Case Letter

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

We report 2 cases of desmoplastic hairless hypopigmented nevi (DHHN), which are giant congenital melanocytic nevi (GCMN) that show sclerosis with progressive loss of pigment and hair. These changes in GCMN could be considered signs of regression.

A 6-year-old boy presented in the dermatology department with an asymptomatic skin lesion on the right buttock since birth. The parents claimed that the lesion was darkly pigmented at birth and gradually increased in size, with progressive reduction in color in the last 2 years. Physical examination revealed a 10×6-cm, well-defined, raised plaque on the upper medial side of the right buttock (Figure 1). The plaque was firm with a shiny smooth surface and was devoid of hair. The surface was flesh colored with scattered pigmented spots. A punch biopsy of the lesion showed increased melanin content in the basal cell layer. The upper dermis showed small nests of epithelioid nevus cells, most of them containing melanin pigment (Figure 2). In the lower two-thirds of the dermis, nevus cells were both epithelioid and spindle shaped and were arranged in between thick sclerotic collagen bundles with an increased number of fibroblasts. There was a marked reduction in the number of hair follicles. Immunohistochemical staining results were S-100 positive and CD34 negative.

A 5-year-old boy presented in the dermatology department with a large hairy GCMN covering most of the trunk since birth. In the last 1.5 years the parents noted gradual fading of color, decreased hair density, and increased induration of the nevus. Physical examination revealed a large plaque covering the anterior aspect of the trunk (Figure 3) and the back extending down to the buttocks. The lesion formed large skin folds that were more pronounced on the back. The nevus was darkly pigmented with large areas of lighter color that were indurated, devoid of hair, and showed small spots of dark pigmentation. A punch biopsy from the lesion showed small nests of nevus cells in the upper part of the reticular dermis. In the lower part of the dermis, nevus cells were arranged in single units in between thick collagen bundles.

In 2003, Ruiz-Maldonado et al¹ described 4 cases of GCMN that showed progressive loss of pigmentation, sclerosis, and hair loss. They proposed the term desmoplastic hairless hypopigmented nevus for their cases and considered it as a variant of GCMN.¹ Prior to these reported cases, 2 similar cases were described. The first was a report by Hogan et al² in 1988 of a 7-month-old girl with a GCMN involving the occipital area and the upper back that became indurated and ulcerated with progressive involution that led to complete disappearance of the nevus. The second was a report by Pattee et al³ in 2001 of a newborn with a GCMN located on the trunk with progressive sclerodermiform reaction. After surgical excision of the nevus, the sclerotic margin disappeared.³

Following the report by Ruiz-Maldonaldo et al,¹ 5 more cases of DHHN were described.^4-8 All cases of DHHN share the same clinical and histopathological features. The clinical features include a GCMN present since birth with progressive sclerosis over time and loss of both pigmentation and hair. Histologically, DHHN shows the typical changes of a congenital melanocytic nevus with decreased numbers of nevus cells, thick sclerotic collagen bundles of the reticular dermis, increased number of fibroblasts, and decreased number of hair follicles. The progressive reduction in the number of nevus cells in melanocytic nevi is considered a sign of regression. Spontaneous regression was rarely described in GCMN, and all the reported cases of regression were associated with desmoplasia.⁴ Desmoplasia is thought to be induced by either melanocytes that function as adaptive fibroblasts or by fibroblasts themselves, as fibroblasts can show multifunctional differentiation capabilities.⁹ The direct correlation between the increased induration of DHHN and pigment depletion supports the former hypothesis. The absence of inflammatory cells within the sections of DHHN lesions is against the possibility of an immune-mediated reaction as a cause for the clinical and histological changes seen in this rare form of GCMN. The progressive hair loss in DHHN may be explained by the progressive fibrotic changes in the reticular dermis that affect the blood supply to follicles, leading to atrophy or even absence of the follicles. The progressive reduction in the number of nevus cells in DHHN reduces the potential for malignant transformation and hence following a watchful waiting strategy is a reasonable way to manage these nevi.

We present 2 patients with DHHN, which is a rare form of GCMN that shows signs of regression. The cause of these changes is still unclear.

To the Editor:

Lyell¹ coined the term cutaneous artifactual disease to describe the spectrum of factitious disorders associated with skin presentations. Interestingly, Lyell was the first to name toxic epidermal necrolysis (TEN).^2,3 We present a rare case of factitial TEN, a dangerous and life-threatening manifestation of factitial disease.

