Case Letter

To the Editor:

Granulomatous cheilitis (GC), also known as Miescher cheilitis, belongs to a larger class of diseases known as orofacial granulomatoses (OFGs), a set of diseases distinguished by their clinical and pathologic features of facial edema and granulomatous inflammation.^1-3 Granulomatous cheilitis, a monosymptomatic variant of a more extensive disease known as Melkersson-Rosenthal syndrome (MRS), presents with labial swelling mimicking angioedema. Timely diagnosis of GC and MRS reduces the number of unnecessary tests, health care costs, and unnecessary patient burden. We present a case of idiopathic persistent swelling of the upper lip that was originally misdiagnosed as angioedema.

A 13-year-old white adolescent boy was referred to the allergy-immunology clinic for an alternate opinion regarding a presumed diagnosis of angioedema. He presented with prominent persistent swelling of the upper lip of 1 year’s duration associated with fissuring and discomfort while eating, which led to weight loss of more than 4.5 kg. The patient denied any history of facial asymmetry, paralysis, dental infections, or gastrointestinal tract symptoms. Additionally, he was not on any medications. His parents reported variable symptomatic worsening associated with egg ingestion, but avoiding egg did not provide any symptomatic relief. The swelling was unresponsive to multiple and prolonged courses of antihistamines and oral glucocorticoids. The patient’s medical history revealed no similar episodes of unexplained swelling, and family history was negative for angioedema. On examination, the upper lip was tender with a firm rubbery consistency. No other areas of swelling were noted. Angular cheilosis and minor labial mucosal ulcerations also were observed (Figure).

The persistent nature of the lip swelling and findings of fissures were not consistent with angioedema. Furthermore, prior laboratory studies did not reveal evidence of hereditary or acquired angioedema, and a complete blood cell count with differential was within reference range. Although the clinical suspicion for egg allergy was low, a blood test for serum-specific IgE showed a mild reactivity to egg allergen. The patient was referred to an oral surgeon for biopsy, which revealed dermal foci of noncaseating granulomas consistent with the preliminary diagnosis of GC.

Intralesional triamcinolone injections were initiated with marked improvement. Shortly after the initial improvement, however, the symptoms recurred, which necessitated several additional intralesional triamcinolone injections, again with remarkable improvement. Approximately 1.5 years later, the patient presented with recurrence of the lip swelling and admitted to having episodic diarrhea and abdominal cramps. He was referred to a pediatric gastroenterologist and a colonoscopy with biopsy confirmed Crohn disease. He was started on azathioprine followed by infliximab. A few months after this treatment was initiated, both his lip swelling and gastrointestinal tract symptoms remarkably improved. He has been maintained on this regimen and in the most recent follow-up had no recurrence of GC. He is scheduled to have another colonoscopy.

Granulomatous cheilitis is a rare chronic inflammatory condition characterized clinically by persistent lip swelling and histologically by granulomatous inflammation in the absence of systemic granulomatous disorders.⁴ Granulomatous cheilitis falls under the umbrella of OFGs. When it is paired with facial paralysis and fissuring of the tongue, it is specifically referred to as MRS. The prevalence of GC has historically been difficult to ascertain. In a review, an estimated incidence of 0.08% in the general population was reported with no predilection for race, sex, or age.^4,5 Initially, the swelling of GC can be misdiagnosed as angioedema; therefore, it is imperative to include OFG and GC in the differential diagnosis of facial angioedema.³ Other possible diagnoses to consider include contact dermatitis, foreign-body reactions, infection, and reactions to medications such as angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs.⁵ Chronic lymphedema and other granulomatous diseases also should be considered in the differential diagnosis. Isolated lymphedema of the head and neck, though rare, typically is seen following surgical or radiological interventions for cancer. Lymphatic fibrosis also can occur in the setting of chronic inflammatory skin conditions but is not typically the first presenting symptom, as was seen in our patient.⁶ Although granulomatous diseases such as sarcoidosis may be difficult to clinically and histologically differentiate from GC, isolated orofacial swelling in sarcoidosis is rare. If clinical suspicion for sarcoidosis does exist, however, a negative chest radiograph as well as serum calcium and angiotensin-converting enzyme levels within reference range may help differentiate GC from sarcoidosis. In our patient, the clinical suspicion for sarcoidosis was low given his clinical history, young age, and race.

The etiology of MRS and GC currently is unknown. Genetic factors, food allergies, infectious processes, and aberrant immunologic functions all have been proposed as possible mechanisms.^1-3,7,8 Genetic factors, such as HLA antigen subtypes, have been investigated but have not shown a definitive correlation.⁸ Numerous food allergens have been suggested as causative factors in OFG via a type of delayed hypersensitivity reaction,⁷ with cinnamon and benzoate reported as 2 of the most cited entities.^9,10 Currently, it is believed that both of these mechanisms may play an exacerbating role to an otherwise unknown disease process.^7,8 The infectious process most often associated with GC is Mycobacterium tuberculosis; however, similar to genetics and food allergens, causality has not been determined.^4,7 At the present time, the best evidence points to an immunologic basis of GC with the inciting event being a random influx of inflammatory cells.^7,11

There is a known association between GC and Crohn disease, especially when oral lesions are present.^1,9 Granulomatous cheilitis can be considered an extraintestinal manifestation of Crohn disease.Up to 20% of OFG patients eventually go on to develop Crohn disease, with some reports being even higher when OFG presents in childhood.^1,9 One study proposed that both GC and Crohn disease patients shared similar histopathologic and immunopathologic features including a helper T cell (T_H1)–predominant inflammatory reaction.¹¹

The treatment of GC is challenging, with most evidence coming from sporadic case reports. Given the relatively high rate of cinnamon and benzoate hypersensitivity seen in GC patients, it has been postulated that a diet lacking in them will improve the disease. At least one study has reported positive clinical outcomes from diets lacking in cinnamon and benzoate and in fact recommended it as a potential first-line treatment.¹⁰ The mainstay of treatment, however, is corticosteroids, but continued use is discouraged due to their large side-effect profile.¹² Currently, the most agreed upon treatment for patients with isolated GC is intralesional triamcinolone injections.¹² Despite the robust initial response often seen with triamcinolone injections, it is not uncommon for the benefit to be short-lived, requiring additional treatments.^1,5,12 Newer medical therapies that have shown promise largely are centered on anti–tumor necrosis factor α medications such as infliximab and adalimumab.^13,14 It is postulated that due to the potential overlapping pathophysiology between Crohn disease and GC, there may be utility in using the same treatments.¹³ In situations where medical therapy fails or in extremely disfiguring cases of GC and MRS, surgical cheiloplasty is performed to reduce lip size and improve cosmetic appearance.¹² In a small study, reduction cheiloplasty gave satisfactory functional and cosmetic outcomes in all 7 patients reviewed at a median follow-up of 6.5 years.¹⁵

This case emphasizes the importance of paying close attention to history and physical examination features in developing any differential diagnosis. In this patient, persistent orofacial swelling with associated mucosal ulcerations were sufficient to exclude drug-induced, idiopathic, hereditary, and acquired angioedema. The clinical history coupled with the biopsy results yielded a confident diagnosis of GC. Furthermore, similar presentations should raise concern for a subclinical inflammatory bowel disease such as Crohn disease.

To the Editor:

Granulomatous cheilitis (GC), also known as Miescher cheilitis, belongs to a larger class of diseases known as orofacial granulomatoses (OFGs), a set of diseases distinguished by their clinical and pathologic features of facial edema and granulomatous inflammation.^1-3 Granulomatous cheilitis, a monosymptomatic variant of a more extensive disease known as Melkersson-Rosenthal syndrome (MRS), presents with labial swelling mimicking angioedema. Timely diagnosis of GC and MRS reduces the number of unnecessary tests, health care costs, and unnecessary patient burden. We present a case of idiopathic persistent swelling of the upper lip that was originally misdiagnosed as angioedema.

A 13-year-old white adolescent boy was referred to the allergy-immunology clinic for an alternate opinion regarding a presumed diagnosis of angioedema. He presented with prominent persistent swelling of the upper lip of 1 year’s duration associated with fissuring and discomfort while eating, which led to weight loss of more than 4.5 kg. The patient denied any history of facial asymmetry, paralysis, dental infections, or gastrointestinal tract symptoms. Additionally, he was not on any medications. His parents reported variable symptomatic worsening associated with egg ingestion, but avoiding egg did not provide any symptomatic relief. The swelling was unresponsive to multiple and prolonged courses of antihistamines and oral glucocorticoids. The patient’s medical history revealed no similar episodes of unexplained swelling, and family history was negative for angioedema. On examination, the upper lip was tender with a firm rubbery consistency. No other areas of swelling were noted. Angular cheilosis and minor labial mucosal ulcerations also were observed (Figure).

The persistent nature of the lip swelling and findings of fissures were not consistent with angioedema. Furthermore, prior laboratory studies did not reveal evidence of hereditary or acquired angioedema, and a complete blood cell count with differential was within reference range. Although the clinical suspicion for egg allergy was low, a blood test for serum-specific IgE showed a mild reactivity to egg allergen. The patient was referred to an oral surgeon for biopsy, which revealed dermal foci of noncaseating granulomas consistent with the preliminary diagnosis of GC.

Intralesional triamcinolone injections were initiated with marked improvement. Shortly after the initial improvement, however, the symptoms recurred, which necessitated several additional intralesional triamcinolone injections, again with remarkable improvement. Approximately 1.5 years later, the patient presented with recurrence of the lip swelling and admitted to having episodic diarrhea and abdominal cramps. He was referred to a pediatric gastroenterologist and a colonoscopy with biopsy confirmed Crohn disease. He was started on azathioprine followed by infliximab. A few months after this treatment was initiated, both his lip swelling and gastrointestinal tract symptoms remarkably improved. He has been maintained on this regimen and in the most recent follow-up had no recurrence of GC. He is scheduled to have another colonoscopy.

Granulomatous cheilitis is a rare chronic inflammatory condition characterized clinically by persistent lip swelling and histologically by granulomatous inflammation in the absence of systemic granulomatous disorders.⁴ Granulomatous cheilitis falls under the umbrella of OFGs. When it is paired with facial paralysis and fissuring of the tongue, it is specifically referred to as MRS. The prevalence of GC has historically been difficult to ascertain. In a review, an estimated incidence of 0.08% in the general population was reported with no predilection for race, sex, or age.^4,5 Initially, the swelling of GC can be misdiagnosed as angioedema; therefore, it is imperative to include OFG and GC in the differential diagnosis of facial angioedema.³ Other possible diagnoses to consider include contact dermatitis, foreign-body reactions, infection, and reactions to medications such as angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs.⁵ Chronic lymphedema and other granulomatous diseases also should be considered in the differential diagnosis. Isolated lymphedema of the head and neck, though rare, typically is seen following surgical or radiological interventions for cancer. Lymphatic fibrosis also can occur in the setting of chronic inflammatory skin conditions but is not typically the first presenting symptom, as was seen in our patient.⁶ Although granulomatous diseases such as sarcoidosis may be difficult to clinically and histologically differentiate from GC, isolated orofacial swelling in sarcoidosis is rare. If clinical suspicion for sarcoidosis does exist, however, a negative chest radiograph as well as serum calcium and angiotensin-converting enzyme levels within reference range may help differentiate GC from sarcoidosis. In our patient, the clinical suspicion for sarcoidosis was low given his clinical history, young age, and race.

The etiology of MRS and GC currently is unknown. Genetic factors, food allergies, infectious processes, and aberrant immunologic functions all have been proposed as possible mechanisms.^1-3,7,8 Genetic factors, such as HLA antigen subtypes, have been investigated but have not shown a definitive correlation.⁸ Numerous food allergens have been suggested as causative factors in OFG via a type of delayed hypersensitivity reaction,⁷ with cinnamon and benzoate reported as 2 of the most cited entities.^9,10 Currently, it is believed that both of these mechanisms may play an exacerbating role to an otherwise unknown disease process.^7,8 The infectious process most often associated with GC is Mycobacterium tuberculosis; however, similar to genetics and food allergens, causality has not been determined.^4,7 At the present time, the best evidence points to an immunologic basis of GC with the inciting event being a random influx of inflammatory cells.^7,11

There is a known association between GC and Crohn disease, especially when oral lesions are present.^1,9 Granulomatous cheilitis can be considered an extraintestinal manifestation of Crohn disease.Up to 20% of OFG patients eventually go on to develop Crohn disease, with some reports being even higher when OFG presents in childhood.^1,9 One study proposed that both GC and Crohn disease patients shared similar histopathologic and immunopathologic features including a helper T cell (T_H1)–predominant inflammatory reaction.¹¹

The treatment of GC is challenging, with most evidence coming from sporadic case reports. Given the relatively high rate of cinnamon and benzoate hypersensitivity seen in GC patients, it has been postulated that a diet lacking in them will improve the disease. At least one study has reported positive clinical outcomes from diets lacking in cinnamon and benzoate and in fact recommended it as a potential first-line treatment.¹⁰ The mainstay of treatment, however, is corticosteroids, but continued use is discouraged due to their large side-effect profile.¹² Currently, the most agreed upon treatment for patients with isolated GC is intralesional triamcinolone injections.¹² Despite the robust initial response often seen with triamcinolone injections, it is not uncommon for the benefit to be short-lived, requiring additional treatments.^1,5,12 Newer medical therapies that have shown promise largely are centered on anti–tumor necrosis factor α medications such as infliximab and adalimumab.^13,14 It is postulated that due to the potential overlapping pathophysiology between Crohn disease and GC, there may be utility in using the same treatments.¹³ In situations where medical therapy fails or in extremely disfiguring cases of GC and MRS, surgical cheiloplasty is performed to reduce lip size and improve cosmetic appearance.¹² In a small study, reduction cheiloplasty gave satisfactory functional and cosmetic outcomes in all 7 patients reviewed at a median follow-up of 6.5 years.¹⁵

This case emphasizes the importance of paying close attention to history and physical examination features in developing any differential diagnosis. In this patient, persistent orofacial swelling with associated mucosal ulcerations were sufficient to exclude drug-induced, idiopathic, hereditary, and acquired angioedema. The clinical history coupled with the biopsy results yielded a confident diagnosis of GC. Furthermore, similar presentations should raise concern for a subclinical inflammatory bowel disease such as Crohn disease.

To the Editor:

Granulomatous cheilitis (GC), also known as Miescher cheilitis, belongs to a larger class of diseases known as orofacial granulomatoses (OFGs), a set of diseases distinguished by their clinical and pathologic features of facial edema and granulomatous inflammation.^1-3 Granulomatous cheilitis, a monosymptomatic variant of a more extensive disease known as Melkersson-Rosenthal syndrome (MRS), presents with labial swelling mimicking angioedema. Timely diagnosis of GC and MRS reduces the number of unnecessary tests, health care costs, and unnecessary patient burden. We present a case of idiopathic persistent swelling of the upper lip that was originally misdiagnosed as angioedema.

