Contact Dermatitis

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

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

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Inundating our popular and academic media circles is information regarding the Zika virus. A recent article by Farahnik et al in the Journal of the American Academy of Dermatology (2016;74:1286-1287) briefly outlines what is known about Zika infection thus far and its dermatologic manifestations. Pairing this article with Centers for Disease Control and Prevention guidelines on the topic, we are presented with an evolving introduction to this new entity. Here’s what we know:

What’s the issue?

As with any new outbreak, the applicability to the general population and true risks remain to be seen. Each of our clinics recalls the stark changes in patient intake and screening questions with infections as ubiquitous as methicillin-resistant Staphylococcus aureus to much rarer exposures such as Ebola virus, each with progressive understanding of risk groups, disease manifestations, and eradication and prevention measures.

By mid-June 2016, 30 hits on PubMed addressing Zika had already been cited just within the month, outlining various aspects of the infection, and many specialties, particularly neurology, obstetrics, primary care, infectious disease, and dermatology, are weighing in. Unfortunately, the majority of cases of primary Zika infection do not manifest with skin or systemic symptoms, and even cases that do are nonspecific, exanthematous, and flulike.

Vague as it may be so far, it is nonetheless imperative that clinicians be familiar with what is concretely known about Zika virus and acquaint ourselves with the travel distribution and restrictions, disease risk factors, known sequelae, testing availability and limitations, and reporting guidelines. From personal experience, as I traveled to Belize earlier this year during my first trimester of pregnancy before the travel restrictions were outlined, even obstetricians are not wholly familiar with the manner in which to order testing and the appropriate window to do so. I have been asymptomatic, my blood was drawn in a period of time that exceeded the interval for accurate results (as outlined above) and was therefore inappropriately recommended/ordered, and now serial fetal ultrasonography is being implemented every few weeks.

With lack of ubiquitous knowledge about the infection, clinicians are not universally certain of the appropriate next steps when a patient presents with Zika risk factors, and therefore anxiety remains high for pregnant patients and their contacts. The Centers for Disease Control and Prevention website is the official home base, and we should review it and await their further evolving specific recommendations as more cases unfortunately accumulate.

Have you encountered any patients this year with exposure to or symptoms of Zika infection, and what, if anything, have you outlined for them?

We want to know your views! Tell us what you think.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

Imatinib mesylate (IM) represents the first-line treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs). Its pharmacological activity is related to a specific action on several tyrosine kinases in different tumors, including Bcr-Abl in CML, c-Kit (CD117) in GIST, and platelet-derived growth factor receptor in dermatofibrosarcoma protuberans.^1,2

Imatinib mesylate has been shown to improve progression-free survival and overall survival²; however, it also has several side effects. Among the adverse effects (AEs), less than 10% are nonhematologic, such as nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions.^3,4

We followed patients who were treated with IM for 5 years to identify AEs of therapy.

Methods

The aim of this prospective study was to identify and collect data regarding IM cutaneous side effects so that clinicians can detect AEs early and differentiate them from AEs caused by other medications. All patients were subjected to a median of 5 years’ follow-up. We included all the patients treated with IM and excluded patients who had a history of eczematous dermatitis, psoriasis, renal impairment, or dyshidrosis palmoplantar. Before starting IM, all patients presented for a dermatologic visit. They were subsequently evaluated every 3 months.

The incidence rate was defined as the ratio of patients with cutaneous side effects and the total patients treated with IM. Furthermore, we calculated the ratio between each class of patient with a specific cutaneous manifestation and the entire cohort of patients with cutaneous side effects related to IM.

When necessary, microbiological, serological, and histopathological analyses were performed.

Results

In 60 months, we followed 220 patients treated with IM. Among them, 55 (25%) developed cutaneous side effects (35 males; 20 females). The incidence rate of the patients with cutaneous side effects was 1:4. The median age of the entire cohort was 52.5 years. Fifty patients were being treated for CML and 5 for GISTs. All patients received IM at a dosage of 400 mg daily.

The following skin diseases were observed in patients treated with IM (Table): 19 patients with maculopapular rash with pruritus (no maculopapular rash without pruritus was detected), 7 patients with eczematous dermatitis such as stasis dermatitis and seborrheic dermatitis, 6 patients with onychodystrophy melanonychia (Figure 1), 5 patients with psoriasis, 5 patients with skin cancers including basal cell carcinoma (BCC)(Figure 2), 3 patients with periorbital edema (Figure 3), 3 patients with mycosis, 3 patients with dermatofibromas, 2 patients with dyshidrosis palmoplantar, 1 patient with pityriasis rosea–like eruption (Figure 4), and 1 patient with actinic keratoses on the face. No hypopigmentation or hyperpigmentation, excluding the individual case of melanonychia, was observed.