A 49-year-old homeless man with a history of Stevens-Johnson syndrome (SJS)/TEN from trimethoprim-sulfamethoxazole (TMP-SMX) was admitted on 4 separate occasions over an 18-month period for recurrent exposure to the medication producing SJS/TEN. Originally, this patient was given TMP-SMX for a skin infection and 10 days later presented with 15% body surface area (BSA) involvement of SJS/TEN. He was successfully treated with intravenous immunoglobulin (IVIg) in the burn intensive care unit (BICU) and discharged. Several months later, the patient was given TMP-SMX for a leg infection by a different clinic. He was admitted to the BICU with 40% BSA, treated with IVIg, and survived. Eight months later, the patient was again admitted to the BICU with 30% BSA and treated with IVIg; however, this admission required intubation due to complications secondary to volume resuscitation. He was evaluated by psychiatry and confessed to purposely seeking TMP-SMX, stating that he “liked the food and care in the hospital.” He was diagnosed with factitial disorder and given a referral for further treatment at an outpatient facility. Two months later, the patient was again admitted to the BICU after taking a single dose of TMP-SMX obtained from a “friend.” He had 10% BSA with conjunctival involvement and was again successfully treated with IVIg. He was discharged with the state psychiatric system for further treatment and evaluation.

Factitial disease in dermatology is difficult to diagnose. Its incidence is unknown, as only case reports exist in the literature. In factitial disease, patients “perform self-mutilating and clinically relevant damage to themselves without the direct intention of suicide.”⁴ Harth et al⁴ described 3 subcategories of factitious disorders: dermatitis artefacta syndrome, dermatitis para-artefacta syndrome, or malingering. Dermatitis artefacta syndrome is “a dissociated self-injury or behavior where the patient unconsciously simulated disease with intention to be cared for as a patient.”⁴ Dermatitis para-artefacta syndrome was described as a disorder of impulse control in which a patient will produce or manipulate a specific dermatosis presentation. The patient usually admits to doing it in a semiconscious state. Dermatitis artefacta and dermatitis para-artefacta differ from malingering in that malingering patients knowingly fake symptoms for external gain, which can be monetary or the avoidance of responsibility.⁴ More familiar examples to dermatologists of factitial disease include factitial panniculitis,¹ direct applications of caustic agents to the skin, and excoriations from instruments or fingernails.^4,5

This case illustrates the difficult and potentially dangerous nature of factitial disorders, specifically dermatitis para-artefacta syndrome. Our patient was intensely preoccupied with the outcome of being a patient in a hospital. Our patient sought out a medication from multiple providers to produce a deadly and severe life-threatening reaction. If his main intentions were solely to obtain a bed and 3 square meals a day, then malingering would have represented his factitial disease. However, his main intent was to be seen as a patient, and then doted on and cared for by medical professionals in a hospital setting. From this assessment, the patient’s behavior would fall under the factitial disorder of dermatitis para-artefacta syndrome.

Factitious disorders pose immense challenges for diagnosis and treatment. It is prudent for physicians to learn to recognize patterns of history and examination that do not coincide. The first step in treatment is the recognition and early involvement of psychiatry to aid in curbing this behavior. Remission of factitial disorders can be induced with proper diagnosis and treatment. Patients with the highest chance of remission are those with treatment centered on behavioral therapy in conjunction with psychotropic medications.¹

To the Editor:

Lyell¹ coined the term cutaneous artifactual disease to describe the spectrum of factitious disorders associated with skin presentations. Interestingly, Lyell was the first to name toxic epidermal necrolysis (TEN).^2,3 We present a rare case of factitial TEN, a dangerous and life-threatening manifestation of factitial disease.

A 49-year-old homeless man with a history of Stevens-Johnson syndrome (SJS)/TEN from trimethoprim-sulfamethoxazole (TMP-SMX) was admitted on 4 separate occasions over an 18-month period for recurrent exposure to the medication producing SJS/TEN. Originally, this patient was given TMP-SMX for a skin infection and 10 days later presented with 15% body surface area (BSA) involvement of SJS/TEN. He was successfully treated with intravenous immunoglobulin (IVIg) in the burn intensive care unit (BICU) and discharged. Several months later, the patient was given TMP-SMX for a leg infection by a different clinic. He was admitted to the BICU with 40% BSA, treated with IVIg, and survived. Eight months later, the patient was again admitted to the BICU with 30% BSA and treated with IVIg; however, this admission required intubation due to complications secondary to volume resuscitation. He was evaluated by psychiatry and confessed to purposely seeking TMP-SMX, stating that he “liked the food and care in the hospital.” He was diagnosed with factitial disorder and given a referral for further treatment at an outpatient facility. Two months later, the patient was again admitted to the BICU after taking a single dose of TMP-SMX obtained from a “friend.” He had 10% BSA with conjunctival involvement and was again successfully treated with IVIg. He was discharged with the state psychiatric system for further treatment and evaluation.