A 13-year-old white adolescent boy was referred to the allergy-immunology clinic for an alternate opinion regarding a presumed diagnosis of angioedema. He presented with prominent persistent swelling of the upper lip of 1 year’s duration associated with fissuring and discomfort while eating, which led to weight loss of more than 4.5 kg. The patient denied any history of facial asymmetry, paralysis, dental infections, or gastrointestinal tract symptoms. Additionally, he was not on any medications. His parents reported variable symptomatic worsening associated with egg ingestion, but avoiding egg did not provide any symptomatic relief. The swelling was unresponsive to multiple and prolonged courses of antihistamines and oral glucocorticoids. The patient’s medical history revealed no similar episodes of unexplained swelling, and family history was negative for angioedema. On examination, the upper lip was tender with a firm rubbery consistency. No other areas of swelling were noted. Angular cheilosis and minor labial mucosal ulcerations also were observed (Figure).

The persistent nature of the lip swelling and findings of fissures were not consistent with angioedema. Furthermore, prior laboratory studies did not reveal evidence of hereditary or acquired angioedema, and a complete blood cell count with differential was within reference range. Although the clinical suspicion for egg allergy was low, a blood test for serum-specific IgE showed a mild reactivity to egg allergen. The patient was referred to an oral surgeon for biopsy, which revealed dermal foci of noncaseating granulomas consistent with the preliminary diagnosis of GC.

Intralesional triamcinolone injections were initiated with marked improvement. Shortly after the initial improvement, however, the symptoms recurred, which necessitated several additional intralesional triamcinolone injections, again with remarkable improvement. Approximately 1.5 years later, the patient presented with recurrence of the lip swelling and admitted to having episodic diarrhea and abdominal cramps. He was referred to a pediatric gastroenterologist and a colonoscopy with biopsy confirmed Crohn disease. He was started on azathioprine followed by infliximab. A few months after this treatment was initiated, both his lip swelling and gastrointestinal tract symptoms remarkably improved. He has been maintained on this regimen and in the most recent follow-up had no recurrence of GC. He is scheduled to have another colonoscopy.

Granulomatous cheilitis is a rare chronic inflammatory condition characterized clinically by persistent lip swelling and histologically by granulomatous inflammation in the absence of systemic granulomatous disorders.⁴ Granulomatous cheilitis falls under the umbrella of OFGs. When it is paired with facial paralysis and fissuring of the tongue, it is specifically referred to as MRS. The prevalence of GC has historically been difficult to ascertain. In a review, an estimated incidence of 0.08% in the general population was reported with no predilection for race, sex, or age.^4,5 Initially, the swelling of GC can be misdiagnosed as angioedema; therefore, it is imperative to include OFG and GC in the differential diagnosis of facial angioedema.³ Other possible diagnoses to consider include contact dermatitis, foreign-body reactions, infection, and reactions to medications such as angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs.⁵ Chronic lymphedema and other granulomatous diseases also should be considered in the differential diagnosis. Isolated lymphedema of the head and neck, though rare, typically is seen following surgical or radiological interventions for cancer. Lymphatic fibrosis also can occur in the setting of chronic inflammatory skin conditions but is not typically the first presenting symptom, as was seen in our patient.⁶ Although granulomatous diseases such as sarcoidosis may be difficult to clinically and histologically differentiate from GC, isolated orofacial swelling in sarcoidosis is rare. If clinical suspicion for sarcoidosis does exist, however, a negative chest radiograph as well as serum calcium and angiotensin-converting enzyme levels within reference range may help differentiate GC from sarcoidosis. In our patient, the clinical suspicion for sarcoidosis was low given his clinical history, young age, and race.

The etiology of MRS and GC currently is unknown. Genetic factors, food allergies, infectious processes, and aberrant immunologic functions all have been proposed as possible mechanisms.^1-3,7,8 Genetic factors, such as HLA antigen subtypes, have been investigated but have not shown a definitive correlation.⁸ Numerous food allergens have been suggested as causative factors in OFG via a type of delayed hypersensitivity reaction,⁷ with cinnamon and benzoate reported as 2 of the most cited entities.^9,10 Currently, it is believed that both of these mechanisms may play an exacerbating role to an otherwise unknown disease process.^7,8 The infectious process most often associated with GC is Mycobacterium tuberculosis; however, similar to genetics and food allergens, causality has not been determined.^4,7 At the present time, the best evidence points to an immunologic basis of GC with the inciting event being a random influx of inflammatory cells.^7,11

There is a known association between GC and Crohn disease, especially when oral lesions are present.^1,9 Granulomatous cheilitis can be considered an extraintestinal manifestation of Crohn disease.Up to 20% of OFG patients eventually go on to develop Crohn disease, with some reports being even higher when OFG presents in childhood.^1,9 One study proposed that both GC and Crohn disease patients shared similar histopathologic and immunopathologic features including a helper T cell (T_H1)–predominant inflammatory reaction.¹¹

The treatment of GC is challenging, with most evidence coming from sporadic case reports. Given the relatively high rate of cinnamon and benzoate hypersensitivity seen in GC patients, it has been postulated that a diet lacking in them will improve the disease. At least one study has reported positive clinical outcomes from diets lacking in cinnamon and benzoate and in fact recommended it as a potential first-line treatment.¹⁰ The mainstay of treatment, however, is corticosteroids, but continued use is discouraged due to their large side-effect profile.¹² Currently, the most agreed upon treatment for patients with isolated GC is intralesional triamcinolone injections.¹² Despite the robust initial response often seen with triamcinolone injections, it is not uncommon for the benefit to be short-lived, requiring additional treatments.^1,5,12 Newer medical therapies that have shown promise largely are centered on anti–tumor necrosis factor α medications such as infliximab and adalimumab.^13,14 It is postulated that due to the potential overlapping pathophysiology between Crohn disease and GC, there may be utility in using the same treatments.¹³ In situations where medical therapy fails or in extremely disfiguring cases of GC and MRS, surgical cheiloplasty is performed to reduce lip size and improve cosmetic appearance.¹² In a small study, reduction cheiloplasty gave satisfactory functional and cosmetic outcomes in all 7 patients reviewed at a median follow-up of 6.5 years.¹⁵

This case emphasizes the importance of paying close attention to history and physical examination features in developing any differential diagnosis. In this patient, persistent orofacial swelling with associated mucosal ulcerations were sufficient to exclude drug-induced, idiopathic, hereditary, and acquired angioedema. The clinical history coupled with the biopsy results yielded a confident diagnosis of GC. Furthermore, similar presentations should raise concern for a subclinical inflammatory bowel disease such as Crohn disease.

To the Editor:

Verrucous porokeratosis of the gluteal cleft is a rare skin condition that has distinct clinical and histologic features. A review of 5 cases described a characteristic clinical presentation of a butterfly-shaped bilateral gluteal cleft lesion on most patients.¹ We present an unusual case of verrucous porokeratosis presenting as a unilateral single lesion in the gluteal area that emulated seborrheic keratosis with histology consistent with verrucous porokeratosis. This case adds to the variable presentation of this unusual disease.

A 40-year-old man who presented to the dermatology clinic for a follow-up on a basal cell carcinoma of the temple region was concerned about a lesion on the left buttock of 1 year’s duration. Physical examination revealed a unilateral hyperkeratotic plaque that clinically resembled seborrheic keratosis (Figure 1). Biopsy revealed hyperkeratosis with numerous columns of parakeratosis, psoriasiform epidermal hyperplasia (Figures 2A and 2B), dyskeratotic keratinocytes (Figure 2C), pigment incontinence, and mild superficial chronic inflammation consistent with verrucous porokeratosis. The patient was treated with urea lotion but ultimately was lost to follow-up.

We present a unique case of unilateral verrucous porokeratosis of the gluteal cleft. The clinical differential diagnosis included seborrheic keratosis, condyloma acuminata, and inflammatory linear verrucous epidermal nevus. Histopathology was consistent with verrucous porokeratosis. Porokeratosis is a heterogeneous group of keratinization disorders containing several described variants such as classici porokeratosis of Mibelli, disseminated superficial porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctuate porokeratosis.^1,2 Most patients present clinically with plaquelike bilateral (butterfly) lesions with threadlike (ridge) borders, though some patients initially have a unilateral lesion that subsequently develops into a bilateral lesion.¹ The clinical course is slow growing, but it can potentially give rise to malignancies such as squamous cell carcinoma.³ Histologically, numerous columns of parakeratosis overlying epidermal cells with attenuated granular layer are observed with the concentric cornoid lamellae considered unique to the verrucous variant.¹ Although our patient had only a single unilateral lesion on the gluteal cleft, the histology was consistent with verrucous porokeratosis. Our case adds to the growing clinical presentations of this unusual disease.

RELATED CONTENT: Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation

To the Editor:

Verrucous porokeratosis of the gluteal cleft is a rare skin condition that has distinct clinical and histologic features. A review of 5 cases described a characteristic clinical presentation of a butterfly-shaped bilateral gluteal cleft lesion on most patients.¹ We present an unusual case of verrucous porokeratosis presenting as a unilateral single lesion in the gluteal area that emulated seborrheic keratosis with histology consistent with verrucous porokeratosis. This case adds to the variable presentation of this unusual disease.

A 40-year-old man who presented to the dermatology clinic for a follow-up on a basal cell carcinoma of the temple region was concerned about a lesion on the left buttock of 1 year’s duration. Physical examination revealed a unilateral hyperkeratotic plaque that clinically resembled seborrheic keratosis (Figure 1). Biopsy revealed hyperkeratosis with numerous columns of parakeratosis, psoriasiform epidermal hyperplasia (Figures 2A and 2B), dyskeratotic keratinocytes (Figure 2C), pigment incontinence, and mild superficial chronic inflammation consistent with verrucous porokeratosis. The patient was treated with urea lotion but ultimately was lost to follow-up.

We present a unique case of unilateral verrucous porokeratosis of the gluteal cleft. The clinical differential diagnosis included seborrheic keratosis, condyloma acuminata, and inflammatory linear verrucous epidermal nevus. Histopathology was consistent with verrucous porokeratosis. Porokeratosis is a heterogeneous group of keratinization disorders containing several described variants such as classici porokeratosis of Mibelli, disseminated superficial porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctuate porokeratosis.^1,2 Most patients present clinically with plaquelike bilateral (butterfly) lesions with threadlike (ridge) borders, though some patients initially have a unilateral lesion that subsequently develops into a bilateral lesion.¹ The clinical course is slow growing, but it can potentially give rise to malignancies such as squamous cell carcinoma.³ Histologically, numerous columns of parakeratosis overlying epidermal cells with attenuated granular layer are observed with the concentric cornoid lamellae considered unique to the verrucous variant.¹ Although our patient had only a single unilateral lesion on the gluteal cleft, the histology was consistent with verrucous porokeratosis. Our case adds to the growing clinical presentations of this unusual disease.

RELATED CONTENT: Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation

To the Editor:

Verrucous porokeratosis of the gluteal cleft is a rare skin condition that has distinct clinical and histologic features. A review of 5 cases described a characteristic clinical presentation of a butterfly-shaped bilateral gluteal cleft lesion on most patients.¹ We present an unusual case of verrucous porokeratosis presenting as a unilateral single lesion in the gluteal area that emulated seborrheic keratosis with histology consistent with verrucous porokeratosis. This case adds to the variable presentation of this unusual disease.

A 40-year-old man who presented to the dermatology clinic for a follow-up on a basal cell carcinoma of the temple region was concerned about a lesion on the left buttock of 1 year’s duration. Physical examination revealed a unilateral hyperkeratotic plaque that clinically resembled seborrheic keratosis (Figure 1). Biopsy revealed hyperkeratosis with numerous columns of parakeratosis, psoriasiform epidermal hyperplasia (Figures 2A and 2B), dyskeratotic keratinocytes (Figure 2C), pigment incontinence, and mild superficial chronic inflammation consistent with verrucous porokeratosis. The patient was treated with urea lotion but ultimately was lost to follow-up.

We present a unique case of unilateral verrucous porokeratosis of the gluteal cleft. The clinical differential diagnosis included seborrheic keratosis, condyloma acuminata, and inflammatory linear verrucous epidermal nevus. Histopathology was consistent with verrucous porokeratosis. Porokeratosis is a heterogeneous group of keratinization disorders containing several described variants such as classici porokeratosis of Mibelli, disseminated superficial porokeratosis, porokeratosis palmaris et plantaris disseminata, linear porokeratosis, and punctuate porokeratosis.^1,2 Most patients present clinically with plaquelike bilateral (butterfly) lesions with threadlike (ridge) borders, though some patients initially have a unilateral lesion that subsequently develops into a bilateral lesion.¹ The clinical course is slow growing, but it can potentially give rise to malignancies such as squamous cell carcinoma.³ Histologically, numerous columns of parakeratosis overlying epidermal cells with attenuated granular layer are observed with the concentric cornoid lamellae considered unique to the verrucous variant.¹ Although our patient had only a single unilateral lesion on the gluteal cleft, the histology was consistent with verrucous porokeratosis. Our case adds to the growing clinical presentations of this unusual disease.

RELATED CONTENT: Diagnosing Porokeratosis of Mibelli Every Time: A Novel Biopsy Technique to Maximize Histopathologic Confirmation

To the Editor:

An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.

On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).

The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.

Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.¹ It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.^1-3

Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.^3,4

Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.^1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.^1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.²

Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.^1-3,6 By far the most common pattern described in the literature is longitudinal banding^1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.^1,6

The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.^5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.² There also may be a genetic and photosensitivity component.^1,2

Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.¹ In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.²

Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.² Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.

To the Editor:

An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.

On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).

The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.

Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.¹ It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.^1-3

Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.^3,4

Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.^1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.^1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.²

Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.^1-3,6 By far the most common pattern described in the literature is longitudinal banding^1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.^1,6

The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.^5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.² There also may be a genetic and photosensitivity component.^1,2

Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.¹ In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.²

Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.² Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.

To the Editor:

An 85-year-old woman with a history of hypertension, hyperlipidemia, stroke, hypothyroidism, chronic obstructive pulmonary disease, and chronic myeloproliferative disorder presented to our clinic for evaluation of brown lesions on the hands and discoloration of the fingernails and toenails of 4 months’ duration. Six months prior to visiting our clinic she was admitted to the hospital for a pulmonary embolism. On admission she was noted to have a platelet count of more than 2 million/μL (reference range, 150,000–350,000/μL). She received urgent plasmapheresis and started hydroxyurea 500 mg twice daily, which she continued as an outpatient.

On physical examination at our clinic she had diffusely scattered red and brown macules on the bilateral palms and transverse hyperpigmented bands of various intensities on all fingernails and toenails (Figure). Her platelet count was 372,000/μL, white blood cell count was 5200/μL (reference range, 4500–11,000/μL), hemoglobin was 12.6 g/dL (reference range, 14.0–17.5 g/dL), hematocrit was 39.0% (reference range, 41%–50%), and mean corpuscular volume was 87.5 fL per red cell (reference range, 80–96 fL per red cell).

The patient was diagnosed with hydroxyurea-induced nail hyperpigmentation and was counseled on the benign nature of the condition. Three months later her platelet count decreased to below 100,000/μL, and hydroxyurea was discontinued. She noticed considerable improvement in the lesions on the hands and nails with the cessation of hydroxyurea.