All cutaneous diseases reported in this study appeared after IM therapy (median, 3.8 months). The median time to onset for each cutaneous disorder is reported in the Table. During the first dermatologic visit before starting IM therapy, none of the patients showed any of these cutaneous diseases.

The adverse cutaneous reactions were treated with appropriate drugs. Generally, eczematous dermatitis was treated using topical steroids, emollients, and oral antihistamines. In patients with maculopapular rash with pruritus, oral corticosteroids (eg, betamethasone 3 mg daily or prednisolone 1 mg/kg) in association with antihistamine was necessary. Psoriasis was completely improved with topical betamethasone 0.5 mg and calcipotriol 50 µg. Skin cancers were treated with surgical excision with histologic examination. All treatments are outlined in the Table.

Imatinib mesylate therapy was suspended in 2 patients with maculopapular rash with moderate to severe pruritus; however, despite the temporary suspension of the drug and the appropriate therapies (corticosteroids and antihistamines), cutaneous side effects reappeared 7 to 10 days after therapy resumed. Therefore, the treatment was permanently suspended in these 2 cases and IM was replaced with erlotinib, a second-generation Bcr-Abl tyrosine kinase inhibitor.

Comment

The introduction of IM for the treatment of GIST and CML has changed the history of these diseases. The drug typically is well tolerated and few patients have reported severe AEs. Mild skin reactions are relatively frequent, ranging from 7% to 21% of patients treated.³ In our case, the percentage was relatively higher (25%), likely because of close monitoring of patients, with an increase in the incidence rate.

Imatinib mesylate cutaneous reactions are dose dependent.⁴ Indeed, in all our cases, the cutaneous reactions arose with an IM dosage of 400 mg daily, which is compatible with the definition of dose-independent cutaneous AEs.

The most common cutaneous AEs reported in the literature were swelling/edema and maculopapular rash. Swelling is the most common AE described during therapy with IM with an incidence of 63% to 84%.⁵ Swelling often involves the periorbital area and occurs approximately 6 weeks after starting IM. Although its pathogenesis is uncertain, it has been shown that IM blocks the platelet-derived growth factor receptor expressed on blood vessels that regulates the transportation transcapillary. The inhibition of this receptor can lead to increased pore pressure, resulting in edema and erythema. Maculopapular eruptions (50% of cases) often affect the trunk and the limbs and are accompanied by pruritus. Commonly, these rashes arise after 9 weeks of IM therapy. These eruptions are self-limiting and only topical emollients and steroids are required, without any change in IM schedule. To treat maculopapular eruptions with pruritus, oral steroids and antihistamines may be helpful, without suspending IM treatment. When grade 2 or 3 pruriginous maculopapular eruptions arise, the suspension of IM combined with steroids and antihistamines may be necessary. When the readministration of IM is required, it is mandatory to start IM at a lower dose (50–100 mg/d), administering prednisolone 0.5 to 1.0 mg/kg daily. Then, the steroid gradually can be tapered.⁶ Critical cutaneous AEs that are resistant to supportive measures warrant suspension of IM therapy. However, the incidence of this event is small (<1% of all patients).⁷

Regarding severe cutaneous AEs from IM therapy, Hsiao et al⁸ reported the case of Stevens-Johnson syndrome. In this case, IM was immediately stopped and systemic steroids were started. Rarely, erythroderma (grade 4 toxicity) can develop for which a prompt and perpetual suspension of IM is necessary and supportive care therapy with oral and topical steroids is recommended.⁹

Hyperpigmentation induced by IM, mostly in patients with Fitzpatrick skin types V to VI and with a general prevalence of 16% to 40% in treated patients, often is related to a mutation of c-Kit or other kinases that are activated rather than inhibited by the drug, resulting in overstimulation of melanogenesis.¹⁰ The prevalence of Fitzpatrick skin types I to III determined the absence of pigmentation changes in our cohort, excluding melanonychia. Hyperpigmentation was observed in the skin as well as the appendages such as nails, resulting in melanonychia (Figure 1). However, Brazzelli et al¹¹ reported hypopigmentation in 5 white patients treated with IM; furthermore, they found a direct correlation between hypopigmentation and development of skin cancers in these patients. The susceptibility to develop skin cancers may persist, even without a clear manifestation of hypopigmentation, as reported in the current analysis. We documented BCC in 5 patients, 1 patient developed actinic keratoses, and 3 patients developed dermatofibromas. However, these neoplasms probably were not provoked by IM. On the contrary, we did not note squamous cell carcinoma, which was reported by Baskaynak et al¹² in 2 CML patients treated with IM.

