Contact Dermatitis

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. The classic presentation of BP is a generalized, pruritic, bullous eruption in elderly patients, which is occasionally preceded by an urticarial prodrome. Immunopathologically, BP is characterized by IgG and sometimes IgE autoantibodies that target basement membrane zone proteins BP180 and BP230 of the epidermis.¹

The diagnosis of BP should be suspected when an elderly patient presents with tense blisters and can be confirmed via diagnostic testing, including tissue histology and direct immunofluorescence (DIF) as the gold standard, as well as indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and most recently biochip technology as supportive tests.² Since its advent, ELISA has gained popularity as a trustworthy diagnostic test for BP. The specificity of ELISA for BP diagnosis is reported to be 98% to 100%, which leads clinicians to believe that a positive ELISA equals certain diagnosis of BP; however, misdiagnosis of BP based on a positive ELISA result can occur.^3-13 The treatment of BP often involves lifelong immunosuppressive therapy. Complications of immunosuppressive therapy contribute to morbidity and mortality in these patients, thus an accurate diagnosis is paramount before introducing therapy.¹⁴

We present the case of a 74-year-old man with a history of a pruritic nonbullous eruption who was diagnosed with BP and treated for 3 years based on positive ELISA results in the absence of confirmatory histology or DIF.

Case Report

A 74-year-old man with diabetes mellitus, hypertension, hyperlipidemia, benign prostatic hypertrophy, and obstructive sleep apnea presented for further evaluation and confirmation of a prior diagnosis of BP by an outside dermatologist. He reported a pruritic rash on the trunk, back, and extremities of 3 years’ duration. He denied occurrence of blisters at any time.

On presentation to an outside dermatologist 3 years ago, a biopsy was performed along with serologic studies due to the patient’s age and the possibility of an urticarial prodrome in BP. The biopsy revealed epidermal acanthosis, subepidermal separation, and a perivascular and interstitial infiltrate of lymphocytes and eosinophils in the papillary dermis. Direct immunofluorescence was nondiagnostic with a weak discontinuous pattern of IgG and IgA linearly along the basement membrane zone as well as few scattered and clumped cytoid bodies of IgM and IgA. Indirect immunofluoresence revealed a positive IgG titer of 1:40 on monkey esophagus substrate and a positive epidermal pattern on human split-skin substrate with a titer of 1:80. An ELISA for IgG autoantibodies against BP180 and BP230 yielded 15 U and 6 U, respectively (cut off value, 9 U). Based on the positive ELISA for IgG against BP180, a diagnosis of BP was made.

Over the following 3 years, the treatment included prednisone, tetracycline, nicotinamide, doxycycline, and dapsone. Therapy was suboptimal due to the patient’s comorbidities and socioeconomic status. Poorly controlled diabetes mellitus precluded consistent use of prednisone as recommended for BP. Tetracycline and nicotinamide were transiently effective in controlling the patient’s symptoms but were discontinued due to changes in his health insurance. Doxycycline and dapsone were ineffective. Throughout this 3-year period, the patient remained blister free, but the pruritic eruption was persistent.

The patient presented to our clinic due to his frustration with the lack of improvement and doubts about the BP diagnosis given the persistent absence of bullous lesions. Physical examination revealed numerous eroded, scaly, crusted papules on erythematous edematous plaques on all extremities, trunk, and back (Figure 1). The head, neck, face, and oral mucosa were spared. His history and clinical findings were atypical for BP and skin biopsies were performed. Histology revealed epidermal erosion with parakeratosis, spongiosis, and superficial perivascular lymphocytic inflammation with rare eosinophils without subepidermal split (Figure 2). Direct immunofluorescence was negative for IgG, IgA, IgM, C3, and C1q. Additionally, further review of the initial histology by another dermatopathologist revealed that the subepidermal separation reported was more likely artifactual clefts. These findings were not consistent with BP.

Given the patient’s clinical history, lack of bullae, and twice-negative DIF, the diagnosis was determined to be more consistent with eczematous spongiotic dermatitis. He refused a referral for phototherapy due to scheduling inconvenience. The patient was started on cyclosporine 0.5 mg/kg twice daily. After 10 days of treatment, he returned for follow-up and reported notable improvement in the pruritus. On physical examination, his dermatitis was improved with decreased erythema and inflammation.

The patient is being continued on extensive dry skin care with thick moisturizers and additional topical corticosteroid application on an as-needed basis.