Hydroxyurea is a cytostatic agent that has been used for more than 40 years in the treatment of myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and sickle cell anemia.¹ It inhibits ribonucleoside diphosphate reductase and promotes cell death in the S phase of the cell cycle.^1-3

Several adverse cutaneous reactions have been associated with hydroxyurea including increased pigmentation, hyperkeratosis, skin atrophy, xerosis, lichenoid eruptions, palmoplantar keratoderma, cutaneous vasculitis, alopecia, chronic leg ulcers, cutaneous carcinomas, and melanonychia.^3,4

Hydroxyurea-induced melanonychia most often occurs after several months of therapy but has been reported to occur as early as 4 months and as late as 5 years after initiating the drug.^1,4-6 The prevalence of melanonychia in the general population has been estimated at 1% and is thought to increase to approximately 4% in patients treated with hydroxyurea.^1,2,6,7 The prevalence of affected individuals increases with age; it is more common in females as well as black and Hispanic patients.²

Multiple patterns of hydroxyurea-induced melanonychia have been described, including longitudinal bands, transverse bands, and diffuse hyperpigmentation.^1-3,6 By far the most common pattern described in the literature is longitudinal banding^1-3,8; transverse bands are more rare. Although there are sporadic case reports linking the transverse bands with hydroxyurea, these bands occur more frequently with systemic chemotherapy such as doxorubicin and cyclosphosphamide.^1,6

The exact pathogenesis of hydroxyurea-induced melanonychia remains unclear, though it is thought to result from focal melanogenesis in the nail bed or matrix followed by deposition of melanin granules on the nail plate.^5,8 When these melanocytes are activated, melanosomes filled with melanin are transferred to differentiating matrix cells, which migrate distally as they become nail plate oncocytes, resulting in a visible band of pigmentation in the nail plate.² There also may be a genetic and photosensitivity component.^1,2

Prior case series have described spontaneous remission of nail hyperpigmentation following discontinuation of hydroxyurea therapy.¹ In many patients, however, the chronic nature of the myeloproliferative disorder and lack of alternative treatments make a therapeutic change difficult. Although the melanonychia itself is benign, it may precede the appearance of more serious mucocutaneous side effects, such as skin ulceration or development of cutaneous carcinomas, so careful monitoring should be performed.²

Our patient presented with melanonychia that was transverse, polydactylic, monochromic, stable in size and shape, and associated with palmar hyperpigmentation. Of note, the pigmentation remitted over time along with discontinuation of the drug. Although this presentation did not warrant a nail matrix biopsy, it should be noted that patients with single nail melanonychia suspicious for melanoma should have a biopsy, even with concomitant use of hydroxyurea.² Although transverse melanonychia most commonly is associated with other systemic chemotherapeutics, in the absence of such medications hydroxyurea was the likely culprit in our patient. The palmar hyperpigmentation, which has previously been reported with hydroxyurea use, further solidifies the diagnosis.

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

To the Editor:

Serpentine supravenous hyperpigmentation (SSH) is a rare phenomenon characterized by linear hyperpigmentation of the skin overlying veins secondary to intravenous antineoplastic therapy. The term was first suggested by Hrushesky¹ in 1976 as an uncommon side effect of administering intravenous 5-fluorouracil (5-FU). Although 5-FU is the most frequent offending agent, cases involving treatment with actinomycin, cyclophosphamide, docetaxel, fotemustine, nitrogen mustard, nitrosoureas, taxanes, and triazinate, as well as various combinations of chemotherapeutic agents, also have been observed.^2,3 We present the case of SSH following a cisplatin and pemetrexed chemotherapy regimen.

A 52-year-old man with newly diagnosed inoperable adenocarcinoma in the left upper lung lobe received 2 cycles of treatment with cisplatin 138 mg and pemetrexed 920 mg 21 days apart. The first cycle of chemotherapy was delivered intravenously through the left forearm and the second cycle through the right forearm. Each infusion was followed by a 20-cc 0.9% saline flush. The patient developed nausea, vomiting, diarrhea, and hyperpigmentation tracing the path of infusion on the right arm as well as a slight darkness on the left arm that were noted by medical staff. At that time, cisplatin was discontinued from the chemotherapeutic regimen.

A port-a-cath was inserted into the patient’s right upper chest 4 weeks later and was used for subsequent infusions. Carboplatin 450 mg was initiated with pemetrexed thereafter. The patient was seen in the dermatology clinic 3 weeks after the insertion of the port-a-cath for evaluation of diffuse tinea versicolor of the trunk. Further examination of the arms revealed asymptomatic serpiginous hyperpigmentation overlying the superficial venous network tracing from the prior intravenous access points in the bilateral forearms to the upper arms (Figure). There was no evidence of extravasation or phlebitis prior to the hyperpigmentation. The patient was continued on pemetrexed and was subsequently lost to follow-up.

Cisplatin was the first member of the platinum-based chemotherapeutic agent class and is now one of the most potent and widely used in the treatment of solid malignancies. The cytotoxic mode of action is primarily mediated through interaction with DNA to form intrastrand cross-link adducts leading to aberrant mitosis and culminating in the activation of apoptosis. A variety of dermatologic complications have been reported with cisplatin chemotherapy including melanonychia, oral mucosal hyperpigmentation, hypersensitivity reactions, extravasation,⁴ Raynaud phenomenon, and flushing.⁵

Two cases of SSH have been reported following combination chemotherapy with cisplatin included in the regimen. A 61-year-old man with inoperable esophageal squamous cell carcinoma received cisplatin and 5-FU in addition to concurrent radiotherapy.⁶ After worsening renal function, cisplatin promptly was replaced with leucovorin. The patient developed SSH after the eighth infusion of 5-FU–leucovorin delivered through a peripheral catheter over a 24-hour period. The cutaneous side effect was attributed to the use of intravenous 5-FU.⁶ The second case involved a 48-year-old woman diagnosed with Paget disease of the breast who received adjuvant therapy with 12 courses of once-daily 5-FU and docetaxel for 5 years as well as 2 courses of vinorelbine and 1 course of cisplatin and etoposide for lung metastases.⁷ Serpentine supravenous hyperpigmentation lesions slowly developed over approximately 6 months. Based on the literature, the authors speculated that 5-FU and vinorelbine were most likely to be responsible. They noted, however, the inability to clarify the relationship between the onset of skin lesions and the time course of the chemotherapy.⁷ Although these cases do not directly implicate cisplatin as the cause of SSH, the possibility of a delayed reaction or augmentation of another drug’s effect cannot be excluded.

Pemetrexed, on the other hand, has not been associated with SSH. Several cutaneous adverse reactions have been reported, including acute generalized exanthematous pustulosis, alopecia, pityriasis lichenoides, radiation recall dermatitis, toxic epidermal necrolysis, and urticarial vasculitis.⁸ Three cases of pemetrexed-induced skin hyperpigmentation including the palms of the hands and soles of the feet as well as diffuse hyperpigmentation sparing only the palms and soles have been reported.^8-10

Similar cases of SSH have demonstrated histopathologic findings with increased basal melanin synthesis and occasional melanophages in the papillary dermis without inflammatory changes.^7,11 Although the unique serpentine pattern of hyperpigmentation is instantly recognizable, clinical differential diagnosis may include thrombophlebitis, cutis marmorata, erythema ab igne, livedo reticularis, and lichen planus.^2,12

The exact mechanism of SSH has not been conclusively elucidated. Several studies postulate that direct cytotoxic damage causes loss of endothelial integrity permitting the extravasation of the agent to the overlying epidermis and interfering with melanogenesis.^2,6,11 Other hypotheses include direct stimulation of melanocytes, depletion of reduced thioredoxin leading to tyrosinase stimulation, hyperthermia-related changes including reduced cytokine production and/or increased expression of melanocyte-stimulating hormone receptor, subclinical phlebitis leading to postinflammatory hyperpigmentation, or hyperpigmentation secondary to increased blood flow in certain areas and therefore increased drug deposition.^12,13

Currently, there is no specific therapy recommended for SSH and the pigment may persist anywhere from a few months to more than a year after completing chemotherapy.^2,7 Although discontinuing the offending agent would certainly prevent further development, due to the benign nature of the reaction, modifying therapy based on cutaneous findings alone is not recommended.¹² Several authors have suggested avoiding peripheral infusions of chemotherapeutic agents known to cause SSH or have recommended using a permanent central venous catheter.^6,7 Another option, which needs further investigation, is the administration of an abundant flush following chemotherapy. This technique was described in a case report of a 47-year-old man who developed persistent SSH in the right forearm following docetaxel injection.¹³ Copious venous washing with 1000 mL of isotonic saline solution following the second infusion in the unaffected arm prevented discoloration. The lack of subsequent reaction may support the theory that direct toxic effect on the vascular endothelium results in hyperpigmentation of the supravenous skin.¹³

Serpentine supravenous hyperpigmentation is an uncommon cutaneous reaction secondary to antineoplastic therapies. Given the widespread use of chemotherapeutic regimens, dermatologists should be aware of the reaction. Additional studies are warranted to better elucidate the pathogenesis and investigate how infusion techniques might aid in the prevention of skin discoloration. Although this side effect originally was described in relation to 5-FU, subsequent observations have included other chemotherapeutic agents. In light of the findings presented in this report, cisplatin and pemetrexed should be considered on the list of offending agents. Ultimately, patients should be reassured that the lesions are benign, self-limiting, and gradually resolve on their own in most cases.¹²

To the Editor:

Both alopecia areata (AA) and psoriasis vulgaris are chronic relapsing autoimmune diseases, with AA causing nonscarring hair loss in approximately 0.1% to 0.2%¹ of the population with a lifetime risk of 1.7%,² and psoriasis more broadly impacting 1.5% to 2% of the population.³ The helper T cell (T_H1) cytokine milieu is pathogenic in both conditions.^4-6 IFN-γ knockout mice, unlike their wild-type counterparts, do not exhibit AA.⁷ Psoriasis is notably improved by IL-10 injections, which dampen the T_H1 response.⁸ Distinct from AA, T_H17 and T_H22 cells have been implicated as key players in psoriasis pathogenesis, along with the associated IL-17 and IL-22 cytokines.^9-12

Few cases of patients with concurrent AA and psoriasis have been described. Interestingly, these cases document normal hair regrowth in the areas of psoriasis.^13-16 These cases may offer unique insight into the immune factors driving each disease. We describe a case of a man with both alopecia universalis (AU) and psoriasis who developed hair regrowth in some of the psoriatic plaques.

A 34-year-old man with concurrent AU and psoriasis who had not used any systemic or topical medication for either condition in the last year presented to our clinic seeking treatment. The patient had a history of alopecia totalis as a toddler that completely resolved by 4 years of age with the use of squaric acid dibutylester (SADBE). At 31 years of age, the alopecia recurred and was localized to the scalp. It was partially responsive to intralesional triamcinolone acetonide. The patient’s alopecia worsened over the 2 years following recurrence, ultimately progressing to AU. Two months after the alopecia recurrence, he developed the first psoriatic plaques. As the plaque psoriasis progressed, systemic therapy was initiated, first methotrexate and then etanercept. Shortly after developing AU, he lost his health insurance and discontinued all therapy. The patient’s psoriasis began to recur approximately 3 months after stopping etanercept. He was not using any other psoriasis medications. At that time, he noted terminal hair regrowth within some of the psoriatic plaques. No terminal hairs grew outside of the psoriatic plaques, and all regions with growth had previously been without hair for an extended period of time. The patient presented to our clinic approximately 1 year later. He had no other medical conditions and no relevant family history.

On initial physical examination, he had nonscarring hair loss involving nearly 100% of the body with psoriatic plaques on approximately 30% of the body surface area. Regions of terminal hair growth were confined to some but not all of the psoriatic plaques (Figure). Interestingly, the terminal hairs were primarily localized to the thickest central regions of the plaques. The patient’s psoriasis was treated with a combination of topical clobetasol and calcipotriene. In addition, he was started on tacrolimus ointment to the face and eyebrows for the AA. Maintenance of terminal hair within a region of topically treated psoriasis on the forearm persisted at the 2-month follow-up despite complete clearance of the corresponding psoriatic plaque. A small psoriatic plaque on the scalp cleared early with topical therapy without noticeable hair regrowth. The patient subsequently was started on contact immunotherapy with SADBE and intralesional triamcinolone acetonide for the scalp alopecia without satisfactory response. He decided to discontinue further attempts at treating the alopecia and requested to be restarted on etanercept therapy for recalcitrant psoriatic plaques. His psoriasis responded well to this therapy and he continues to be followed in our psoriasis clinic. One year after clearance of the treated psoriatic plaques, the corresponding terminal hairs persist.

Contact immunotherapy, most commonly with diphenylcyclopropenone or SADBE, is reported to have a 50% to 60% success rate in extensive AA, with a broad range of 9% to 87%¹⁷; however, randomized controlled trials testing the efficacy of contact immunotherapy are lacking. Although the mechanism of action of these topical sensitizers is not clearly delineated, it has been postulated that by inducing a new type of inflammatory response in the region, the immunologic milieu is changed, allowing the hair to grow. Some proposed mechanisms include promoting perifollicular lymphocyte apoptosis, preventing new recruitment of autoreactive lymphocytes, and allowing for the correction of aberrant major histocompatibility complex expression on the hair matrix epithelium to regain follicle immune privilege.^18-20

Iatrogenic immunotherapy may work analogously to the natural immune system deviation demonstrated in our patient. Psoriasis and AA are believed to form competing immune cells and cytokine milieus, thus explaining how an individual with AA could regain normal hair growth in areas of psoriasis.^15,16 The Renbök phenomenon, or reverse Köbner phenomenon, coined by Happle et al¹³ can be used to describe both the iatrogenic and natural cases of dermatologic disease improvement in response to secondary insults.¹⁴

A complex cascade of immune cells and cytokines coordinate AA pathogenesis. In the acute stage of AA, an inflammatory infiltrate of CD4⁺ T cells, CD8⁺ T cells, and antigen-presenting cells target anagen phase follicles, with a higher CD4⁺:CD8⁺ ratio in clinically active disease.^21-23 Subcutaneous injections of either CD4⁺ or CD8⁺ lymphocyte subsets from mice with AA into normal-haired mice induces disease. However, CD8⁺ T cell injections rapidly produce apparent hair loss, whereas CD4⁺ T cells cause hair loss after several weeks, suggesting that CD8⁺ T cells directly modulate AA hair loss and CD4⁺ T cells act as an aide.²⁴ The growth, differentiation, and survival of CD8⁺ T cells are stimulated by IL-2 and IFN-γ. Alopecia areata biopsies demonstrate a prevalence of T_H1 cytokines, and patients with localized AA, alopecia totalis, and AU have notably higher serum IFN-γ levels compared to controls.²⁵ In murine models, IL-1α and IL-1β increase during the catagen phase of the hair cycle and peak during the telogen phase.²⁶ Excessive IL-1β expression is detected in the early stages of human disease, and certain IL-1β polymorphisms are associated with severe forms of AA.²⁶ The role of tumor necrosis factor (TNF) α in AA is not well understood. In vitro studies show it inhibits hair growth, suggesting the cytokine may play a role in AA.²⁷ However, anti–TNF-α therapy is not effective in AA, and case reports propose these therapies rarely induce AA.^28-31

The T_H1 response is likewise critical to psoriatic plaque development. IFN-γ and TNF-α are overexpressed in psoriatic plaques.³² IFN-γ has an antiproliferative and differentiation-inducing effect on normal keratinocytes, but psoriatic epithelial cells in vitro respond differently to the cytokine with a notably diminished growth inhibition.^33,34 One explanation for the role of IFN-γ is that it stimulates dendritic cells to produce IL-1 and IL-23.³⁵ IL-23 activates T_H17 cells³⁶; T_H1 and T_H17 conditions produce IL-22 whose serum level correlates with disease severity.^37-39 IL-22 induces keratinocyte proliferation and migration and inhibits keratinocyte differentiation, helping account for hallmarks of the disease.⁴⁰ Patients with psoriasis have increased levels of T_H1, T_H17, and T_H22 cells, as well as their associated cytokines, in the skin and blood compared to controls.^{4,11,32,39,41}

Alopecia areata and psoriasis are regulated by complex and still not entirely understood immune interactions. The fact that many of the same therapies are used to treat both diseases emphasizes both their overlapping characteristics and the lack of targeted therapy. It is unclear if and how the topical or systemic therapies used in our patient to treat one disease affected the natural history of the other condition. It is important to highlight, however, that the patient had not been treated for months when he developed the psoriatic plaques with hair regrowth. Other case reports also document hair regrowth in untreated plaques,^13,16 making it unlikely to be a side effect of the medication regimen. For both psoriasis and AA, the immune cell composition and cytokine levels in the skin or serum vary throughout a patient’s disease course depending on severity of disease or response to treatment.^6,39,42,43 Therefore, we hypothesize that the 2 conditions interact in a similarly distinct manner based on each disease’s stage and intensity in the patient. Both our patient’s course thus far and the various presentations described by other groups support this hypothesis. Our patient had a small region of psoriasis on the scalp that cleared without any terminal hair growth. He also had larger plaques on the forearms that developed hair growth most predominantly within the thicker regions of the plaques. His unique presentation highlights the fluidity of the immune factors driving psoriasis vulgaris and AA.