The administration of IM can be associated with exacerbation of psoriasis. Paradoxically, in genetically predisposed individuals, tumor necrosis factor α (TNF-α) antagonists, such as IM, seem to induce psoriasis, producing IFN-α rather than TNF-α and increasing inflammation.¹³ In fact, some research shows induction of psoriasis by anti–TNF-α drugs.^14-16 Two cases of IM associated with psoriasis have been reported, and both cases represented an exacerbation of previously diagnosed psoriasis.^13,17 On the contrary, in our analysis we reported 5 cases of psoriasis vulgaris induced by IM administration. Our patients developed cutaneous psoriatic lesions approximately 1.7 months after the start of IM therapy.

The pityriasis rosea–like eruption (Figure 4) presented as nonpruritic, erythematous, scaly patches on the trunk and extremities, and arose 3.6 months after the start of treatment. This particular cutaneous AE is rare. In 3 case reports, the IM dosage also was 400 mg daily.^18-20 The pathophysiology of this rare skin reaction stems from the pharmacological effect of IM rather than a hypersensitivity reaction.¹⁸

Deininger et al⁷ reported that patients with a high basophil count (>20%) rarely show urticarial eruptions after IM due to histamine release from basophils. Premedication with an antihistamine was helpful and the urticarial eruption resolved after normalization in basophil count.⁷

Given the importance of IM for patients who have limited therapeutic alternatives for their disease and the ability to safely treat the cutaneous AEs, as demonstrated in our analysis, the suspension of IM for dermatological complications is necessary only in rare cases, as shown by the low number of patients (n=2) who had to discontinue therapy. The cutaneous AEs should be diagnosed and treated early with less impact on chemotherapy treatments. The administration of IM should involve a coordinated effort among oncologists and dermatologists to prevent important complications.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

To the Editor:

A 52-year-old man presented with recalcitrant dermatitis of 6 years’ duration. He was otherwise in excellent health. On initial presentation, physical examination revealed symmetrical, erythematous, blanching plaques with areas of erosions and overlying hemorrhagic crust on the eyebrows, scalp, back, dorsal aspects of the hands, axillae, abdomen (Figure), buttocks, groin, scrotum, pubis, and lower legs. Some areas showed slight necrosis. He denied any fevers, chills, night sweats, cough, chest pain, shortness of breath, dizziness, lightheadedness, weight loss, or appetite change.

Throughout the disease course the patient had visited numerous dermatologists seeking treatment. He had response to higher doses of oral prednisone (80 mg taper), but the condition would recur at the end of an extended taper. Treatment with narrowband UVB, mycophenolate mofetil, methotrexate, acitretin, topical clobetasol, and topical pimecrolimus provided no relief. Eventually he was placed on azathioprine 100 mg twice daily, which led to near-complete resolution. Outbreaks continued every few months and required courses of prednisone.

Multiple biopsies over the years revealed subacute spongiotic or psoriasiform dermatitis. At multiple visits it was noted that during flares there were areas of crusting and mild necrosis, which led to an extensive biochemical investigation. The glucagon level was markedly elevated at 630 ng/L (reference range, 40–130 ng/L), as was insulin at 71 μIU/mL (reference range, 6–27 μIU/mL). Complete blood cell counts over the disease course showed mild normochromic normocytic anemia. The abnormal laboratory findings led to computed tomography of the abdomen, which revealed a mass in the body of the pancreas measuring 3×3.8 cm. After computed tomography, the patient underwent a laparoscopic distal pancreatectomy and splenectomy. Histologic examination revealed a well-differentiated pancreatic endocrine tumor (glucagonoma) confined to the pancreas. After the surgery, the patient’s rash resolved within a few days and he discontinued all medications.

