Medical Oncology, University of Colorado School of Medicine, Aurora. Dr. Alkousakis is from the Colorado Center for Dermatology and Skin Surgery, Denver.

The authors report no conflict of interest.

Correspondence: David R. Pearson, MD, 4-240 Phillips Wangensteen Building, 516 Delaware St SE, MMC 98, Minneapolis, MN 55455 ([email protected]).

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Author(s)
David R. Pearson, MD
Karl Lewis, MD
Theodore Alkousakis, MD
Author(s)
David R. Pearson, MD
Karl Lewis, MD
Theodore Alkousakis, MD
Author and Disclosure Information

Dr. Pearson is from the Department of Dermatology, University of Minnesota School of Medicine, Minneapolis. Dr. Lewis is from the Division of Medical Oncology, University of Colorado School of Medicine, Aurora. Dr. Alkousakis is from the Colorado Center for Dermatology and Skin Surgery, Denver.

The authors report no conflict of interest.

Correspondence: David R. Pearson, MD, 4-240 Phillips Wangensteen Building, 516 Delaware St SE, MMC 98, Minneapolis, MN 55455 ([email protected]).

Author and Disclosure Information

Dr. Pearson is from the Department of Dermatology, University of Minnesota School of Medicine, Minneapolis. Dr. Lewis is from the Division of Medical Oncology, University of Colorado School of Medicine, Aurora. Dr. Alkousakis is from the Colorado Center for Dermatology and Skin Surgery, Denver.

The authors report no conflict of interest.

Correspondence: David R. Pearson, MD, 4-240 Phillips Wangensteen Building, 516 Delaware St SE, MMC 98, Minneapolis, MN 55455 ([email protected]).

Article PDF
CT104006025_e.PDF
Article PDF
CT104006025_e.PDF

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.4 Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25+CD4+ regulatory T cells (Tregs), where it plays a role in immune tolerance.5 Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).6

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,7-10 with 3-year survival rates ranging from 20.8% to 46.5%.10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.12 The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.13 Immune-related adverse effects occur in 64.2% of patients,14 with severe or life-threatening irAEs in 17.8% of patients.14 Rates of irAEs appear dose dependent but consistent across increased doses.15 Cutaneous irAEs occur in more than 47% of patients16 and commonly manifest as pruritus with or without a diffuse morbilliform rash,10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Well-circumscribed, nonscarring alopecia (6 cm) on the right occipital scalp consistent with alopecia areata.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.24

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.27 More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,28 and Megiorni et al29 identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.



Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,12 less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.4 Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25+CD4+ regulatory T cells (Tregs), where it plays a role in immune tolerance.5 Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).6

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,7-10 with 3-year survival rates ranging from 20.8% to 46.5%.10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.12 The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.13 Immune-related adverse effects occur in 64.2% of patients,14 with severe or life-threatening irAEs in 17.8% of patients.14 Rates of irAEs appear dose dependent but consistent across increased doses.15 Cutaneous irAEs occur in more than 47% of patients16 and commonly manifest as pruritus with or without a diffuse morbilliform rash,10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Well-circumscribed, nonscarring alopecia (6 cm) on the right occipital scalp consistent with alopecia areata.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.24

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.27 More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,28 and Megiorni et al29 identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.



Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,12 less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