To the Editor:

Both alopecia areata (AA) and psoriasis vulgaris are chronic relapsing autoimmune diseases, with AA causing nonscarring hair loss in approximately 0.1% to 0.2%¹ of the population with a lifetime risk of 1.7%,² and psoriasis more broadly impacting 1.5% to 2% of the population.³ The helper T cell (T_H1) cytokine milieu is pathogenic in both conditions.^4-6 IFN-γ knockout mice, unlike their wild-type counterparts, do not exhibit AA.⁷ Psoriasis is notably improved by IL-10 injections, which dampen the T_H1 response.⁸ Distinct from AA, T_H17 and T_H22 cells have been implicated as key players in psoriasis pathogenesis, along with the associated IL-17 and IL-22 cytokines.^9-12

Few cases of patients with concurrent AA and psoriasis have been described. Interestingly, these cases document normal hair regrowth in the areas of psoriasis.^13-16 These cases may offer unique insight into the immune factors driving each disease. We describe a case of a man with both alopecia universalis (AU) and psoriasis who developed hair regrowth in some of the psoriatic plaques.

A 34-year-old man with concurrent AU and psoriasis who had not used any systemic or topical medication for either condition in the last year presented to our clinic seeking treatment. The patient had a history of alopecia totalis as a toddler that completely resolved by 4 years of age with the use of squaric acid dibutylester (SADBE). At 31 years of age, the alopecia recurred and was localized to the scalp. It was partially responsive to intralesional triamcinolone acetonide. The patient’s alopecia worsened over the 2 years following recurrence, ultimately progressing to AU. Two months after the alopecia recurrence, he developed the first psoriatic plaques. As the plaque psoriasis progressed, systemic therapy was initiated, first methotrexate and then etanercept. Shortly after developing AU, he lost his health insurance and discontinued all therapy. The patient’s psoriasis began to recur approximately 3 months after stopping etanercept. He was not using any other psoriasis medications. At that time, he noted terminal hair regrowth within some of the psoriatic plaques. No terminal hairs grew outside of the psoriatic plaques, and all regions with growth had previously been without hair for an extended period of time. The patient presented to our clinic approximately 1 year later. He had no other medical conditions and no relevant family history.

On initial physical examination, he had nonscarring hair loss involving nearly 100% of the body with psoriatic plaques on approximately 30% of the body surface area. Regions of terminal hair growth were confined to some but not all of the psoriatic plaques (Figure). Interestingly, the terminal hairs were primarily localized to the thickest central regions of the plaques. The patient’s psoriasis was treated with a combination of topical clobetasol and calcipotriene. In addition, he was started on tacrolimus ointment to the face and eyebrows for the AA. Maintenance of terminal hair within a region of topically treated psoriasis on the forearm persisted at the 2-month follow-up despite complete clearance of the corresponding psoriatic plaque. A small psoriatic plaque on the scalp cleared early with topical therapy without noticeable hair regrowth. The patient subsequently was started on contact immunotherapy with SADBE and intralesional triamcinolone acetonide for the scalp alopecia without satisfactory response. He decided to discontinue further attempts at treating the alopecia and requested to be restarted on etanercept therapy for recalcitrant psoriatic plaques. His psoriasis responded well to this therapy and he continues to be followed in our psoriasis clinic. One year after clearance of the treated psoriatic plaques, the corresponding terminal hairs persist.

Contact immunotherapy, most commonly with diphenylcyclopropenone or SADBE, is reported to have a 50% to 60% success rate in extensive AA, with a broad range of 9% to 87%¹⁷; however, randomized controlled trials testing the efficacy of contact immunotherapy are lacking. Although the mechanism of action of these topical sensitizers is not clearly delineated, it has been postulated that by inducing a new type of inflammatory response in the region, the immunologic milieu is changed, allowing the hair to grow. Some proposed mechanisms include promoting perifollicular lymphocyte apoptosis, preventing new recruitment of autoreactive lymphocytes, and allowing for the correction of aberrant major histocompatibility complex expression on the hair matrix epithelium to regain follicle immune privilege.^18-20

Iatrogenic immunotherapy may work analogously to the natural immune system deviation demonstrated in our patient. Psoriasis and AA are believed to form competing immune cells and cytokine milieus, thus explaining how an individual with AA could regain normal hair growth in areas of psoriasis.^15,16 The Renbök phenomenon, or reverse Köbner phenomenon, coined by Happle et al¹³ can be used to describe both the iatrogenic and natural cases of dermatologic disease improvement in response to secondary insults.¹⁴

A complex cascade of immune cells and cytokines coordinate AA pathogenesis. In the acute stage of AA, an inflammatory infiltrate of CD4⁺ T cells, CD8⁺ T cells, and antigen-presenting cells target anagen phase follicles, with a higher CD4⁺:CD8⁺ ratio in clinically active disease.^21-23 Subcutaneous injections of either CD4⁺ or CD8⁺ lymphocyte subsets from mice with AA into normal-haired mice induces disease. However, CD8⁺ T cell injections rapidly produce apparent hair loss, whereas CD4⁺ T cells cause hair loss after several weeks, suggesting that CD8⁺ T cells directly modulate AA hair loss and CD4⁺ T cells act as an aide.²⁴ The growth, differentiation, and survival of CD8⁺ T cells are stimulated by IL-2 and IFN-γ. Alopecia areata biopsies demonstrate a prevalence of T_H1 cytokines, and patients with localized AA, alopecia totalis, and AU have notably higher serum IFN-γ levels compared to controls.²⁵ In murine models, IL-1α and IL-1β increase during the catagen phase of the hair cycle and peak during the telogen phase.²⁶ Excessive IL-1β expression is detected in the early stages of human disease, and certain IL-1β polymorphisms are associated with severe forms of AA.²⁶ The role of tumor necrosis factor (TNF) α in AA is not well understood. In vitro studies show it inhibits hair growth, suggesting the cytokine may play a role in AA.²⁷ However, anti–TNF-α therapy is not effective in AA, and case reports propose these therapies rarely induce AA.^28-31

The T_H1 response is likewise critical to psoriatic plaque development. IFN-γ and TNF-α are overexpressed in psoriatic plaques.³² IFN-γ has an antiproliferative and differentiation-inducing effect on normal keratinocytes, but psoriatic epithelial cells in vitro respond differently to the cytokine with a notably diminished growth inhibition.^33,34 One explanation for the role of IFN-γ is that it stimulates dendritic cells to produce IL-1 and IL-23.³⁵ IL-23 activates T_H17 cells³⁶; T_H1 and T_H17 conditions produce IL-22 whose serum level correlates with disease severity.^37-39 IL-22 induces keratinocyte proliferation and migration and inhibits keratinocyte differentiation, helping account for hallmarks of the disease.⁴⁰ Patients with psoriasis have increased levels of T_H1, T_H17, and T_H22 cells, as well as their associated cytokines, in the skin and blood compared to controls.^{4,11,32,39,41}

Alopecia areata and psoriasis are regulated by complex and still not entirely understood immune interactions. The fact that many of the same therapies are used to treat both diseases emphasizes both their overlapping characteristics and the lack of targeted therapy. It is unclear if and how the topical or systemic therapies used in our patient to treat one disease affected the natural history of the other condition. It is important to highlight, however, that the patient had not been treated for months when he developed the psoriatic plaques with hair regrowth. Other case reports also document hair regrowth in untreated plaques,^13,16 making it unlikely to be a side effect of the medication regimen. For both psoriasis and AA, the immune cell composition and cytokine levels in the skin or serum vary throughout a patient’s disease course depending on severity of disease or response to treatment.^6,39,42,43 Therefore, we hypothesize that the 2 conditions interact in a similarly distinct manner based on each disease’s stage and intensity in the patient. Both our patient’s course thus far and the various presentations described by other groups support this hypothesis. Our patient had a small region of psoriasis on the scalp that cleared without any terminal hair growth. He also had larger plaques on the forearms that developed hair growth most predominantly within the thicker regions of the plaques. His unique presentation highlights the fluidity of the immune factors driving psoriasis vulgaris and AA.

To the Editor:

Both alopecia areata (AA) and psoriasis vulgaris are chronic relapsing autoimmune diseases, with AA causing nonscarring hair loss in approximately 0.1% to 0.2%¹ of the population with a lifetime risk of 1.7%,² and psoriasis more broadly impacting 1.5% to 2% of the population.³ The helper T cell (T_H1) cytokine milieu is pathogenic in both conditions.^4-6 IFN-γ knockout mice, unlike their wild-type counterparts, do not exhibit AA.⁷ Psoriasis is notably improved by IL-10 injections, which dampen the T_H1 response.⁸ Distinct from AA, T_H17 and T_H22 cells have been implicated as key players in psoriasis pathogenesis, along with the associated IL-17 and IL-22 cytokines.^9-12

Few cases of patients with concurrent AA and psoriasis have been described. Interestingly, these cases document normal hair regrowth in the areas of psoriasis.^13-16 These cases may offer unique insight into the immune factors driving each disease. We describe a case of a man with both alopecia universalis (AU) and psoriasis who developed hair regrowth in some of the psoriatic plaques.

A 34-year-old man with concurrent AU and psoriasis who had not used any systemic or topical medication for either condition in the last year presented to our clinic seeking treatment. The patient had a history of alopecia totalis as a toddler that completely resolved by 4 years of age with the use of squaric acid dibutylester (SADBE). At 31 years of age, the alopecia recurred and was localized to the scalp. It was partially responsive to intralesional triamcinolone acetonide. The patient’s alopecia worsened over the 2 years following recurrence, ultimately progressing to AU. Two months after the alopecia recurrence, he developed the first psoriatic plaques. As the plaque psoriasis progressed, systemic therapy was initiated, first methotrexate and then etanercept. Shortly after developing AU, he lost his health insurance and discontinued all therapy. The patient’s psoriasis began to recur approximately 3 months after stopping etanercept. He was not using any other psoriasis medications. At that time, he noted terminal hair regrowth within some of the psoriatic plaques. No terminal hairs grew outside of the psoriatic plaques, and all regions with growth had previously been without hair for an extended period of time. The patient presented to our clinic approximately 1 year later. He had no other medical conditions and no relevant family history.

On initial physical examination, he had nonscarring hair loss involving nearly 100% of the body with psoriatic plaques on approximately 30% of the body surface area. Regions of terminal hair growth were confined to some but not all of the psoriatic plaques (Figure). Interestingly, the terminal hairs were primarily localized to the thickest central regions of the plaques. The patient’s psoriasis was treated with a combination of topical clobetasol and calcipotriene. In addition, he was started on tacrolimus ointment to the face and eyebrows for the AA. Maintenance of terminal hair within a region of topically treated psoriasis on the forearm persisted at the 2-month follow-up despite complete clearance of the corresponding psoriatic plaque. A small psoriatic plaque on the scalp cleared early with topical therapy without noticeable hair regrowth. The patient subsequently was started on contact immunotherapy with SADBE and intralesional triamcinolone acetonide for the scalp alopecia without satisfactory response. He decided to discontinue further attempts at treating the alopecia and requested to be restarted on etanercept therapy for recalcitrant psoriatic plaques. His psoriasis responded well to this therapy and he continues to be followed in our psoriasis clinic. One year after clearance of the treated psoriatic plaques, the corresponding terminal hairs persist.