Diagnosis of glucagonomas often is delayed due to their rarity and lack of classical signs and symptoms. The distribution of the lesions seen in necrolytic migratory erythema (NME) usually involves the inguinal crease, perineum, lower extremities, buttocks, and other intertriginous areas.¹ Our patient had involvement in the typical distribution but also had involvement of the scalp, face, and upper body. The typical histology for NME is crusted psoriasiform dermatitis with a tendency for the upper epidermis to have necrosis and a vacuolated pale epidermis.² Our patient’s histologic findings were less specific showing epidermal spongiosis with a scant lymphocytic infiltrate and at times acanthosis. The lack of classical skin findings and histology delayed diagnosis. In more than 50% of patients, metastasis has already occurred by the time the patient is diagnosed.³ Treatment is aimed at complete removal of the pancreatic tumor, which typically leads to a rapid improvement in symptoms. For patients unable to undergo surgery, chemotherapy agents and octreotide are used; unfortunately, symptoms may persist.⁴ The response to azathioprine in our patient suggests it is a possible alternate therapy for those with persistent NME.

This patient highlights the difficulty of diagnosing a glucagonoma when the only clinical manifestation may be NME. Moreover, skin biopsies that can sometimes be diagnostic may be nonspecific. This patient also shows a potential benefit of azathioprine in the treatment of NME.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.

In parts 1 and 2 of this series on atopic dermatitis (AD),^1,2 the current putative pathogenesis, scoring systems for severity grading, and epidemiology were reviewed. Part 3 reviews the differential diagnosis, with an emphasis on the difficulty of differentiation from some rare but notable illnesses, as well as the recently expanding data on comorbidities that identify AD as a multisystem disorder with widespread health implications for the patient.

Differential Diagnosis for Pediatric AD

The differential diagnosis for pediatric AD includes chronic dermatoses (eg, seborrheic dermatitis, psoriasis), congenital disorders (eg, Netherton syndrome), malignant diseases (eg, cutaneous T-cell lymphoma [CTCL]), immunodeficiencies, infections, and metabolic disorders.³ Netherton syndrome must be ruled out to prevent extensive drug absorption when treating with topical calcineurin inhibitors (TCIs).⁴ Due to the presence of bamboo hairs in these patients, a hair mount may aid in the diagnosis of Netherton syndrome. Misdiagnosis of CTCL as AD may complicate the analysis of safety data on TCIs.^4,5 Multiple skin biopsies are essential in cases of suspected CTCL to provide an accurate diagnosis. Biopsy can be considered in AD cases with changing and/or unusual morphology, erythrodermic skin changes, and disease that is poorly responsive to multiple therapeutic modalities.

Comorbidities in Pediatric AD

Psychosocial Comorbidities

Pediatric AD often takes a psychological toll on patients as well as household members. Almost half of children with AD are reported to have a severely impaired quality of life (QOL).⁶ Contributing factors include fatigue, sleep disturbance, activity restriction (eg, inability to participate in sports), and depression.⁷

Chamlin et al⁸ developed the Childhood Atopic Dermatitis Impact Scale (CADIS), a 45-item instrument (refined from a 62-item prototype), to measure QOL in young children with AD and their family members. Responses were evaluated with consideration of 5 domains: symptoms and activity limitations/behaviors in children, as well as family/social function, sleep, and emotions in parents. The top 12 factors that parents found most bothersome about AD included itching/scratching, child’s pain/discomfort, sleep issues, embarrassment or worry about appearance, child’s fussiness/irritability/crying/unhappiness, helplessness/can’t control it/predict it, worry about skin infection, dryness of skin/nonsmooth skin, skin bleeding, worry about damage/scars, stares/comments of strangers and other children, and rashes/redness of skin/discoloration. Parents were asked to respond to items about their emotional health and social functioning, such as “My child’s skin condition has strained my relationship with my spouse or partner,” “My child’s skin condition makes me feel sad or depressed,” and “I am bothered by the reaction of strangers to this skin condition.”⁸

Kiebert et al⁹ found that AD patients had lower scores on the Short Form-36 Health Survey’s vitality, social functioning, and mental health subscales compared to individuals in the general population. The authors noted that anxiety in AD patients is of particular concern, as stress has been found to trigger the itch-scratch cycle, potentially setting off AD flare-ups.⁹ Family impact of AD is aggravated by disease severity. Sleeplessness, relationship stress, and time management can all cause family problems in patients with AD.⁸