Factitial disease in dermatology is difficult to diagnose. Its incidence is unknown, as only case reports exist in the literature. In factitial disease, patients “perform self-mutilating and clinically relevant damage to themselves without the direct intention of suicide.”⁴ Harth et al⁴ described 3 subcategories of factitious disorders: dermatitis artefacta syndrome, dermatitis para-artefacta syndrome, or malingering. Dermatitis artefacta syndrome is “a dissociated self-injury or behavior where the patient unconsciously simulated disease with intention to be cared for as a patient.”⁴ Dermatitis para-artefacta syndrome was described as a disorder of impulse control in which a patient will produce or manipulate a specific dermatosis presentation. The patient usually admits to doing it in a semiconscious state. Dermatitis artefacta and dermatitis para-artefacta differ from malingering in that malingering patients knowingly fake symptoms for external gain, which can be monetary or the avoidance of responsibility.⁴ More familiar examples to dermatologists of factitial disease include factitial panniculitis,¹ direct applications of caustic agents to the skin, and excoriations from instruments or fingernails.^4,5

This case illustrates the difficult and potentially dangerous nature of factitial disorders, specifically dermatitis para-artefacta syndrome. Our patient was intensely preoccupied with the outcome of being a patient in a hospital. Our patient sought out a medication from multiple providers to produce a deadly and severe life-threatening reaction. If his main intentions were solely to obtain a bed and 3 square meals a day, then malingering would have represented his factitial disease. However, his main intent was to be seen as a patient, and then doted on and cared for by medical professionals in a hospital setting. From this assessment, the patient’s behavior would fall under the factitial disorder of dermatitis para-artefacta syndrome.

Factitious disorders pose immense challenges for diagnosis and treatment. It is prudent for physicians to learn to recognize patterns of history and examination that do not coincide. The first step in treatment is the recognition and early involvement of psychiatry to aid in curbing this behavior. Remission of factitial disorders can be induced with proper diagnosis and treatment. Patients with the highest chance of remission are those with treatment centered on behavioral therapy in conjunction with psychotropic medications.¹

To the Editor:

Lyell¹ coined the term cutaneous artifactual disease to describe the spectrum of factitious disorders associated with skin presentations. Interestingly, Lyell was the first to name toxic epidermal necrolysis (TEN).^2,3 We present a rare case of factitial TEN, a dangerous and life-threatening manifestation of factitial disease.

A 49-year-old homeless man with a history of Stevens-Johnson syndrome (SJS)/TEN from trimethoprim-sulfamethoxazole (TMP-SMX) was admitted on 4 separate occasions over an 18-month period for recurrent exposure to the medication producing SJS/TEN. Originally, this patient was given TMP-SMX for a skin infection and 10 days later presented with 15% body surface area (BSA) involvement of SJS/TEN. He was successfully treated with intravenous immunoglobulin (IVIg) in the burn intensive care unit (BICU) and discharged. Several months later, the patient was given TMP-SMX for a leg infection by a different clinic. He was admitted to the BICU with 40% BSA, treated with IVIg, and survived. Eight months later, the patient was again admitted to the BICU with 30% BSA and treated with IVIg; however, this admission required intubation due to complications secondary to volume resuscitation. He was evaluated by psychiatry and confessed to purposely seeking TMP-SMX, stating that he “liked the food and care in the hospital.” He was diagnosed with factitial disorder and given a referral for further treatment at an outpatient facility. Two months later, the patient was again admitted to the BICU after taking a single dose of TMP-SMX obtained from a “friend.” He had 10% BSA with conjunctival involvement and was again successfully treated with IVIg. He was discharged with the state psychiatric system for further treatment and evaluation.

Factitial disease in dermatology is difficult to diagnose. Its incidence is unknown, as only case reports exist in the literature. In factitial disease, patients “perform self-mutilating and clinically relevant damage to themselves without the direct intention of suicide.”⁴ Harth et al⁴ described 3 subcategories of factitious disorders: dermatitis artefacta syndrome, dermatitis para-artefacta syndrome, or malingering. Dermatitis artefacta syndrome is “a dissociated self-injury or behavior where the patient unconsciously simulated disease with intention to be cared for as a patient.”⁴ Dermatitis para-artefacta syndrome was described as a disorder of impulse control in which a patient will produce or manipulate a specific dermatosis presentation. The patient usually admits to doing it in a semiconscious state. Dermatitis artefacta and dermatitis para-artefacta differ from malingering in that malingering patients knowingly fake symptoms for external gain, which can be monetary or the avoidance of responsibility.⁴ More familiar examples to dermatologists of factitial disease include factitial panniculitis,¹ direct applications of caustic agents to the skin, and excoriations from instruments or fingernails.^4,5

This case illustrates the difficult and potentially dangerous nature of factitial disorders, specifically dermatitis para-artefacta syndrome. Our patient was intensely preoccupied with the outcome of being a patient in a hospital. Our patient sought out a medication from multiple providers to produce a deadly and severe life-threatening reaction. If his main intentions were solely to obtain a bed and 3 square meals a day, then malingering would have represented his factitial disease. However, his main intent was to be seen as a patient, and then doted on and cared for by medical professionals in a hospital setting. From this assessment, the patient’s behavior would fall under the factitial disorder of dermatitis para-artefacta syndrome.

Factitious disorders pose immense challenges for diagnosis and treatment. It is prudent for physicians to learn to recognize patterns of history and examination that do not coincide. The first step in treatment is the recognition and early involvement of psychiatry to aid in curbing this behavior. Remission of factitial disorders can be induced with proper diagnosis and treatment. Patients with the highest chance of remission are those with treatment centered on behavioral therapy in conjunction with psychotropic medications.¹

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

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Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

[[{"attributes":{},"fields":{}}]][[{"attributes":{},"fields":{}}]]

Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

To the Editor:

Telaprevir is a hepatitis C virus (HCV) protease inhibitor used with ribavirin and interferon for the treatment of increased viral load clearance in specific HCV genotypes. We report a case of eruptive seborrheic keratoses (SKs) secondary to telaprevir-related dermatitis.