Contact immunotherapy, most commonly with diphenylcyclopropenone or SADBE, is reported to have a 50% to 60% success rate in extensive AA, with a broad range of 9% to 87%¹⁷; however, randomized controlled trials testing the efficacy of contact immunotherapy are lacking. Although the mechanism of action of these topical sensitizers is not clearly delineated, it has been postulated that by inducing a new type of inflammatory response in the region, the immunologic milieu is changed, allowing the hair to grow. Some proposed mechanisms include promoting perifollicular lymphocyte apoptosis, preventing new recruitment of autoreactive lymphocytes, and allowing for the correction of aberrant major histocompatibility complex expression on the hair matrix epithelium to regain follicle immune privilege.^18-20

Iatrogenic immunotherapy may work analogously to the natural immune system deviation demonstrated in our patient. Psoriasis and AA are believed to form competing immune cells and cytokine milieus, thus explaining how an individual with AA could regain normal hair growth in areas of psoriasis.^15,16 The Renbök phenomenon, or reverse Köbner phenomenon, coined by Happle et al¹³ can be used to describe both the iatrogenic and natural cases of dermatologic disease improvement in response to secondary insults.¹⁴

A complex cascade of immune cells and cytokines coordinate AA pathogenesis. In the acute stage of AA, an inflammatory infiltrate of CD4⁺ T cells, CD8⁺ T cells, and antigen-presenting cells target anagen phase follicles, with a higher CD4⁺:CD8⁺ ratio in clinically active disease.^21-23 Subcutaneous injections of either CD4⁺ or CD8⁺ lymphocyte subsets from mice with AA into normal-haired mice induces disease. However, CD8⁺ T cell injections rapidly produce apparent hair loss, whereas CD4⁺ T cells cause hair loss after several weeks, suggesting that CD8⁺ T cells directly modulate AA hair loss and CD4⁺ T cells act as an aide.²⁴ The growth, differentiation, and survival of CD8⁺ T cells are stimulated by IL-2 and IFN-γ. Alopecia areata biopsies demonstrate a prevalence of T_H1 cytokines, and patients with localized AA, alopecia totalis, and AU have notably higher serum IFN-γ levels compared to controls.²⁵ In murine models, IL-1α and IL-1β increase during the catagen phase of the hair cycle and peak during the telogen phase.²⁶ Excessive IL-1β expression is detected in the early stages of human disease, and certain IL-1β polymorphisms are associated with severe forms of AA.²⁶ The role of tumor necrosis factor (TNF) α in AA is not well understood. In vitro studies show it inhibits hair growth, suggesting the cytokine may play a role in AA.²⁷ However, anti–TNF-α therapy is not effective in AA, and case reports propose these therapies rarely induce AA.^28-31

The T_H1 response is likewise critical to psoriatic plaque development. IFN-γ and TNF-α are overexpressed in psoriatic plaques.³² IFN-γ has an antiproliferative and differentiation-inducing effect on normal keratinocytes, but psoriatic epithelial cells in vitro respond differently to the cytokine with a notably diminished growth inhibition.^33,34 One explanation for the role of IFN-γ is that it stimulates dendritic cells to produce IL-1 and IL-23.³⁵ IL-23 activates T_H17 cells³⁶; T_H1 and T_H17 conditions produce IL-22 whose serum level correlates with disease severity.^37-39 IL-22 induces keratinocyte proliferation and migration and inhibits keratinocyte differentiation, helping account for hallmarks of the disease.⁴⁰ Patients with psoriasis have increased levels of T_H1, T_H17, and T_H22 cells, as well as their associated cytokines, in the skin and blood compared to controls.^{4,11,32,39,41}

Alopecia areata and psoriasis are regulated by complex and still not entirely understood immune interactions. The fact that many of the same therapies are used to treat both diseases emphasizes both their overlapping characteristics and the lack of targeted therapy. It is unclear if and how the topical or systemic therapies used in our patient to treat one disease affected the natural history of the other condition. It is important to highlight, however, that the patient had not been treated for months when he developed the psoriatic plaques with hair regrowth. Other case reports also document hair regrowth in untreated plaques,^13,16 making it unlikely to be a side effect of the medication regimen. For both psoriasis and AA, the immune cell composition and cytokine levels in the skin or serum vary throughout a patient’s disease course depending on severity of disease or response to treatment.^6,39,42,43 Therefore, we hypothesize that the 2 conditions interact in a similarly distinct manner based on each disease’s stage and intensity in the patient. Both our patient’s course thus far and the various presentations described by other groups support this hypothesis. Our patient had a small region of psoriasis on the scalp that cleared without any terminal hair growth. He also had larger plaques on the forearms that developed hair growth most predominantly within the thicker regions of the plaques. His unique presentation highlights the fluidity of the immune factors driving psoriasis vulgaris and AA.

To the Editor:

Atopic dermatitis (AD) is a common skin condition with an increasing prevalence, affecting up to 20% of children and 3% of adults.^1,2 More than 80% of patients with AD have elevated IgE levels.^3,4 IgE modulates the inflammatory response in AD in several ways including “a biphasic immediate/late phase reaction, allergen presentation by IgE-bearing Langerhans cells, allergen-induced activation of IgE-bearing macrophages, and IgE autoreactivity to human proteins.”⁵ Historically, most therapies have focused on mitigating the allergic symptoms caused by degranulated effector cells, such as antihistamines. However, a new class of biologically engineered medications (eg, anti-IgE [omalizumab]) aim to prevent the initiation of the allergic response.⁶ Variable success has been reported using omalizumab in the treatment of AD, though the majority of studies have shown improvement, especially when used in combination with conventional therapies.^4,5,7-22 Omalizumab dosage is determined by body weight and pretreatment serum total IgE levels and is administered via subcutaneous injections every 2 to 4 weeks.^6,7,23-26 However, the dosing tables are based on asthma therapy, in which serum IgE levels may be much lower than chronic AD,^7,24 and the appropriate dosage in AD patients with markedly elevated IgE is unclear. We report an interesting case of a 57-year-old man with erythroderma from long-standing severe chronic AD that was unresponsive to conventional therapy as well as an associated serum IgE level of 17,183 IU/mL who dramatically improved when omalizumab was added to his treatment regimen.

A 57-year-old man presented with essentially 100% body surface area involvement of AD with erythroderma and pruritus. Severe AD developed at infancy and cleared at 5 years of age; childhood onset of asthma was responsive to theophylline and oral inhalers. He developed recurrent AD and asthma at 38 years of age, which was progressive and developed into severe recalcitrant erythroderma by 50 years of age. His AD was unresponsive to multiple therapies, including topical steroids, antibiotics, tacrolimus, bleach baths, antihistamines, methotrexate (15 mg weekly for 1 year, then 12.5 mg weekly for 6 months), UVB phototherapy, and psoralen plus UVA photochemotherapy. He had minimal improvement with cyclosporine (200 mg daily for 4 weeks) and mycophenolate mofetil (3 g daily), and required systemic steroids for relief. The skin was violaceous and lichenified (Figure, A). Laboratory studies were normal, except for a serum IgE level of 17,183 IU/mL (reference range, <150 IU/mL) and peripheral blood eosinophilia up to 29.8% (reference range, 1%–5%) of the differential. Skin biopsies showed AD progressing to lichen simplex chronicus. Omalizumab was added to the therapeutic regimen at a dose of 375 mg every 2 weeks, with noticeable improvement after 3 months. The patient had approximately 80% to 90% clearing with resolution of erythroderma and pruritus, and only limited residual lichenification (Figure, B). The mycophenolate was tapered slowly, and the patient experienced a mild flare at 1 g daily. He is presently on 1 g of mycophenolate daily and omalizumab (375 mg every 2 weeks) and remains remarkably improved. His IgE level decreased to 11,983 IU/mL.

Omalizumab is a monoclonal IgG1 antibody that specifically binds to the FcεRI domain of serum IgE. It blocks binding to high-affinity receptors on effector cells, primarily mast cells, basophils, macrophages, and dendritic cells; it also decreases free IgE serum levels and downregulates the IgE receptor.^{4,6-10,23-25,27,28} Currently, omalizumab is US Food and Drug Administration approved for moderate to severe persistent asthma in patients 6 years or older with a positive aeroallergen skin test and IgE levels up to 700 IU/mL.^{6,7,23-25,27,28}

However, scattered case reports and small case series have described variable success in the treatment of severe AD that is unresponsive to conventional therapy in patients with markedly elevated serum IgE levels.^4,5,7-22 The majority of patients (approximately 80% of published cases yielded by a PubMed search of articles indexed for MEDLINE using the search terms omalizumab and atopic dermatitis) showed improvement when measured by clinical severity scores and quality of life improvement, especially when used in conjunction with conventional therapy. Possible reasons for reported treatment failure include insufficient dosage, lack of established treatment guidelines for markedly elevated serum IgE levels, severity of disease, or variable response with failure to lower IgE level below a required threshold.^7,9,23,24,27

Krathen and Hsu⁹ reported treatment failure with omalizumab for AD in 3 patients with serum IgE levels ranging from 5440 and 24,400 IU/mL, and one review indicated omalizumab may work best in patients with only moderately elevated serum IgE levels.²¹ However, Toledo et al¹⁸ reported efficacy of low-dose omalizumab for pretreatment IgE levels up to 30,000 IU/mL in 6 of 11 reported cases. The pretreatment serum IgE level is not predictive of response, and lowering the serum IgE level without normalization can be efficacious,^12,23 as in the current case. Serum IgE levels are not used for monitoring therapeutic response or calculating future dosing, given potential increases in serum IgE levels during and after therapy (for up to 12 months) secondary to the formation of anti-IgE:IgE complexes.^6,28 Omalizumab appears most effective when used in combination with conventional therapies. Hopefully ongoing studies will further elucidate the role of omalizumab in recalcitrant AD with elevated serum IgE levels.

To the Editor:

Atopic dermatitis (AD) is a common skin condition with an increasing prevalence, affecting up to 20% of children and 3% of adults.^1,2 More than 80% of patients with AD have elevated IgE levels.^3,4 IgE modulates the inflammatory response in AD in several ways including “a biphasic immediate/late phase reaction, allergen presentation by IgE-bearing Langerhans cells, allergen-induced activation of IgE-bearing macrophages, and IgE autoreactivity to human proteins.”⁵ Historically, most therapies have focused on mitigating the allergic symptoms caused by degranulated effector cells, such as antihistamines. However, a new class of biologically engineered medications (eg, anti-IgE [omalizumab]) aim to prevent the initiation of the allergic response.⁶ Variable success has been reported using omalizumab in the treatment of AD, though the majority of studies have shown improvement, especially when used in combination with conventional therapies.^4,5,7-22 Omalizumab dosage is determined by body weight and pretreatment serum total IgE levels and is administered via subcutaneous injections every 2 to 4 weeks.^6,7,23-26 However, the dosing tables are based on asthma therapy, in which serum IgE levels may be much lower than chronic AD,^7,24 and the appropriate dosage in AD patients with markedly elevated IgE is unclear. We report an interesting case of a 57-year-old man with erythroderma from long-standing severe chronic AD that was unresponsive to conventional therapy as well as an associated serum IgE level of 17,183 IU/mL who dramatically improved when omalizumab was added to his treatment regimen.

A 57-year-old man presented with essentially 100% body surface area involvement of AD with erythroderma and pruritus. Severe AD developed at infancy and cleared at 5 years of age; childhood onset of asthma was responsive to theophylline and oral inhalers. He developed recurrent AD and asthma at 38 years of age, which was progressive and developed into severe recalcitrant erythroderma by 50 years of age. His AD was unresponsive to multiple therapies, including topical steroids, antibiotics, tacrolimus, bleach baths, antihistamines, methotrexate (15 mg weekly for 1 year, then 12.5 mg weekly for 6 months), UVB phototherapy, and psoralen plus UVA photochemotherapy. He had minimal improvement with cyclosporine (200 mg daily for 4 weeks) and mycophenolate mofetil (3 g daily), and required systemic steroids for relief. The skin was violaceous and lichenified (Figure, A). Laboratory studies were normal, except for a serum IgE level of 17,183 IU/mL (reference range, <150 IU/mL) and peripheral blood eosinophilia up to 29.8% (reference range, 1%–5%) of the differential. Skin biopsies showed AD progressing to lichen simplex chronicus. Omalizumab was added to the therapeutic regimen at a dose of 375 mg every 2 weeks, with noticeable improvement after 3 months. The patient had approximately 80% to 90% clearing with resolution of erythroderma and pruritus, and only limited residual lichenification (Figure, B). The mycophenolate was tapered slowly, and the patient experienced a mild flare at 1 g daily. He is presently on 1 g of mycophenolate daily and omalizumab (375 mg every 2 weeks) and remains remarkably improved. His IgE level decreased to 11,983 IU/mL.

Omalizumab is a monoclonal IgG1 antibody that specifically binds to the FcεRI domain of serum IgE. It blocks binding to high-affinity receptors on effector cells, primarily mast cells, basophils, macrophages, and dendritic cells; it also decreases free IgE serum levels and downregulates the IgE receptor.^{4,6-10,23-25,27,28} Currently, omalizumab is US Food and Drug Administration approved for moderate to severe persistent asthma in patients 6 years or older with a positive aeroallergen skin test and IgE levels up to 700 IU/mL.^{6,7,23-25,27,28}

However, scattered case reports and small case series have described variable success in the treatment of severe AD that is unresponsive to conventional therapy in patients with markedly elevated serum IgE levels.^4,5,7-22 The majority of patients (approximately 80% of published cases yielded by a PubMed search of articles indexed for MEDLINE using the search terms omalizumab and atopic dermatitis) showed improvement when measured by clinical severity scores and quality of life improvement, especially when used in conjunction with conventional therapy. Possible reasons for reported treatment failure include insufficient dosage, lack of established treatment guidelines for markedly elevated serum IgE levels, severity of disease, or variable response with failure to lower IgE level below a required threshold.^7,9,23,24,27

Krathen and Hsu⁹ reported treatment failure with omalizumab for AD in 3 patients with serum IgE levels ranging from 5440 and 24,400 IU/mL, and one review indicated omalizumab may work best in patients with only moderately elevated serum IgE levels.²¹ However, Toledo et al¹⁸ reported efficacy of low-dose omalizumab for pretreatment IgE levels up to 30,000 IU/mL in 6 of 11 reported cases. The pretreatment serum IgE level is not predictive of response, and lowering the serum IgE level without normalization can be efficacious,^12,23 as in the current case. Serum IgE levels are not used for monitoring therapeutic response or calculating future dosing, given potential increases in serum IgE levels during and after therapy (for up to 12 months) secondary to the formation of anti-IgE:IgE complexes.^6,28 Omalizumab appears most effective when used in combination with conventional therapies. Hopefully ongoing studies will further elucidate the role of omalizumab in recalcitrant AD with elevated serum IgE levels.

To the Editor:

Atopic dermatitis (AD) is a common skin condition with an increasing prevalence, affecting up to 20% of children and 3% of adults.^1,2 More than 80% of patients with AD have elevated IgE levels.^3,4 IgE modulates the inflammatory response in AD in several ways including “a biphasic immediate/late phase reaction, allergen presentation by IgE-bearing Langerhans cells, allergen-induced activation of IgE-bearing macrophages, and IgE autoreactivity to human proteins.”⁵ Historically, most therapies have focused on mitigating the allergic symptoms caused by degranulated effector cells, such as antihistamines. However, a new class of biologically engineered medications (eg, anti-IgE [omalizumab]) aim to prevent the initiation of the allergic response.⁶ Variable success has been reported using omalizumab in the treatment of AD, though the majority of studies have shown improvement, especially when used in combination with conventional therapies.^4,5,7-22 Omalizumab dosage is determined by body weight and pretreatment serum total IgE levels and is administered via subcutaneous injections every 2 to 4 weeks.^6,7,23-26 However, the dosing tables are based on asthma therapy, in which serum IgE levels may be much lower than chronic AD,^7,24 and the appropriate dosage in AD patients with markedly elevated IgE is unclear. We report an interesting case of a 57-year-old man with erythroderma from long-standing severe chronic AD that was unresponsive to conventional therapy as well as an associated serum IgE level of 17,183 IU/mL who dramatically improved when omalizumab was added to his treatment regimen.

A 57-year-old man presented with essentially 100% body surface area involvement of AD with erythroderma and pruritus. Severe AD developed at infancy and cleared at 5 years of age; childhood onset of asthma was responsive to theophylline and oral inhalers. He developed recurrent AD and asthma at 38 years of age, which was progressive and developed into severe recalcitrant erythroderma by 50 years of age. His AD was unresponsive to multiple therapies, including topical steroids, antibiotics, tacrolimus, bleach baths, antihistamines, methotrexate (15 mg weekly for 1 year, then 12.5 mg weekly for 6 months), UVB phototherapy, and psoralen plus UVA photochemotherapy. He had minimal improvement with cyclosporine (200 mg daily for 4 weeks) and mycophenolate mofetil (3 g daily), and required systemic steroids for relief. The skin was violaceous and lichenified (Figure, A). Laboratory studies were normal, except for a serum IgE level of 17,183 IU/mL (reference range, <150 IU/mL) and peripheral blood eosinophilia up to 29.8% (reference range, 1%–5%) of the differential. Skin biopsies showed AD progressing to lichen simplex chronicus. Omalizumab was added to the therapeutic regimen at a dose of 375 mg every 2 weeks, with noticeable improvement after 3 months. The patient had approximately 80% to 90% clearing with resolution of erythroderma and pruritus, and only limited residual lichenification (Figure, B). The mycophenolate was tapered slowly, and the patient experienced a mild flare at 1 g daily. He is presently on 1 g of mycophenolate daily and omalizumab (375 mg every 2 weeks) and remains remarkably improved. His IgE level decreased to 11,983 IU/mL.