In a survey of 3775 older teenagers aged 18 to 19 years (80% response rate out of 4774 prospective participants), 9.7% of participants reported having current AD.¹⁰ Suicidal ideation was higher in those with current AD than those without AD (15.5% vs 9.1%). The prevalence of suicidal ideation rose to 23.8% in those with both AD and itch. Diagnosis of AD (as determined through participant responses to the question, ‘‘Do you have, or have you had eczema?’’) was associated with mental health problems in 16.0% of those with AD compared to 10.1% of those without AD, with an especially reduced likelihood of romantic relationships for adolescent boys with AD, as measured using the Strength and Difficulties Questionnaire, which measures 4 problem domains and assesses presence of mental health issues in the past 6 months, and the Hopkins Symptom Checklist 10, which uses 10 questions to measure anxiety and depression symptoms in the past week.¹⁰

Dalgard et al¹¹ assessed whether the psychological burden of AD persists in adulthood in an international, multicenter, observational, cross-sectional study conducted in 13 European countries. Each dermatology clinic recruited 250 consecutive adult outpatients to complete a questionnaire along with a control group of 125 hospital employees without skin disease from the same institution but from different departments. The study included a total of 4994 participants (3635 patients and 1359 controls). Clinical depression and anxiety were present in 10.1% and 17.6% of patients, respectively, versus 4.3% and 11.1% of controls, respectively. The prevalence of depression and anxiety was highest in patients with leg ulcers, hand eczema, psoriasis, and AD.¹¹ This study demonstrated that the psychological comorbidities of childhood conditions such as AD may persist into adulthood.

Lymphoma

In a systematic review of the literature and a separate meta-analysis, Legendre et al¹² identified a slight increase in lymphoma among AD patients, with an uncertain but potential increase associated with topical corticosteroid application. This finding is similar to trends seen in other systemic inflammatory conditions that involve the skin, such as psoriasis, and is felt to relate to long-term inflammation.

Obesity

Obesity has been associated with a greater risk for moderate to severe AD in children.^13,14

Infections

Children with AD are at a higher risk for cutaneous infections and generalization of these infections. The leading infections would be with Staphylococcus aureus, but group A streptococci infections do occur. Herpes simplex virus, vaccinia virus or Kaposi varicelliform eruption (KVE), molluscum with or without dermatitis, and fungal infections occur less commonly but with greater morbidity, largely due to the impaired barrier and some innate reduction in cutaneous immunity.¹⁵

Atopic dermatitis in children also is associated with a higher prevalence of extracutaneous infections such as influenza, pneumonia, urinary tract infections, varicella-zoster virus, recurrent ear infections, sinus infections, sore throat, and head or chest colds.¹⁶ Children with AD and warts (human papillomavirus infection) have an even greater risk for these comorbidities.¹⁷ Warts and molluscum infections may become more extensive in children with AD.¹⁸ Generalization of herpetic infections occurs more easily in AD patients due to the impaired skin barrier, which includes generalized skin surface extension of herpes simplex virus type 1, varicella-zoster virus, and historically smallpox. A similar clinical appearance of generalized vesiculopustular lesions with fever can be seen when coxsackievirus A6 infections occur in AD patients; these conditions are called eczema herpeticum due to herpes simplex virus, KVE due to varicella-zoster virus and smallpox, and eczema coxsackium due to coxsackievirus A6,¹⁹ though some authors refer to all of these as KVE.²⁰ These generalized viral illnesses overlying AD often result in fever, malaise, pain, and life-threatening skin denudation with risk for dehydration and superinfection with S aureus.^7,18 It has been shown that the occurrence of eczema herpeticum in AD is associated with and may be caused by an inability to induce human β-defensin 2 and 3 as well as cathelicidin.²¹

Staphylococcus aureus colonization has been noted in 90% to 100% of AD cases, which can be associated with a higher eczema area and severity index score.^22-24 The role of S aureus in AD includes flare triggering through release of superantigens, leading to IL-31–induced pruritis.²⁵ Recurrent infection with either methicillin-sensitive or methicillin-resistant S aureus has been noted in AD.^18,26 Skin infections also occur in AD and appear as erosions and pustules, and coinfection with Streptococcus and Staphylococcus does occur; therefore, cultures often are needed to determine the type of bacteria present on the skin in severe cases and when infection is suspected.²⁷ Perianal bacterial dermatitis is a variant of infected AD occurring in the anal/groin area that is associated with S aureus and/or streptococcal superinfection in which topical corticosteroids and topical anti-infectives can be used. In some severe cases, oral antibiotics may be needed.²⁸

Injury/Hyperactivity

Children aged 0 to 5 years with AD carry an increased risk for injuries requiring medical attention, with association in part due to attention deficit disorder, depression, and anxiety. Antihistamines are believed to aggravate this issue by promoting daytime somnolence²⁹; however, pruritus-induced sleep disturbances in AD also may be responsible for daytime somnolence.³⁰