A 65-year-old woman with a history of depression, basal cell carcinoma, and HCV presented 5 months after initiation of antiviral treatment with interferon, ribavirin, and telaprevir. Shortly after initiation of therapy, the patient developed a diffuse itch with a “pricking” sensation. The patient reported that approximately 2 months after starting treatment she developed an erythematous scaling rash that covered 75% of the body, which led to the discontinuation of telaprevir after 10 weeks of therapy; interferon and ribavirin were continued for a total of 6 months. In concert with the eczematous eruption, the patient noticed many new hyperpigmented lesions with enlargement of the few preexisting SKs. She presented to our clinic 6 weeks after the discontinuation of telaprevir for evaluation of these lesions.

On examination, several brown, hyperpigmented, stuck-on papules and plaques were noted diffusely on the body, most prominently along the frontal hairline (Figure 1). A biopsy of the right side of the forehead showed a reticulated epidermis, horn pseudocysts, and increased basilar pigment diagnostic of an SK (Figure 2).

[[{"attributes":{},"fields":{}}]][[{"attributes":{},"fields":{}}]]

Telaprevir is an HCV protease inhibitor that is given in combination with interferon and ribavirin for increased clearance of genotype 1 HCV infection. Cutaneous reactions to telaprevir are seen in 41% to 61% of treated patients and include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, sarcoidosis, pityriasis rubra pilaris–like drug eruption, and most commonly telaprevir-related dermatitis.^1-3 Telaprevir-related dermatitis accounts for up to 95% of cutaneous reactions and presents at a median of 15 days (interquartile range, 4–41 days) after initiation of therapy. Nearly 25% of cases occur in the first 4 days and 46% of cases occur within 4 weeks. It presents as an erythematous eczematous dermatitis commonly associated with pruritus in contrast to the common morbilliform drug eruption. Secondary xerosis, excoriation, and lichenification can be appreciated. With appropriate treatment, resolution occurs in a median of 44 days.¹ Treatment of the dermatitis can allow completion of the recommended 12-week course of telaprevir and involves oral antihistamines and topical corticosteroids. Severe cases may require oral corticosteroids and discontinuation of telaprevir. If the cutaneous eruption does not resolve, discontinuation of ribavirin also may be required, as it can cause a similar cutaneous eruption.⁴

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

To the Editor:

Azathioprine (AZA) hypersensitivity is an immunologically mediated reaction that presents within 1 to 4 weeks of drug initiation.¹ Its cutaneous manifestations include Sweet syndrome, erythema nodosum (EN), and acute generalized exanthematous pustulosis, with 88% of cases presenting as neutrophilic dermatoses.² Confirmation with cutaneous biopsy and cessation of medication is essential to prevent life-threatening anaphylactoid reactions.

A 58-year-old man with a history of Crohn disease was admitted with high fevers (>38.9°C); abdominal pain; diarrhea; and a nonpruritic “pimplelike” rash on the face, chest, and back with a tender nodule on the right leg of 5 days’ duration. Eight days prior to admission, he had started AZA for treatment of Crohn disease. In the hospital he received intravenous metronidazole for a presumed bowel infection; however, the lesions and symptoms did not resolve. Other medical history included psoriatic arthritis for which he was taking oral prednisone 50 mg daily; prednisone was continued during hospitalization.

Physical examination showed that the patient was alert and well appearing. On the face, upper chest and back (Figure 1), shoulders, and knees were fewer than 20 sparsely distributed, nontender, 3- to 4-mm pustules. The patient’s scalp, lower back, abdomen, arms, and feet were spared. There also was a solitary 3.5-cm, tender, erythematous nodule on the right lower leg (Figure 2). Blood tests revealed leukocytosis (15,000/mm³ [reference range, 4300–10,300/mm³]) with neutrophilia (90%) and an elevated C-reactive protein level of 173 mg/L (reference range, <10 mg/L). Liver function tests were normal. Thiopurine methyltransferase (TPMT) was on the low end of the reference range. Tissue culture of a shoulder pustule grew only Staphylococcus non-aureus. Blood cultures were negative. A 4-mm punch biopsy specimen from the right leg nodule revealed septal panniculitis with neutrophilic and granulomatous infiltrate consistent with EN.

A clinical diagnosis of AZA hypersensitivity was made. Antibiotics and AZA were discontinued and the patient’s lesions resolved within 6 days. Medication rechallenge was not attempted and the patient is now managed with infliximab.

Azathioprine is a well-known and commonly used drug for inflammatory bowel diseases, rheumatoid arthritis, and prevention of transplant rejection. Hypersensitivity is a lesser-known complication of AZA therapy, with most reactions occurring within 4 weeks of treatment initiation. A PubMed search of articles indexed for MEDLINE using the search terms azathioprine and hypersensitivity found only 67 documented cases of AZA hypersensitivity between 1986 and 2009.² Common findings include fever, malaise, arthralgia, nausea, vomiting, diarrhea, headache, and neutrophilic dermatoses.