Omalizumab is a monoclonal IgG1 antibody that specifically binds to the FcεRI domain of serum IgE. It blocks binding to high-affinity receptors on effector cells, primarily mast cells, basophils, macrophages, and dendritic cells; it also decreases free IgE serum levels and downregulates the IgE receptor.^{4,6-10,23-25,27,28} Currently, omalizumab is US Food and Drug Administration approved for moderate to severe persistent asthma in patients 6 years or older with a positive aeroallergen skin test and IgE levels up to 700 IU/mL.^{6,7,23-25,27,28}

However, scattered case reports and small case series have described variable success in the treatment of severe AD that is unresponsive to conventional therapy in patients with markedly elevated serum IgE levels.^4,5,7-22 The majority of patients (approximately 80% of published cases yielded by a PubMed search of articles indexed for MEDLINE using the search terms omalizumab and atopic dermatitis) showed improvement when measured by clinical severity scores and quality of life improvement, especially when used in conjunction with conventional therapy. Possible reasons for reported treatment failure include insufficient dosage, lack of established treatment guidelines for markedly elevated serum IgE levels, severity of disease, or variable response with failure to lower IgE level below a required threshold.^7,9,23,24,27

Krathen and Hsu⁹ reported treatment failure with omalizumab for AD in 3 patients with serum IgE levels ranging from 5440 and 24,400 IU/mL, and one review indicated omalizumab may work best in patients with only moderately elevated serum IgE levels.²¹ However, Toledo et al¹⁸ reported efficacy of low-dose omalizumab for pretreatment IgE levels up to 30,000 IU/mL in 6 of 11 reported cases. The pretreatment serum IgE level is not predictive of response, and lowering the serum IgE level without normalization can be efficacious,^12,23 as in the current case. Serum IgE levels are not used for monitoring therapeutic response or calculating future dosing, given potential increases in serum IgE levels during and after therapy (for up to 12 months) secondary to the formation of anti-IgE:IgE complexes.^6,28 Omalizumab appears most effective when used in combination with conventional therapies. Hopefully ongoing studies will further elucidate the role of omalizumab in recalcitrant AD with elevated serum IgE levels.

To the Editor:
Collagenous and elastotic marginal plaques of the hands (CEMPHs) has several names including degenerative collagenous plaques of the hands, keratoelastoidosis marginalis, and digital papular calcific elastosis. This rare disorder is an acquired, slowly progressive, asymptomatic, dermal connective tissue abnormality that is underrecognized and underdiagnosed. Clinical presentation includes hyperkeratotic translucent papules arranged linearly on the radial aspect of the hands.

A 74-year-old woman described having "rough hands" of more than 20 years' duration. She presented with 4-cm wide longitudinal, erythematous, firm, depressed plaques along the lateral edge of the second finger and extending to the medial thumb in both hands (Figure 1). She had attempted multiple treatments by her primary care physician, including topical and oral medications unknown to the patient and light therapy, all without benefit over a period of several years. We have attempted salicylic acid 40%, clobetasol cream 0.05%, and emollient creams containing α-hydroxy acid. At best the condition fluctuated between a subtle raised scale at the edge to smooth and occasionally more red-pink, seemingly unrelated to any treatments.

The patient did not have plaques elsewhere on the body, and notably, the feet were clear. She did not have a history of repeated trauma to the hands and did not engage in manual labor. She denied excessive sun exposure, though she had Fitzpatrick skin type III and a history of multiple precancers and nonmelanoma skin cancers 7 years prior to presentation.

Histology of CEMPH reveals a hyperkeratotic epidermis with an avascular and acellular replacement of the superficial reticular dermis by haphazardly arranged, thickened collagen fibers (Figure 2A-2C). Collagen fibers were oriented perpendicularly to the epidermal surface. Intervening amorphous basophilic elastotic masses were present in the upper dermis with occasional calcification and degenerative elastic fibers (Figure 2D).

Collagenous and elastotic marginal plaques of the hands is a chronic, asymptomatic, sclerotic skin disorder described in a 1960 case series of 5 patients reported by Burks et al.¹ Although it has many names, the most common is CEMPH. Collagenous and elastotic marginal plaques of the hands most often presents in white men aged 50 to 60 years.² Patients typically are asymptomatic with plaques limited to the junction of the palmar and dorsal surfaces of the hands with only minimal intermittent stiffness around the flexor creases. Lesions begin as discrete yellow papules that coalesce to form hyperkeratotic linear plaques with occasional telangiectasia.³

The etiology of CEMPH is attributed to collagen and elastin degeneration by chronic actinic damage, pressure, or trauma.^4,5 The 3 stages of degeneration include an initial linear padded stage, an intermediate padded plaque stage, and an advanced padded hyperkeratotic plaque stage.⁴ Vascular compromise is seen from the enlarged and fused thickened collagen and elastic fibers that in turn lead to ischemic changes, hyperkeratosis with epidermal atrophy, and papillary dermis telangiectasia. Absence or weak expression of keratins 14 and 10 and strong expression of keratin 16 have been reported in the epidermis of CEMPH patients.⁴

Collagenous and elastotic marginal plaques of the hands do not have a specific treatment, as it is a benign, slowly progressive condition. Several treatments such as laser therapy, high-potency topical corticosteroids, topical tazarotene and tretinoin, oral isotretinoin, and cryotherapy have been tried with little long-term success.⁴ Moisturizing may help reduce fissuring, and patients are advised to avoid the sun and repeated trauma to the hands.

The differential diagnosis of CEMPH is summarized in the Table. Two genodermatoses—acrokeratoelastoidosis of Costa and focal acral hyperkeratosis—clinically resemble CEMPH. Acrokeratoelastoidosis of Costa is an autosomal-dominant condition that occurs without trauma in children and young adults. Histopathology shows orthokeratotic hyperkeratosis due to an overproduction of filaggrin in the granular layer of the epidermis. The reticular dermis shows basophilic, thick, curled and fragmented elastic fibers with dilated capillaries that can be seen with Weigert elastic, Verhoeff-van Gieson, or orcein stains. Focal acral hyperkeratosis occurs on the hands and feet, predominantly in black patients. On histology, the epidermis shows a characteristic orthohyperkeratosis, moderate acanthosis, and slight hypergranulosis with no dermal involvment.⁶

Chronic hyperkeratotic eczematous dermatitis is another common entity in the differential characterized by hyperkeratotic plaques that scale and fissure. Biopsy demonstrates a spongiotic acanthotic epidermis.^7,8

Psoriasis of the hands, specifically hyperkeratotic palmoplantar psoriasis, is associated with manual labor, similar to CEMPH. Histology shows epidermal hyperplasia; regular acanthosis; loss of the granular skin layer with prominent dermal capillaries; and a mixed dermal infiltrate of lymphocytes, macrophages, and neutrophils.⁹ Hyperkeratotic palmoplantar lichen planus presents with pruritic papules in the third and fifth decades of life. Histologically, hyperkeratosis, acanthosis, and wedge-shaped hypergranulosis with a lichenoid lymphocytic infiltration at the dermoepidermal junction is seen.¹⁰

Palmoplantar keratodermas due to inflammatory reactive dermatoses include callosities that develop in response to repeated trauma or friction on the skin. On histology, there is prominent hyperkeratosis and acanthosis with moderate papillomatosis.¹¹ Drug-related palmoplantar keratodermas such as those from arsenic exposure can lead to multiple, irregular, verrucous, keratotic, and pigmented lesions on the palms and soles. Histologically, atypical keratinocytes are seen in the epidermis with thick hyperkeratosis and vacuolated cells without solar elastosis.¹²

In conclusion, CEMPH is an underdiagnosed and underrecognized condition characterized by asymptomatic hyperkeratotic linear plaques along the medial aspect of the thumb and radial aspect of the index finger. It is important to keep CEMPH in mind when dealing with occupational cases of repeated long-term trauma or pressure to the hands as well as excessive sun exposure. It also is imperative to separate it from other diseases and avoid misdiagnosing this degenerative collagenous and elastotic disease as a malignant lesion. 

To the Editor:
Collagenous and elastotic marginal plaques of the hands (CEMPHs) has several names including degenerative collagenous plaques of the hands, keratoelastoidosis marginalis, and digital papular calcific elastosis. This rare disorder is an acquired, slowly progressive, asymptomatic, dermal connective tissue abnormality that is underrecognized and underdiagnosed. Clinical presentation includes hyperkeratotic translucent papules arranged linearly on the radial aspect of the hands.

A 74-year-old woman described having "rough hands" of more than 20 years' duration. She presented with 4-cm wide longitudinal, erythematous, firm, depressed plaques along the lateral edge of the second finger and extending to the medial thumb in both hands (Figure 1). She had attempted multiple treatments by her primary care physician, including topical and oral medications unknown to the patient and light therapy, all without benefit over a period of several years. We have attempted salicylic acid 40%, clobetasol cream 0.05%, and emollient creams containing α-hydroxy acid. At best the condition fluctuated between a subtle raised scale at the edge to smooth and occasionally more red-pink, seemingly unrelated to any treatments.

The patient did not have plaques elsewhere on the body, and notably, the feet were clear. She did not have a history of repeated trauma to the hands and did not engage in manual labor. She denied excessive sun exposure, though she had Fitzpatrick skin type III and a history of multiple precancers and nonmelanoma skin cancers 7 years prior to presentation.

Histology of CEMPH reveals a hyperkeratotic epidermis with an avascular and acellular replacement of the superficial reticular dermis by haphazardly arranged, thickened collagen fibers (Figure 2A-2C). Collagen fibers were oriented perpendicularly to the epidermal surface. Intervening amorphous basophilic elastotic masses were present in the upper dermis with occasional calcification and degenerative elastic fibers (Figure 2D).

Collagenous and elastotic marginal plaques of the hands is a chronic, asymptomatic, sclerotic skin disorder described in a 1960 case series of 5 patients reported by Burks et al.¹ Although it has many names, the most common is CEMPH. Collagenous and elastotic marginal plaques of the hands most often presents in white men aged 50 to 60 years.² Patients typically are asymptomatic with plaques limited to the junction of the palmar and dorsal surfaces of the hands with only minimal intermittent stiffness around the flexor creases. Lesions begin as discrete yellow papules that coalesce to form hyperkeratotic linear plaques with occasional telangiectasia.³

The etiology of CEMPH is attributed to collagen and elastin degeneration by chronic actinic damage, pressure, or trauma.^4,5 The 3 stages of degeneration include an initial linear padded stage, an intermediate padded plaque stage, and an advanced padded hyperkeratotic plaque stage.⁴ Vascular compromise is seen from the enlarged and fused thickened collagen and elastic fibers that in turn lead to ischemic changes, hyperkeratosis with epidermal atrophy, and papillary dermis telangiectasia. Absence or weak expression of keratins 14 and 10 and strong expression of keratin 16 have been reported in the epidermis of CEMPH patients.⁴

Collagenous and elastotic marginal plaques of the hands do not have a specific treatment, as it is a benign, slowly progressive condition. Several treatments such as laser therapy, high-potency topical corticosteroids, topical tazarotene and tretinoin, oral isotretinoin, and cryotherapy have been tried with little long-term success.⁴ Moisturizing may help reduce fissuring, and patients are advised to avoid the sun and repeated trauma to the hands.

The differential diagnosis of CEMPH is summarized in the Table. Two genodermatoses—acrokeratoelastoidosis of Costa and focal acral hyperkeratosis—clinically resemble CEMPH. Acrokeratoelastoidosis of Costa is an autosomal-dominant condition that occurs without trauma in children and young adults. Histopathology shows orthokeratotic hyperkeratosis due to an overproduction of filaggrin in the granular layer of the epidermis. The reticular dermis shows basophilic, thick, curled and fragmented elastic fibers with dilated capillaries that can be seen with Weigert elastic, Verhoeff-van Gieson, or orcein stains. Focal acral hyperkeratosis occurs on the hands and feet, predominantly in black patients. On histology, the epidermis shows a characteristic orthohyperkeratosis, moderate acanthosis, and slight hypergranulosis with no dermal involvment.⁶

Chronic hyperkeratotic eczematous dermatitis is another common entity in the differential characterized by hyperkeratotic plaques that scale and fissure. Biopsy demonstrates a spongiotic acanthotic epidermis.^7,8

Psoriasis of the hands, specifically hyperkeratotic palmoplantar psoriasis, is associated with manual labor, similar to CEMPH. Histology shows epidermal hyperplasia; regular acanthosis; loss of the granular skin layer with prominent dermal capillaries; and a mixed dermal infiltrate of lymphocytes, macrophages, and neutrophils.⁹ Hyperkeratotic palmoplantar lichen planus presents with pruritic papules in the third and fifth decades of life. Histologically, hyperkeratosis, acanthosis, and wedge-shaped hypergranulosis with a lichenoid lymphocytic infiltration at the dermoepidermal junction is seen.¹⁰

Palmoplantar keratodermas due to inflammatory reactive dermatoses include callosities that develop in response to repeated trauma or friction on the skin. On histology, there is prominent hyperkeratosis and acanthosis with moderate papillomatosis.¹¹ Drug-related palmoplantar keratodermas such as those from arsenic exposure can lead to multiple, irregular, verrucous, keratotic, and pigmented lesions on the palms and soles. Histologically, atypical keratinocytes are seen in the epidermis with thick hyperkeratosis and vacuolated cells without solar elastosis.¹²

In conclusion, CEMPH is an underdiagnosed and underrecognized condition characterized by asymptomatic hyperkeratotic linear plaques along the medial aspect of the thumb and radial aspect of the index finger. It is important to keep CEMPH in mind when dealing with occupational cases of repeated long-term trauma or pressure to the hands as well as excessive sun exposure. It also is imperative to separate it from other diseases and avoid misdiagnosing this degenerative collagenous and elastotic disease as a malignant lesion. 

To the Editor:
Collagenous and elastotic marginal plaques of the hands (CEMPHs) has several names including degenerative collagenous plaques of the hands, keratoelastoidosis marginalis, and digital papular calcific elastosis. This rare disorder is an acquired, slowly progressive, asymptomatic, dermal connective tissue abnormality that is underrecognized and underdiagnosed. Clinical presentation includes hyperkeratotic translucent papules arranged linearly on the radial aspect of the hands.