Contact Allergy and Sensitization

Children with AD may become sensitized to environmental allergens through delayed-type hypersensitivity. The presumed mechanism is that these agents include ingredients added into applied medicaments and application occurs over an impaired skin barrier allowing for absorption and greater risk of antigen presentation. Approximately 50% of children with difficult-to-control AD will react to 1 or more epicutaneous allergens, and patch testing can be performed to identify relevant allergens that can improve skin severity.⁷ Severe dermatitis and id generalized hypersensitivity reactions in patients with AD and nickel allergic contact dermatitis have been described and may aggravate underlying AD.³¹

Family Burden of AD

Parents or caregivers of children with moderate and severe AD spend nearly 3 hours a day caring for their child’s skin and experience QOL impairments including lack of sleep and/or privacy, often due to cosleeping; treatment-related financial expenditures; and feelings of hopelessness, guilt, and depression.⁷

Steroid Phobia

Steroid phobia is the fear of topical application of corticosteroids resulting in systemic side effects including unrealistic fears (eg, fear that the child will develop muscles such as an anabolic steroid user) as well as realistic but statistically low-risk fears (eg, fear of systemic absorption). These fears often result in underutilization of prescribed topical corticosteroid therapies and undertreatment of children with AD.^32,33

Financial Burden

The cost of AD can be high in the United States, with adult data demonstrating costs ranging from $371 to $489 per person.³⁴ The last published cost data for pediatric AD was from 2003, with an average cost of $219 per year.³⁵ Costs include time lost from work, household purchases (eg, skin care products), and co-pays for visits and medication, with an estimated average expenditure per person (SE) of $601.06 ($137.26) annually in 2012.³⁶ The cost of ambulatory care and emergency department visits for AD in children in the United States in 1993 was estimated at $364 million.^37-39 In 2002, Ellis et al⁴⁰ estimated the overall cost of AD to be between $900 million and $3.8 billion in the United States (1997-1998) based on projections from claims, prescriptions, and comorbidities reported to a private insurer and Medicaid. Ellis et al⁴¹ further determined that topical tacrolimus was similar in cost to high-potency corticosteroids.

Pediatric AD often progresses to adult hand eczema and leads to further morbidity, especially in health care workers.⁴² Kemp⁴³ reviewed the cost of AD in children and concluded that AD was a condition with major handicap with personal, financial, and social effects. A cost review of studies conducted in 163,700 children with AD showed that costs related to AD totaled $316.7 million per year. The author concluded that there were substantial psychosocial and financial stresses associated with pediatric AD but no clear path to potential reduction in related costs.⁴³

Sleep Disturbances

Sleep disturbances are common in pediatric AD patients. Pruritus usually is exacerbated at bedtime due to reduced humidity and lack of distractions to prevent scratching. Sleep deprivation has a substantial impact on both the patient and his/her household. Parental frustration increases with sleep disturbance.^18,44 Sleep deprivation is associated with greater severity, both because it is one of the most difficult aspects of illness and because the associated pruritus makes for greater damage done to the skin through injurious scratching.

Sleep disturbances also may interfere with growth and overnight release of growth hormones.^18,44 This latter issue can result in reduced linear growth velocity. Furthermore, sleep deprivation can cause increased risk of accidents and poor school performance.^18,44,45

Many children do not outgrow AD. In adults, AD-associated sleep deprivation has been shown to have an association with fatigue, regular daytime sleepiness, and regular insomnia, correlating to number of sick days, doctor visits, and poorer overall health status.⁴⁵

Inadequate Disease Control

Inadequate disease control has been described by Eichenfeld⁴⁶ as an important issue in AD at this time. Untreated, undertreated, and improperly treated AD are important issues affecting long-term AD care. He further cited steroid phobia as a contributor to undertreatment.⁴⁶ Fleischer⁴⁷ has cited the black box warning present on TCIs as a further deterrent to adequate therapeutic control in our current therapeutic paradigm. Undertreatment may result in uncontrolled disease activity, impaired QOL, infections, and sleep disturbances. The role of undertreatment as a driver of the atopic march is unknown.

Conclusion

Atopic dermatitis is a multisystem disorder that has wide-reaching comorbidities and may mimic a variety of skin conditions. The topic of comorbidities is new and emerging and bears further review to define risk factors, prevention strategies, and long-term monitoring requirements.