Previously reported cases of AZA hypersensitivity with cutaneous manifestations include Sweet syndrome (17.9%), small vessel vasculitis (10.4%), EN (4.4%), acute generalized exanthematous pustulosis (4.4%), and nonspecific cutaneous findings (11.9%).² One other case reported AZA hypersensitivity presenting as EN with a neutrophilic pustular dermatosis.³ Although Sweet syndrome–like lesions, EN, and acute generalized exanthematous pustulosis have been reported in the context of inflammatory bowel disease, in this case the appearance of these symptoms within 1 week of AZA initiation and resolution after AZA discontinuation is highly suggestive of AZA hypersensitivity. Also, several reports have documented rapid (within a few hours) recurrence of symptoms on rechallenge with AZA.^4-6 Moreover, cases of cutaneous AZA hypersensitivity reactions in patients with no history of inflammatory bowel diseases have been reported.^6-8

As in this case, cutaneous AZA hypersensitivity can occur even in the setting of normal TPMT levels, suggesting that this phenomenon is a dose-independent reaction.² Abnormal metabolism of AZA does not appear to be related to previously reported neutrophilic pustular dermatosis^3,4 or EN.⁴ Although the mechanism of hypersensitivity is unclear, there is a report of a patient who developed AZA hypersensitivity but was able to tolerate 6-mercaptopurine, a metabolite of AZA. The authors suggested that the imidazole component of AZA might be responsible for hypersensitivity reactions.⁹

The differential diagnosis of a patient with these findings includes infectious, rheumatologic, neurologic, or autoimmune diseases, as well as septic shock. Hence, negative cultures and a failure to respond to antibiotics make infection less likely. An appropriate time course of AZA initiation, the development of rash, and a cutaneous biopsy can lead to prompt diagnosis and cessation of AZA.

Once AZA hypersensitivity is suspected, the drug should be discontinued and the reaction should resolve within 2 to 3 days² and the skin lesions within 5 to 6 days.^2,10 Medication rechallenge is contraindicated because AZA rarely has been associated with shock syndrome and hypotension.^11-19

Azathioprine hypersensitivity is a serious yet still underrecognized condition in the dermatologic community. In our case, symptoms appeared rapidly and resolved quickly after AZA was discontinued. Azathioprine-induced neutrophilic dermatosis presenting with EN should be recognized as a potential dermatologic manifestation of AZA hypersensitivity, which is a dose-dependent reaction even with normal TPMT levels. Rechallenge with AZA is not recommended due to the risk of a life-threatening anaphylactoid reaction.

To the Editor:

Azathioprine (AZA) hypersensitivity is an immunologically mediated reaction that presents within 1 to 4 weeks of drug initiation.¹ Its cutaneous manifestations include Sweet syndrome, erythema nodosum (EN), and acute generalized exanthematous pustulosis, with 88% of cases presenting as neutrophilic dermatoses.² Confirmation with cutaneous biopsy and cessation of medication is essential to prevent life-threatening anaphylactoid reactions.

A 58-year-old man with a history of Crohn disease was admitted with high fevers (>38.9°C); abdominal pain; diarrhea; and a nonpruritic “pimplelike” rash on the face, chest, and back with a tender nodule on the right leg of 5 days’ duration. Eight days prior to admission, he had started AZA for treatment of Crohn disease. In the hospital he received intravenous metronidazole for a presumed bowel infection; however, the lesions and symptoms did not resolve. Other medical history included psoriatic arthritis for which he was taking oral prednisone 50 mg daily; prednisone was continued during hospitalization.

Physical examination showed that the patient was alert and well appearing. On the face, upper chest and back (Figure 1), shoulders, and knees were fewer than 20 sparsely distributed, nontender, 3- to 4-mm pustules. The patient’s scalp, lower back, abdomen, arms, and feet were spared. There also was a solitary 3.5-cm, tender, erythematous nodule on the right lower leg (Figure 2). Blood tests revealed leukocytosis (15,000/mm³ [reference range, 4300–10,300/mm³]) with neutrophilia (90%) and an elevated C-reactive protein level of 173 mg/L (reference range, <10 mg/L). Liver function tests were normal. Thiopurine methyltransferase (TPMT) was on the low end of the reference range. Tissue culture of a shoulder pustule grew only Staphylococcus non-aureus. Blood cultures were negative. A 4-mm punch biopsy specimen from the right leg nodule revealed septal panniculitis with neutrophilic and granulomatous infiltrate consistent with EN.

A clinical diagnosis of AZA hypersensitivity was made. Antibiotics and AZA were discontinued and the patient’s lesions resolved within 6 days. Medication rechallenge was not attempted and the patient is now managed with infliximab.