A 74-year-old woman described having "rough hands" of more than 20 years' duration. She presented with 4-cm wide longitudinal, erythematous, firm, depressed plaques along the lateral edge of the second finger and extending to the medial thumb in both hands (Figure 1). She had attempted multiple treatments by her primary care physician, including topical and oral medications unknown to the patient and light therapy, all without benefit over a period of several years. We have attempted salicylic acid 40%, clobetasol cream 0.05%, and emollient creams containing α-hydroxy acid. At best the condition fluctuated between a subtle raised scale at the edge to smooth and occasionally more red-pink, seemingly unrelated to any treatments.

The patient did not have plaques elsewhere on the body, and notably, the feet were clear. She did not have a history of repeated trauma to the hands and did not engage in manual labor. She denied excessive sun exposure, though she had Fitzpatrick skin type III and a history of multiple precancers and nonmelanoma skin cancers 7 years prior to presentation.

Histology of CEMPH reveals a hyperkeratotic epidermis with an avascular and acellular replacement of the superficial reticular dermis by haphazardly arranged, thickened collagen fibers (Figure 2A-2C). Collagen fibers were oriented perpendicularly to the epidermal surface. Intervening amorphous basophilic elastotic masses were present in the upper dermis with occasional calcification and degenerative elastic fibers (Figure 2D).

Collagenous and elastotic marginal plaques of the hands is a chronic, asymptomatic, sclerotic skin disorder described in a 1960 case series of 5 patients reported by Burks et al.¹ Although it has many names, the most common is CEMPH. Collagenous and elastotic marginal plaques of the hands most often presents in white men aged 50 to 60 years.² Patients typically are asymptomatic with plaques limited to the junction of the palmar and dorsal surfaces of the hands with only minimal intermittent stiffness around the flexor creases. Lesions begin as discrete yellow papules that coalesce to form hyperkeratotic linear plaques with occasional telangiectasia.³

The etiology of CEMPH is attributed to collagen and elastin degeneration by chronic actinic damage, pressure, or trauma.^4,5 The 3 stages of degeneration include an initial linear padded stage, an intermediate padded plaque stage, and an advanced padded hyperkeratotic plaque stage.⁴ Vascular compromise is seen from the enlarged and fused thickened collagen and elastic fibers that in turn lead to ischemic changes, hyperkeratosis with epidermal atrophy, and papillary dermis telangiectasia. Absence or weak expression of keratins 14 and 10 and strong expression of keratin 16 have been reported in the epidermis of CEMPH patients.⁴

Collagenous and elastotic marginal plaques of the hands do not have a specific treatment, as it is a benign, slowly progressive condition. Several treatments such as laser therapy, high-potency topical corticosteroids, topical tazarotene and tretinoin, oral isotretinoin, and cryotherapy have been tried with little long-term success.⁴ Moisturizing may help reduce fissuring, and patients are advised to avoid the sun and repeated trauma to the hands.

The differential diagnosis of CEMPH is summarized in the Table. Two genodermatoses—acrokeratoelastoidosis of Costa and focal acral hyperkeratosis—clinically resemble CEMPH. Acrokeratoelastoidosis of Costa is an autosomal-dominant condition that occurs without trauma in children and young adults. Histopathology shows orthokeratotic hyperkeratosis due to an overproduction of filaggrin in the granular layer of the epidermis. The reticular dermis shows basophilic, thick, curled and fragmented elastic fibers with dilated capillaries that can be seen with Weigert elastic, Verhoeff-van Gieson, or orcein stains. Focal acral hyperkeratosis occurs on the hands and feet, predominantly in black patients. On histology, the epidermis shows a characteristic orthohyperkeratosis, moderate acanthosis, and slight hypergranulosis with no dermal involvment.⁶

Chronic hyperkeratotic eczematous dermatitis is another common entity in the differential characterized by hyperkeratotic plaques that scale and fissure. Biopsy demonstrates a spongiotic acanthotic epidermis.^7,8

Psoriasis of the hands, specifically hyperkeratotic palmoplantar psoriasis, is associated with manual labor, similar to CEMPH. Histology shows epidermal hyperplasia; regular acanthosis; loss of the granular skin layer with prominent dermal capillaries; and a mixed dermal infiltrate of lymphocytes, macrophages, and neutrophils.⁹ Hyperkeratotic palmoplantar lichen planus presents with pruritic papules in the third and fifth decades of life. Histologically, hyperkeratosis, acanthosis, and wedge-shaped hypergranulosis with a lichenoid lymphocytic infiltration at the dermoepidermal junction is seen.¹⁰

Palmoplantar keratodermas due to inflammatory reactive dermatoses include callosities that develop in response to repeated trauma or friction on the skin. On histology, there is prominent hyperkeratosis and acanthosis with moderate papillomatosis.¹¹ Drug-related palmoplantar keratodermas such as those from arsenic exposure can lead to multiple, irregular, verrucous, keratotic, and pigmented lesions on the palms and soles. Histologically, atypical keratinocytes are seen in the epidermis with thick hyperkeratosis and vacuolated cells without solar elastosis.¹²

In conclusion, CEMPH is an underdiagnosed and underrecognized condition characterized by asymptomatic hyperkeratotic linear plaques along the medial aspect of the thumb and radial aspect of the index finger. It is important to keep CEMPH in mind when dealing with occupational cases of repeated long-term trauma or pressure to the hands as well as excessive sun exposure. It also is imperative to separate it from other diseases and avoid misdiagnosing this degenerative collagenous and elastotic disease as a malignant lesion. 

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.

To the Editor:

Primary cutaneous cryptococcal infection is rare. Cryptococcal skin infections, either primary or disseminated, can be highly pleomorphic and mimic entities such as basal cell carcinoma or even severe dermatitis, as in our case. 

An 80-year-old woman who was residing in a nursing facility presented to the emergency department with an itchy nontender rash on the left arm of 2 to 3 weeks' duration that gradually spread. The patient had not started any new topical or oral medications and was otherwise healthy. A review of symptoms was negative for fever, weight loss, or new cough. Her medical history was notable for congestive heart failure, chronic obstructive pulmonary disease requiring chronic low-dose prednisone, hypothyroidism, atrial fibrillation, hypertension, and dementia. On physical examination the patient had a large, well-demarcated, pink, scaly plaque with areas of ulceration extending from the dorsal aspect of the hand and fingers to the mid upper arm. There was minimal overlying yellow-brown crust (Figure 1). A potassium hydroxide preparation from a superficial scraping was negative. A punch biopsy specimen was obtained from the lesion and microscopic examination revealed histiocytes with innumerable intracytoplasmic yeast forms demonstrating small buds (Figure 2). The organisms were highlighted by periodic acid-Schiff and Grocott-Gomori methenamine-silver stains (Figure 3), while acid-fast bacillus and Fite stains were negative. The presumptive diagnosis of cutaneous cryptococcosis was made, and subsequent culture and latex agglutination test was positive for Cryptococcus neoformans. A chest radiograph showed no evidence of active disease. Infectious disease specialists were consulted and ordered additional laboratory studies, which were negative for human immunodeficiency virus, hepatitis, and fungemia. The patient had a low CD4 count of 119 cells/μL (reference range, 496-2186 cells/μL). Workup for systemic Cryptococcus, including head computed tomography, cerebral spinal fluid analysis, and bone marrow biopsy were all negative. Epstein-Barr virus and human T lymphotropic virus tests were both negative. The source of the patient's low CD4 count was never discovered. She gradually began to improve with diligent wound care and continued fluconazole 400 mg daily. The patient's history did reveal working on a chicken farm as an adult many years ago.

Cryptococcus is a yeast that causes infection primarily through airborne spores that lead to pulmonary infection. Cryptococcus neoformans is the most common pathogenic strain, though infection with other strains such as Cryptococcus albidus¹ and Cryptococcus laurentii² have been reported. Primary cutaneous cryptococcosis is an exceedingly rare entity, with the majority of cases of cutaneous cryptococcosis originating from primary pulmonary infection with hematogenous dissemination to the skin. Primary cutaneous cryptococcosis rarely can be caused by inoculation in nonimmunosuppressed hosts and infection of nonimmunosuppressed hosts is more common in men than in women.³ Manifestations of cutaneous cryptococcosis can be incredibly varied and diagnosis requires a high index of suspicion along with appropriate histological and serological confirmation. Cutaneous cryptococcosis can present in various clinical ways, including molluscumlike lesions, which are more common in patients with AIDS; acneform lesions; vesicles; dermal plaques or nodules; and rarely cellulitis with ulcerations, as in our patient. Cryptococcosis also can imitate basal cell carcinoma, nummular and follicular eczema, and Kaposi sarcoma.⁴ 

Histologic examination reveals either a gelatinous or granulomatous pattern based on the number of organisms present. The gelatinous pattern is characterized by little inflammation and a large number of phagocytosed organisms floating in mucin. The granulomatous pattern shows prominent inflammation with lymphocytes, histiocytes, and giant cells, as well as associated necrosis.

Treatment depends on the type of infection and host immunological status. Immunocompetent hosts with cutaneous infection may spontaneously heal. Treatment consists of surgical excision, if possible, followed by fluconazole or itraconazole. For disseminated cryptococcal infections in immunosuppressed hosts, the standard of care is amphotericin B with or without flucytosine.³

To the Editor:

Primary cutaneous cryptococcal infection is rare. Cryptococcal skin infections, either primary or disseminated, can be highly pleomorphic and mimic entities such as basal cell carcinoma or even severe dermatitis, as in our case. 

An 80-year-old woman who was residing in a nursing facility presented to the emergency department with an itchy nontender rash on the left arm of 2 to 3 weeks' duration that gradually spread. The patient had not started any new topical or oral medications and was otherwise healthy. A review of symptoms was negative for fever, weight loss, or new cough. Her medical history was notable for congestive heart failure, chronic obstructive pulmonary disease requiring chronic low-dose prednisone, hypothyroidism, atrial fibrillation, hypertension, and dementia. On physical examination the patient had a large, well-demarcated, pink, scaly plaque with areas of ulceration extending from the dorsal aspect of the hand and fingers to the mid upper arm. There was minimal overlying yellow-brown crust (Figure 1). A potassium hydroxide preparation from a superficial scraping was negative. A punch biopsy specimen was obtained from the lesion and microscopic examination revealed histiocytes with innumerable intracytoplasmic yeast forms demonstrating small buds (Figure 2). The organisms were highlighted by periodic acid-Schiff and Grocott-Gomori methenamine-silver stains (Figure 3), while acid-fast bacillus and Fite stains were negative. The presumptive diagnosis of cutaneous cryptococcosis was made, and subsequent culture and latex agglutination test was positive for Cryptococcus neoformans. A chest radiograph showed no evidence of active disease. Infectious disease specialists were consulted and ordered additional laboratory studies, which were negative for human immunodeficiency virus, hepatitis, and fungemia. The patient had a low CD4 count of 119 cells/μL (reference range, 496-2186 cells/μL). Workup for systemic Cryptococcus, including head computed tomography, cerebral spinal fluid analysis, and bone marrow biopsy were all negative. Epstein-Barr virus and human T lymphotropic virus tests were both negative. The source of the patient's low CD4 count was never discovered. She gradually began to improve with diligent wound care and continued fluconazole 400 mg daily. The patient's history did reveal working on a chicken farm as an adult many years ago.

Cryptococcus is a yeast that causes infection primarily through airborne spores that lead to pulmonary infection. Cryptococcus neoformans is the most common pathogenic strain, though infection with other strains such as Cryptococcus albidus¹ and Cryptococcus laurentii² have been reported. Primary cutaneous cryptococcosis is an exceedingly rare entity, with the majority of cases of cutaneous cryptococcosis originating from primary pulmonary infection with hematogenous dissemination to the skin. Primary cutaneous cryptococcosis rarely can be caused by inoculation in nonimmunosuppressed hosts and infection of nonimmunosuppressed hosts is more common in men than in women.³ Manifestations of cutaneous cryptococcosis can be incredibly varied and diagnosis requires a high index of suspicion along with appropriate histological and serological confirmation. Cutaneous cryptococcosis can present in various clinical ways, including molluscumlike lesions, which are more common in patients with AIDS; acneform lesions; vesicles; dermal plaques or nodules; and rarely cellulitis with ulcerations, as in our patient. Cryptococcosis also can imitate basal cell carcinoma, nummular and follicular eczema, and Kaposi sarcoma.⁴ 

Histologic examination reveals either a gelatinous or granulomatous pattern based on the number of organisms present. The gelatinous pattern is characterized by little inflammation and a large number of phagocytosed organisms floating in mucin. The granulomatous pattern shows prominent inflammation with lymphocytes, histiocytes, and giant cells, as well as associated necrosis.

Treatment depends on the type of infection and host immunological status. Immunocompetent hosts with cutaneous infection may spontaneously heal. Treatment consists of surgical excision, if possible, followed by fluconazole or itraconazole. For disseminated cryptococcal infections in immunosuppressed hosts, the standard of care is amphotericin B with or without flucytosine.³

To the Editor:

Primary cutaneous cryptococcal infection is rare. Cryptococcal skin infections, either primary or disseminated, can be highly pleomorphic and mimic entities such as basal cell carcinoma or even severe dermatitis, as in our case. 

An 80-year-old woman who was residing in a nursing facility presented to the emergency department with an itchy nontender rash on the left arm of 2 to 3 weeks' duration that gradually spread. The patient had not started any new topical or oral medications and was otherwise healthy. A review of symptoms was negative for fever, weight loss, or new cough. Her medical history was notable for congestive heart failure, chronic obstructive pulmonary disease requiring chronic low-dose prednisone, hypothyroidism, atrial fibrillation, hypertension, and dementia. On physical examination the patient had a large, well-demarcated, pink, scaly plaque with areas of ulceration extending from the dorsal aspect of the hand and fingers to the mid upper arm. There was minimal overlying yellow-brown crust (Figure 1). A potassium hydroxide preparation from a superficial scraping was negative. A punch biopsy specimen was obtained from the lesion and microscopic examination revealed histiocytes with innumerable intracytoplasmic yeast forms demonstrating small buds (Figure 2). The organisms were highlighted by periodic acid-Schiff and Grocott-Gomori methenamine-silver stains (Figure 3), while acid-fast bacillus and Fite stains were negative. The presumptive diagnosis of cutaneous cryptococcosis was made, and subsequent culture and latex agglutination test was positive for Cryptococcus neoformans. A chest radiograph showed no evidence of active disease. Infectious disease specialists were consulted and ordered additional laboratory studies, which were negative for human immunodeficiency virus, hepatitis, and fungemia. The patient had a low CD4 count of 119 cells/μL (reference range, 496-2186 cells/μL). Workup for systemic Cryptococcus, including head computed tomography, cerebral spinal fluid analysis, and bone marrow biopsy were all negative. Epstein-Barr virus and human T lymphotropic virus tests were both negative. The source of the patient's low CD4 count was never discovered. She gradually began to improve with diligent wound care and continued fluconazole 400 mg daily. The patient's history did reveal working on a chicken farm as an adult many years ago.