References
  1. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328:267-270.
  2. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev. 2008;223:143-155.
  3. Buchbinder E, Hodi FS. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J Clin Invest. 2015;125:3377-3383.
  4. Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162:5813-5820.
  5. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-310.
  6. Carroll JM, McElwee KJ, E King L, et al. Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol. 2002;119:392-402.
  7. Weber J, Thompson JA, Hamid O, 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;15:5591-5598.
  8. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
  9. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  10. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  11. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-530.
  12. Yervoy (ipilimumab)[package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019.
  13. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864-872.
  14. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma [abstract]. J Clin Oncol. 2011;29(suppl):8583.
  15. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
  16. Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277-286.
  17. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 2006;142:166-172.
  18. Voskens CJ, Goldinger SM, Loquai 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:E537545.
  19. Assi H, Wilson KS. Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Curr Oncol. 2013;20:E165-E169.
  20. Zarbo A, Belum VR, Sibaud V, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol. 2017;176:1649-1652.
  21. Lakhmiri M, Cavelier-Balloy B, Lacoste C, et al. Nivolumab-induced alopecia areata: a reversible factor of good prognosis? JAAD Case Rep. 2018;4:761-765.
  22. Tan E, Tay YK, Goh CL, et al. The pattern and profile of alopecia areata in Singapore–a study of 219 Asians. Int J Dermatol. 2002;41:748-753.
  23. Goh C, Finkel M, Christos PJ, et al. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol. 2006;20:1055-1060.
  24. Mirzoyev SA, Schrum AG, Davis MD, et al. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol. 2014;134:1141-1142.
  25. Zöller M, McElwee KJ, Engel P, et al. Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata. J Invest Dermatol. 2002;118:983-992.
  26. Zöller M, McElwee KJ, Vitacolonna M, et al. The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells. Exp Dermatol. 2004;13:435-444.
  27. Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466:113-117.
  28. John KK, Brockschmidt FF, Redler S, et al. Genetic variants in CTLA4 are strongly associated with alopecia areata. J Invest Dermatol. 2011;131:1169-1172.
  29. Megiorni F, Mora B, Maxia C, et al. Cytotoxic T-lymphocyte antigen 4 (CTLA4) +49AG and CT60 gene polymorphisms in alopecia areata: a case-control association study in the Italian population. Arch Dermatol Res. 2013;305:665-670
References
  1. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328:267-270.
  2. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev. 2008;223:143-155.
  3. Buchbinder E, Hodi FS. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J Clin Invest. 2015;125:3377-3383.
  4. Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162:5813-5820.
  5. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-310.
  6. Carroll JM, McElwee KJ, E King L, et al. Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol. 2002;119:392-402.
  7. Weber J, Thompson JA, Hamid O, 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;15:5591-5598.
  8. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.
  9. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  10. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  11. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-530.
  12. Yervoy (ipilimumab)[package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019.
  13. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864-872.
  14. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma [abstract]. J Clin Oncol. 2011;29(suppl):8583.
  15. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
  16. Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277-286.
  17. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 2006;142:166-172.
  18. Voskens CJ, Goldinger SM, Loquai 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:E537545.
  19. Assi H, Wilson KS. Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Curr Oncol. 2013;20:E165-E169.
  20. Zarbo A, Belum VR, Sibaud V, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol. 2017;176:1649-1652.
  21. Lakhmiri M, Cavelier-Balloy B, Lacoste C, et al. Nivolumab-induced alopecia areata: a reversible factor of good prognosis? JAAD Case Rep. 2018;4:761-765.
  22. Tan E, Tay YK, Goh CL, et al. The pattern and profile of alopecia areata in Singapore–a study of 219 Asians. Int J Dermatol. 2002;41:748-753.
  23. Goh C, Finkel M, Christos PJ, et al. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol. 2006;20:1055-1060.
  24. Mirzoyev SA, Schrum AG, Davis MD, et al. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol. 2014;134:1141-1142.
  25. Zöller M, McElwee KJ, Engel P, et al. Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata. J Invest Dermatol. 2002;118:983-992.
  26. Zöller M, McElwee KJ, Vitacolonna M, et al. The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells. Exp Dermatol. 2004;13:435-444.
  27. Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466:113-117.
  28. John KK, Brockschmidt FF, Redler S, et al. Genetic variants in CTLA4 are strongly associated with alopecia areata. J Invest Dermatol. 2011;131:1169-1172.
  29. Megiorni F, Mora B, Maxia C, et al. Cytotoxic T-lymphocyte antigen 4 (CTLA4) +49AG and CT60 gene polymorphisms in alopecia areata: a case-control association study in the Italian population. Arch Dermatol Res. 2013;305:665-670
Issue
Cutis - 104(6)
Issue
Cutis - 104(6)
Page Number
E25-E27
Page Number
E25-E27
Publications
MDedge Dermatology
Cutis
Publications
MDedge Dermatology
Cutis
Topics
Hair & Nails
Article Type
Article
Sections
Case Reports
Inside the Article

Practice Points

  • Cutaneous immune-related adverse effects (irAEs) are among the most common adverse effects of ipilimumab, a fully humanized monoclonal antibody directed against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) used to treat advanced-stage melanoma.
  • Alopecia areata is a rarely reported irAE, but its connection to CTLA-4 dysregulation may mean that clinicians see an increased incidence at higher ipilimumab doses.
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