Azathioprine is a well-known and commonly used drug for inflammatory bowel diseases, rheumatoid arthritis, and prevention of transplant rejection. Hypersensitivity is a lesser-known complication of AZA therapy, with most reactions occurring within 4 weeks of treatment initiation. A PubMed search of articles indexed for MEDLINE using the search terms azathioprine and hypersensitivity found only 67 documented cases of AZA hypersensitivity between 1986 and 2009.² Common findings include fever, malaise, arthralgia, nausea, vomiting, diarrhea, headache, and neutrophilic dermatoses.

Previously reported cases of AZA hypersensitivity with cutaneous manifestations include Sweet syndrome (17.9%), small vessel vasculitis (10.4%), EN (4.4%), acute generalized exanthematous pustulosis (4.4%), and nonspecific cutaneous findings (11.9%).² One other case reported AZA hypersensitivity presenting as EN with a neutrophilic pustular dermatosis.³ Although Sweet syndrome–like lesions, EN, and acute generalized exanthematous pustulosis have been reported in the context of inflammatory bowel disease, in this case the appearance of these symptoms within 1 week of AZA initiation and resolution after AZA discontinuation is highly suggestive of AZA hypersensitivity. Also, several reports have documented rapid (within a few hours) recurrence of symptoms on rechallenge with AZA.^4-6 Moreover, cases of cutaneous AZA hypersensitivity reactions in patients with no history of inflammatory bowel diseases have been reported.^6-8

As in this case, cutaneous AZA hypersensitivity can occur even in the setting of normal TPMT levels, suggesting that this phenomenon is a dose-independent reaction.² Abnormal metabolism of AZA does not appear to be related to previously reported neutrophilic pustular dermatosis^3,4 or EN.⁴ Although the mechanism of hypersensitivity is unclear, there is a report of a patient who developed AZA hypersensitivity but was able to tolerate 6-mercaptopurine, a metabolite of AZA. The authors suggested that the imidazole component of AZA might be responsible for hypersensitivity reactions.⁹

The differential diagnosis of a patient with these findings includes infectious, rheumatologic, neurologic, or autoimmune diseases, as well as septic shock. Hence, negative cultures and a failure to respond to antibiotics make infection less likely. An appropriate time course of AZA initiation, the development of rash, and a cutaneous biopsy can lead to prompt diagnosis and cessation of AZA.

Once AZA hypersensitivity is suspected, the drug should be discontinued and the reaction should resolve within 2 to 3 days² and the skin lesions within 5 to 6 days.^2,10 Medication rechallenge is contraindicated because AZA rarely has been associated with shock syndrome and hypotension.^11-19

Azathioprine hypersensitivity is a serious yet still underrecognized condition in the dermatologic community. In our case, symptoms appeared rapidly and resolved quickly after AZA was discontinued. Azathioprine-induced neutrophilic dermatosis presenting with EN should be recognized as a potential dermatologic manifestation of AZA hypersensitivity, which is a dose-dependent reaction even with normal TPMT levels. Rechallenge with AZA is not recommended due to the risk of a life-threatening anaphylactoid reaction.

To the Editor:

Azathioprine (AZA) hypersensitivity is an immunologically mediated reaction that presents within 1 to 4 weeks of drug initiation.¹ Its cutaneous manifestations include Sweet syndrome, erythema nodosum (EN), and acute generalized exanthematous pustulosis, with 88% of cases presenting as neutrophilic dermatoses.² Confirmation with cutaneous biopsy and cessation of medication is essential to prevent life-threatening anaphylactoid reactions.

A 58-year-old man with a history of Crohn disease was admitted with high fevers (>38.9°C); abdominal pain; diarrhea; and a nonpruritic “pimplelike” rash on the face, chest, and back with a tender nodule on the right leg of 5 days’ duration. Eight days prior to admission, he had started AZA for treatment of Crohn disease. In the hospital he received intravenous metronidazole for a presumed bowel infection; however, the lesions and symptoms did not resolve. Other medical history included psoriatic arthritis for which he was taking oral prednisone 50 mg daily; prednisone was continued during hospitalization.

Physical examination showed that the patient was alert and well appearing. On the face, upper chest and back (Figure 1), shoulders, and knees were fewer than 20 sparsely distributed, nontender, 3- to 4-mm pustules. The patient’s scalp, lower back, abdomen, arms, and feet were spared. There also was a solitary 3.5-cm, tender, erythematous nodule on the right lower leg (Figure 2). Blood tests revealed leukocytosis (15,000/mm³ [reference range, 4300–10,300/mm³]) with neutrophilia (90%) and an elevated C-reactive protein level of 173 mg/L (reference range, <10 mg/L). Liver function tests were normal. Thiopurine methyltransferase (TPMT) was on the low end of the reference range. Tissue culture of a shoulder pustule grew only Staphylococcus non-aureus. Blood cultures were negative. A 4-mm punch biopsy specimen from the right leg nodule revealed septal panniculitis with neutrophilic and granulomatous infiltrate consistent with EN.

A clinical diagnosis of AZA hypersensitivity was made. Antibiotics and AZA were discontinued and the patient’s lesions resolved within 6 days. Medication rechallenge was not attempted and the patient is now managed with infliximab.