Cryptococcus is a yeast that causes infection primarily through airborne spores that lead to pulmonary infection. Cryptococcus neoformans is the most common pathogenic strain, though infection with other strains such as Cryptococcus albidus¹ and Cryptococcus laurentii² have been reported. Primary cutaneous cryptococcosis is an exceedingly rare entity, with the majority of cases of cutaneous cryptococcosis originating from primary pulmonary infection with hematogenous dissemination to the skin. Primary cutaneous cryptococcosis rarely can be caused by inoculation in nonimmunosuppressed hosts and infection of nonimmunosuppressed hosts is more common in men than in women.³ Manifestations of cutaneous cryptococcosis can be incredibly varied and diagnosis requires a high index of suspicion along with appropriate histological and serological confirmation. Cutaneous cryptococcosis can present in various clinical ways, including molluscumlike lesions, which are more common in patients with AIDS; acneform lesions; vesicles; dermal plaques or nodules; and rarely cellulitis with ulcerations, as in our patient. Cryptococcosis also can imitate basal cell carcinoma, nummular and follicular eczema, and Kaposi sarcoma.⁴ 

Histologic examination reveals either a gelatinous or granulomatous pattern based on the number of organisms present. The gelatinous pattern is characterized by little inflammation and a large number of phagocytosed organisms floating in mucin. The granulomatous pattern shows prominent inflammation with lymphocytes, histiocytes, and giant cells, as well as associated necrosis.

Treatment depends on the type of infection and host immunological status. Immunocompetent hosts with cutaneous infection may spontaneously heal. Treatment consists of surgical excision, if possible, followed by fluconazole or itraconazole. For disseminated cryptococcal infections in immunosuppressed hosts, the standard of care is amphotericin B with or without flucytosine.³

To the Editor:

A 57-year-old man with a history of type 2 diabetes mellitus and hypertension was hospitalized for heart disease resulting in an aortic valve replacement and multiple-vessel bypass grafting. He experienced a stormy septic postoperative course during which he developed numerous palpable purplish plaques (Figure 1). The lesions were bilateral and more heavily involved the lower legs and buttocks. The head and neck remained free of skin lesions. Additionally, the patient reported a bilateral burning sensation from the knees to the feet.

Punch biopsies of lesions from the right upper arm were obtained. Hematoxylin and eosin staining revealed neutrophilic-predominant small vessel vasculitis (Figure 2A) with the upper dermal location more heavily involved, as demonstrated by involvement of a superficial vascular plexus (Figures 2B and 2C) that was consistent with Henoch-Schönlein purpura (HSP). The diagnosis later was confirmed with immunofluorescence. Direct immunofluorescence revealed granular IgA deposition around the superficial vascular plexus (Figure 3). No IgG, IgM, C3, C5b-9 complement complex, or fibrinogen deposition was seen. Additionally, periodic acid-Schiff staining failed to show microorganisms, thrombi, or intravascular hyaline material.

At our initial consultation, we observed an ill-appearing afebrile man with purplish plaques. Our impression was that he had vasculitis and not warfarin necrosis, which had been suspected by the cardiovascular team. The burning sensation noted by the patient lent credence to our vasculitic diagnosis. Proteinuria and hematuria were present; however, the values for blood urea nitrogen, creatinine, and glomerular filtration rate all remained within reference range. His signs and symptoms responded dramatically to prednisone. He remains on 1 mg of prednisone daily and a nephrologist continues to monitor renal function as an outpatient.

Henoch-Schönlein purpura is a systemic leukocytoclastic vasculitis involving small vessels. The small vessel vasculitis is associated with IgA antigen-antibody complex deposition in areas throughout the body. Palpable purpura typically is seen on the skin, which characteristically involves dependent areas such as the legs and the buttocks. Lesions normally are present bilaterally in a symmetric distribution. Initially, the lesions develop as erythematous macules that progress to purple, nonblanching, palpable, and purpuric plaques.¹ Henoch-Schönlein purpura most commonly involves the skin; however, other locations for the immune complexes include the gastrointestinal tract, joints, and kidneys.² The cause for the body's immunogenic deposition response is unknown in a majority of cases.

Henoch-Schönlein purpura most commonly is seen in the pediatric population with a predilection for males.³ The incidence in the pediatric population is 13.5 to 20 per 100,000 children per year; HSP is more rare in adults.^4-6 Henoch-Schönlein purpura most often is a self-limiting disease that requires only supportive treatment. The signs and symptoms last 4 to 6 weeks in most patients and resolve completely in 94% of children and 89% of adults.⁷ Renal involvement carries a worse prognosis. Adult patients have a higher incidence of renal involvement, renal insufficiency, and subsequent progression to end-stage renal disease.^3,8-10 In a study by Hung et al⁸ of 65 children and 22 adult HSP patients, 12 adults presented with renal involvement in which hematuria or proteinuria were present. Of them, 6 progressed to renal insufficiency (defined as having a plasma creatinine concentration>1.2 mg/dL).⁸ Fogazzi et al¹¹ reported similar findings; 8 of 16 patients affected with HSP progressed to renal insufficiency with creatinine clearances ranging from 31 to 60 mL/min, and 3 patients required chronic dialysis. Pillebout et al⁹ evaluated 250 adults with HSP and 32% reached renal insufficiency with creatinine clearances of less than 50 mL/min, with 11% of patients developing end-stage renal disease. The degree of hematuria and/or proteinuria has been shown to be an effective prognostic indicator.^9,10 Coppo et al¹⁰ found a similar prognosis among children and adults with HSP-related nephritis.

Our patient described the burning sensation as occurring bilaterally from the knees down to the feet, which provided an additional clue that small vessel vasculitis was involved, as occluded blood vessels can cause ischemia to nerves and perivascular involvement can affect nearby neural structures. Sais et al¹² demonstrated that paresthesia in the setting of HSP was a risk factor for systemic involvement. Of note,  our patient's paresthesia lasted only several days.

The cause of HSP is not always as evident in the adult population as in the pediatric population. Early diagnosis of HSP in adults may allow for the proper instatement of treatment to deter long-term renal complications. Follow-up with urinalysis is recommended because a small percentage of patients have a late progression to renal failure.^13,14

Because the dermatologists involved in this case knew where and what types of biopsies to perform, a correct diagnosis was obtained quickly, allowing for the correct therapeutic intervention. After the diagnosis of HSP is made in an adult, nephrology should be consulted early in the treatment course.

To the Editor:

A 57-year-old man with a history of type 2 diabetes mellitus and hypertension was hospitalized for heart disease resulting in an aortic valve replacement and multiple-vessel bypass grafting. He experienced a stormy septic postoperative course during which he developed numerous palpable purplish plaques (Figure 1). The lesions were bilateral and more heavily involved the lower legs and buttocks. The head and neck remained free of skin lesions. Additionally, the patient reported a bilateral burning sensation from the knees to the feet.

Punch biopsies of lesions from the right upper arm were obtained. Hematoxylin and eosin staining revealed neutrophilic-predominant small vessel vasculitis (Figure 2A) with the upper dermal location more heavily involved, as demonstrated by involvement of a superficial vascular plexus (Figures 2B and 2C) that was consistent with Henoch-Schönlein purpura (HSP). The diagnosis later was confirmed with immunofluorescence. Direct immunofluorescence revealed granular IgA deposition around the superficial vascular plexus (Figure 3). No IgG, IgM, C3, C5b-9 complement complex, or fibrinogen deposition was seen. Additionally, periodic acid-Schiff staining failed to show microorganisms, thrombi, or intravascular hyaline material.

At our initial consultation, we observed an ill-appearing afebrile man with purplish plaques. Our impression was that he had vasculitis and not warfarin necrosis, which had been suspected by the cardiovascular team. The burning sensation noted by the patient lent credence to our vasculitic diagnosis. Proteinuria and hematuria were present; however, the values for blood urea nitrogen, creatinine, and glomerular filtration rate all remained within reference range. His signs and symptoms responded dramatically to prednisone. He remains on 1 mg of prednisone daily and a nephrologist continues to monitor renal function as an outpatient.

Henoch-Schönlein purpura is a systemic leukocytoclastic vasculitis involving small vessels. The small vessel vasculitis is associated with IgA antigen-antibody complex deposition in areas throughout the body. Palpable purpura typically is seen on the skin, which characteristically involves dependent areas such as the legs and the buttocks. Lesions normally are present bilaterally in a symmetric distribution. Initially, the lesions develop as erythematous macules that progress to purple, nonblanching, palpable, and purpuric plaques.¹ Henoch-Schönlein purpura most commonly involves the skin; however, other locations for the immune complexes include the gastrointestinal tract, joints, and kidneys.² The cause for the body's immunogenic deposition response is unknown in a majority of cases.

Henoch-Schönlein purpura most commonly is seen in the pediatric population with a predilection for males.³ The incidence in the pediatric population is 13.5 to 20 per 100,000 children per year; HSP is more rare in adults.^4-6 Henoch-Schönlein purpura most often is a self-limiting disease that requires only supportive treatment. The signs and symptoms last 4 to 6 weeks in most patients and resolve completely in 94% of children and 89% of adults.⁷ Renal involvement carries a worse prognosis. Adult patients have a higher incidence of renal involvement, renal insufficiency, and subsequent progression to end-stage renal disease.^3,8-10 In a study by Hung et al⁸ of 65 children and 22 adult HSP patients, 12 adults presented with renal involvement in which hematuria or proteinuria were present. Of them, 6 progressed to renal insufficiency (defined as having a plasma creatinine concentration>1.2 mg/dL).⁸ Fogazzi et al¹¹ reported similar findings; 8 of 16 patients affected with HSP progressed to renal insufficiency with creatinine clearances ranging from 31 to 60 mL/min, and 3 patients required chronic dialysis. Pillebout et al⁹ evaluated 250 adults with HSP and 32% reached renal insufficiency with creatinine clearances of less than 50 mL/min, with 11% of patients developing end-stage renal disease. The degree of hematuria and/or proteinuria has been shown to be an effective prognostic indicator.^9,10 Coppo et al¹⁰ found a similar prognosis among children and adults with HSP-related nephritis.

Our patient described the burning sensation as occurring bilaterally from the knees down to the feet, which provided an additional clue that small vessel vasculitis was involved, as occluded blood vessels can cause ischemia to nerves and perivascular involvement can affect nearby neural structures. Sais et al¹² demonstrated that paresthesia in the setting of HSP was a risk factor for systemic involvement. Of note,  our patient's paresthesia lasted only several days.

The cause of HSP is not always as evident in the adult population as in the pediatric population. Early diagnosis of HSP in adults may allow for the proper instatement of treatment to deter long-term renal complications. Follow-up with urinalysis is recommended because a small percentage of patients have a late progression to renal failure.^13,14

Because the dermatologists involved in this case knew where and what types of biopsies to perform, a correct diagnosis was obtained quickly, allowing for the correct therapeutic intervention. After the diagnosis of HSP is made in an adult, nephrology should be consulted early in the treatment course.

To the Editor:

A 57-year-old man with a history of type 2 diabetes mellitus and hypertension was hospitalized for heart disease resulting in an aortic valve replacement and multiple-vessel bypass grafting. He experienced a stormy septic postoperative course during which he developed numerous palpable purplish plaques (Figure 1). The lesions were bilateral and more heavily involved the lower legs and buttocks. The head and neck remained free of skin lesions. Additionally, the patient reported a bilateral burning sensation from the knees to the feet.

Punch biopsies of lesions from the right upper arm were obtained. Hematoxylin and eosin staining revealed neutrophilic-predominant small vessel vasculitis (Figure 2A) with the upper dermal location more heavily involved, as demonstrated by involvement of a superficial vascular plexus (Figures 2B and 2C) that was consistent with Henoch-Schönlein purpura (HSP). The diagnosis later was confirmed with immunofluorescence. Direct immunofluorescence revealed granular IgA deposition around the superficial vascular plexus (Figure 3). No IgG, IgM, C3, C5b-9 complement complex, or fibrinogen deposition was seen. Additionally, periodic acid-Schiff staining failed to show microorganisms, thrombi, or intravascular hyaline material.

At our initial consultation, we observed an ill-appearing afebrile man with purplish plaques. Our impression was that he had vasculitis and not warfarin necrosis, which had been suspected by the cardiovascular team. The burning sensation noted by the patient lent credence to our vasculitic diagnosis. Proteinuria and hematuria were present; however, the values for blood urea nitrogen, creatinine, and glomerular filtration rate all remained within reference range. His signs and symptoms responded dramatically to prednisone. He remains on 1 mg of prednisone daily and a nephrologist continues to monitor renal function as an outpatient.

Henoch-Schönlein purpura is a systemic leukocytoclastic vasculitis involving small vessels. The small vessel vasculitis is associated with IgA antigen-antibody complex deposition in areas throughout the body. Palpable purpura typically is seen on the skin, which characteristically involves dependent areas such as the legs and the buttocks. Lesions normally are present bilaterally in a symmetric distribution. Initially, the lesions develop as erythematous macules that progress to purple, nonblanching, palpable, and purpuric plaques.¹ Henoch-Schönlein purpura most commonly involves the skin; however, other locations for the immune complexes include the gastrointestinal tract, joints, and kidneys.² The cause for the body's immunogenic deposition response is unknown in a majority of cases.

Henoch-Schönlein purpura most commonly is seen in the pediatric population with a predilection for males.³ The incidence in the pediatric population is 13.5 to 20 per 100,000 children per year; HSP is more rare in adults.^4-6 Henoch-Schönlein purpura most often is a self-limiting disease that requires only supportive treatment. The signs and symptoms last 4 to 6 weeks in most patients and resolve completely in 94% of children and 89% of adults.⁷ Renal involvement carries a worse prognosis. Adult patients have a higher incidence of renal involvement, renal insufficiency, and subsequent progression to end-stage renal disease.^3,8-10 In a study by Hung et al⁸ of 65 children and 22 adult HSP patients, 12 adults presented with renal involvement in which hematuria or proteinuria were present. Of them, 6 progressed to renal insufficiency (defined as having a plasma creatinine concentration>1.2 mg/dL).⁸ Fogazzi et al¹¹ reported similar findings; 8 of 16 patients affected with HSP progressed to renal insufficiency with creatinine clearances ranging from 31 to 60 mL/min, and 3 patients required chronic dialysis. Pillebout et al⁹ evaluated 250 adults with HSP and 32% reached renal insufficiency with creatinine clearances of less than 50 mL/min, with 11% of patients developing end-stage renal disease. The degree of hematuria and/or proteinuria has been shown to be an effective prognostic indicator.^9,10 Coppo et al¹⁰ found a similar prognosis among children and adults with HSP-related nephritis.

Our patient described the burning sensation as occurring bilaterally from the knees down to the feet, which provided an additional clue that small vessel vasculitis was involved, as occluded blood vessels can cause ischemia to nerves and perivascular involvement can affect nearby neural structures. Sais et al¹² demonstrated that paresthesia in the setting of HSP was a risk factor for systemic involvement. Of note,  our patient's paresthesia lasted only several days.

The cause of HSP is not always as evident in the adult population as in the pediatric population. Early diagnosis of HSP in adults may allow for the proper instatement of treatment to deter long-term renal complications. Follow-up with urinalysis is recommended because a small percentage of patients have a late progression to renal failure.^13,14

Because the dermatologists involved in this case knew where and what types of biopsies to perform, a correct diagnosis was obtained quickly, allowing for the correct therapeutic intervention. After the diagnosis of HSP is made in an adult, nephrology should be consulted early in the treatment course.