Azathioprine is a well-known and commonly used drug for inflammatory bowel diseases, rheumatoid arthritis, and prevention of transplant rejection. Hypersensitivity is a lesser-known complication of AZA therapy, with most reactions occurring within 4 weeks of treatment initiation. A PubMed search of articles indexed for MEDLINE using the search terms azathioprine and hypersensitivity found only 67 documented cases of AZA hypersensitivity between 1986 and 2009.² Common findings include fever, malaise, arthralgia, nausea, vomiting, diarrhea, headache, and neutrophilic dermatoses.

Previously reported cases of AZA hypersensitivity with cutaneous manifestations include Sweet syndrome (17.9%), small vessel vasculitis (10.4%), EN (4.4%), acute generalized exanthematous pustulosis (4.4%), and nonspecific cutaneous findings (11.9%).² One other case reported AZA hypersensitivity presenting as EN with a neutrophilic pustular dermatosis.³ Although Sweet syndrome–like lesions, EN, and acute generalized exanthematous pustulosis have been reported in the context of inflammatory bowel disease, in this case the appearance of these symptoms within 1 week of AZA initiation and resolution after AZA discontinuation is highly suggestive of AZA hypersensitivity. Also, several reports have documented rapid (within a few hours) recurrence of symptoms on rechallenge with AZA.^4-6 Moreover, cases of cutaneous AZA hypersensitivity reactions in patients with no history of inflammatory bowel diseases have been reported.^6-8

As in this case, cutaneous AZA hypersensitivity can occur even in the setting of normal TPMT levels, suggesting that this phenomenon is a dose-independent reaction.² Abnormal metabolism of AZA does not appear to be related to previously reported neutrophilic pustular dermatosis^3,4 or EN.⁴ Although the mechanism of hypersensitivity is unclear, there is a report of a patient who developed AZA hypersensitivity but was able to tolerate 6-mercaptopurine, a metabolite of AZA. The authors suggested that the imidazole component of AZA might be responsible for hypersensitivity reactions.⁹

The differential diagnosis of a patient with these findings includes infectious, rheumatologic, neurologic, or autoimmune diseases, as well as septic shock. Hence, negative cultures and a failure to respond to antibiotics make infection less likely. An appropriate time course of AZA initiation, the development of rash, and a cutaneous biopsy can lead to prompt diagnosis and cessation of AZA.

Once AZA hypersensitivity is suspected, the drug should be discontinued and the reaction should resolve within 2 to 3 days² and the skin lesions within 5 to 6 days.^2,10 Medication rechallenge is contraindicated because AZA rarely has been associated with shock syndrome and hypotension.^11-19

Azathioprine hypersensitivity is a serious yet still underrecognized condition in the dermatologic community. In our case, symptoms appeared rapidly and resolved quickly after AZA was discontinued. Azathioprine-induced neutrophilic dermatosis presenting with EN should be recognized as a potential dermatologic manifestation of AZA hypersensitivity, which is a dose-dependent reaction even with normal TPMT levels. Rechallenge with AZA is not recommended due to the risk of a life-threatening anaphylactoid reaction.

To the Editor:

Disseminated granuloma annulare is a noninfectious granulomatous disease of unknown etiology. Reported precipitating factors include trauma, sun exposure, viral infection, vaccination, and malignancy.¹ In contrast to a localized variant, disseminated granuloma annulare is associated with a later age of onset, longer duration, and recalcitrance to therapy.² Although a variety of therapeutic approaches exist, there are limited efficacy data, which is complicated by the spontaneous, self-limited nature of the disease.^3,4

A 47-year-old man presented with an eruption of a thick red plaque on the dorsal aspect of the left hand (Figure). The eruption began 6 weeks following fixation of a Galeazzi fracture of the right radius with a stainless steel volar plate. Subsequent to the initial eruption, similar indurated plaques developed on the left thenar area, bilateral axillae, and bilateral legs. A punch biopsy was conducted to rule out necrobiosis lipoidica diabeticorum and sarcoidosis as well as to histopathologically confirm the clinical diagnosis of disseminated granuloma annulare. Following diagnosis, the patient received topical clobetasol for application to the advancing borders of the plaques. At 4-month follow-up, additional plaques continued to develop. The patient was not interested in pursuing alternative courses of therapy and felt that the implantation of surgical hardware was the cause. To the best of our knowledge, there have been no reports of precipitation of disseminated granuloma annulare in response to surgical hardware. Given the time course of onset of the eruption it was plausible that the hardware was the inciting event. The orthopedist thought that the fracture had healed sufficiently to remove the volar plate. The patient elected to have the hardware removed to potentially resolve or arrest the progression of the plaques. Resolution of the plaques was observed by the patient 2 weeks following surgical removal of the volar plate. At 4 months following hardware removal, the patient only had 2 slightly pink, hyperpigmented lesions on the left hand in the areas most severely affected, with complete resolution of all other plaques. The patient was given topical clobetasol for the residual lesions.

Precipitation and spontaneous resolution of disseminated granuloma annulare following the implantation and removal of surgical hardware is rare. Resolution following hardware removal is consistent with the theory that pathogenesis is due to a delayed-type hypersensitivity reaction to an inciting factor.⁵ Our case suggests that disseminated granuloma annulare may occur as a delayed-type hypersensitivity reaction to implanted surgical hardware, which should be considered in the etiology and potential therapeutic options for this disorder.

To the Editor:

Disseminated granuloma annulare is a noninfectious granulomatous disease of unknown etiology. Reported precipitating factors include trauma, sun exposure, viral infection, vaccination, and malignancy.¹ In contrast to a localized variant, disseminated granuloma annulare is associated with a later age of onset, longer duration, and recalcitrance to therapy.² Although a variety of therapeutic approaches exist, there are limited efficacy data, which is complicated by the spontaneous, self-limited nature of the disease.^3,4

A 47-year-old man presented with an eruption of a thick red plaque on the dorsal aspect of the left hand (Figure). The eruption began 6 weeks following fixation of a Galeazzi fracture of the right radius with a stainless steel volar plate. Subsequent to the initial eruption, similar indurated plaques developed on the left thenar area, bilateral axillae, and bilateral legs. A punch biopsy was conducted to rule out necrobiosis lipoidica diabeticorum and sarcoidosis as well as to histopathologically confirm the clinical diagnosis of disseminated granuloma annulare. Following diagnosis, the patient received topical clobetasol for application to the advancing borders of the plaques. At 4-month follow-up, additional plaques continued to develop. The patient was not interested in pursuing alternative courses of therapy and felt that the implantation of surgical hardware was the cause. To the best of our knowledge, there have been no reports of precipitation of disseminated granuloma annulare in response to surgical hardware. Given the time course of onset of the eruption it was plausible that the hardware was the inciting event. The orthopedist thought that the fracture had healed sufficiently to remove the volar plate. The patient elected to have the hardware removed to potentially resolve or arrest the progression of the plaques. Resolution of the plaques was observed by the patient 2 weeks following surgical removal of the volar plate. At 4 months following hardware removal, the patient only had 2 slightly pink, hyperpigmented lesions on the left hand in the areas most severely affected, with complete resolution of all other plaques. The patient was given topical clobetasol for the residual lesions.

Precipitation and spontaneous resolution of disseminated granuloma annulare following the implantation and removal of surgical hardware is rare. Resolution following hardware removal is consistent with the theory that pathogenesis is due to a delayed-type hypersensitivity reaction to an inciting factor.⁵ Our case suggests that disseminated granuloma annulare may occur as a delayed-type hypersensitivity reaction to implanted surgical hardware, which should be considered in the etiology and potential therapeutic options for this disorder.

To the Editor:

Disseminated granuloma annulare is a noninfectious granulomatous disease of unknown etiology. Reported precipitating factors include trauma, sun exposure, viral infection, vaccination, and malignancy.¹ In contrast to a localized variant, disseminated granuloma annulare is associated with a later age of onset, longer duration, and recalcitrance to therapy.² Although a variety of therapeutic approaches exist, there are limited efficacy data, which is complicated by the spontaneous, self-limited nature of the disease.^3,4

A 47-year-old man presented with an eruption of a thick red plaque on the dorsal aspect of the left hand (Figure). The eruption began 6 weeks following fixation of a Galeazzi fracture of the right radius with a stainless steel volar plate. Subsequent to the initial eruption, similar indurated plaques developed on the left thenar area, bilateral axillae, and bilateral legs. A punch biopsy was conducted to rule out necrobiosis lipoidica diabeticorum and sarcoidosis as well as to histopathologically confirm the clinical diagnosis of disseminated granuloma annulare. Following diagnosis, the patient received topical clobetasol for application to the advancing borders of the plaques. At 4-month follow-up, additional plaques continued to develop. The patient was not interested in pursuing alternative courses of therapy and felt that the implantation of surgical hardware was the cause. To the best of our knowledge, there have been no reports of precipitation of disseminated granuloma annulare in response to surgical hardware. Given the time course of onset of the eruption it was plausible that the hardware was the inciting event. The orthopedist thought that the fracture had healed sufficiently to remove the volar plate. The patient elected to have the hardware removed to potentially resolve or arrest the progression of the plaques. Resolution of the plaques was observed by the patient 2 weeks following surgical removal of the volar plate. At 4 months following hardware removal, the patient only had 2 slightly pink, hyperpigmented lesions on the left hand in the areas most severely affected, with complete resolution of all other plaques. The patient was given topical clobetasol for the residual lesions.

Precipitation and spontaneous resolution of disseminated granuloma annulare following the implantation and removal of surgical hardware is rare. Resolution following hardware removal is consistent with the theory that pathogenesis is due to a delayed-type hypersensitivity reaction to an inciting factor.⁵ Our case suggests that disseminated granuloma annulare may occur as a delayed-type hypersensitivity reaction to implanted surgical hardware, which should be considered in the etiology and potential therapeutic options for this disorder.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.