Comment

Chronic immunosuppression contributes to morbidity and mortality in patients with BP; therefore, accurate diagnosis of BP is of utmost importance.¹⁴ A meta-analysis described ELISA as a test with high sensitivity and specificity (87% and 98%–100%, respectively) for diagnosis of BP.³ Nevertheless, there are opportunities for misdiagnosis using ELISA, as demonstrated in our case. To determine if the reported sensitivity and specificity of ELISA is accurate and reliable for clinical use, individual studies from the meta-analysis were reviewed.^{4,5,7-10,13,15} Issues identified in our review included dissimilar diagnostic procedures and patient populations among individual studies, several reports of positive ELISA in patients without BP, and a lack of explanation for these false-positive results.

There are notable differences in diagnostic procedures and patient populations among reports that establish the sensitivity and specificity of ELISA for BP diagnosis.^3-13 Studies have detected IgG that targets the NC16A domain of the BP180 kD antigen, the C-terminal of the BP180 kD antigen, or the entire ectodomain of the BP180 kD antigen. Study patient populations varied in disease activity, stage, and treatment. Control patients included healthy patients as well as those with many dermatoses, including pemphigus vulgaris, systemic scleroderma, systemic lupus erythematosus, rheumatoid arthritis, lichen planus, and discoid lupus erythematosus.^3-13 Due to these differences between individual studies, we believe the results that determine the overall sensitivity and specificity of ELISA for BP diagnosis must be interpreted with caution. For ELISA statistics to be clinically applicable to a specific patient, he/she should be similar to the patients studied. Therefore, we believe each study must be evaluated individually for applicability, given the differences that exist between them.

Furthermore, there have been several reports of false-positive ELISA results in patients with other dermatologic disorders, specifically in elderly patients with pruritus who do not fulfill clinical criteria for diagnosis with BP.^16-18 In a population of elderly patients with pruritus for which no specific dermatological or systemic cause was identified, Hofmann et al¹⁸ found that 12% (3/25) of patients showed IgG reactivity to BP180 despite having negative DIF results. In another study of elderly patients with pruritic dermatoses, Feliciani et al¹⁷ found that 33% (5/15) of patients had IgG reactivity against BP230 or BP180, though they did not fulfill BP criteria based on clinical presentation and showed negative DIF and IIF results. These findings suggest that IgG reactivity against BP autoantibodies as determined by ELISA is not uncommon in pruritic diseases of the elderly.

Explanations for false-positive ELISA results were rare. A few authors suggested that false-positives could be attributed to an excessively low cutoff value,^7-9 which was consistent with reports that the titer of autoantibodies to BP180 correlates with disease severity, suggesting that the higher titer of antibodies correlates with more severe disease and likely more accurate diagnosis.^10,19,20 It is important to consider that patients who have low titers of BP180 autoantibodies with inconsistent clinical characteristics and DIF results may not truly have BP. Furthermore, to determine the clinical value of ELISA in identifying patients in the initial phase of BP, sera of BP patients should be compared with sera of elderly patients with pruritic skin disorders because they comprise the patient population that often requires diagnosis.¹⁸

Given the issues identified in our review of the literature, the published sensitivity and specificity of ELISA for BP diagnosis are likely overstated. In conclusion, ELISA should not be relied on as a single criterion adequate for diagnosis of BP.^12,21 Rather, the diagnosis of BP can be obtained with a positive predictive value of 95% when a patient meets 3 of 4 clinical criteria (ie, absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and older than 70 years) and demonstrates linear deposits of predominantly IgG and/or C3 along the basement membrane zone of a perilesional biopsy on DIF.¹⁵ The gold standard for diagnosis of BP remains clinical presentation along with DIF, which can be supported by histology, IIF, and ELISA.²²

Adverse drug reactions account for 3% to 6% of hospital admissions in the United States and occur in 10% to 15% of hospitalized patients.^1,2 The most common culprits are antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).^3-12 In most cases, diagnoses are made clinically without diagnostic testing. To identify drug allergies associated with diagnostic testing, one center selected patients with suspected cutaneous drug reactions (2006-2010) for further evaluation.¹³ Of 612 patients who were evaluated, 141 had a high suspicion of drug allergy and were included in the analysis. The excluded patients had pseudoallergic reactions, reactive exanthemas due to infection, histopathologic exclusion of drug allergy, angioedema, or other dermatological conditions such as contact dermatitis and eczema. Of the included patients, 107 were diagnosed with drug reactions, while the remainder had non–drug-related exanthemas or unknown etiology after testing. Identified culprit drugs were predominantly antibiotics (39.8%) and NSAIDs (21.2%); contrast media, anticoagulants, anticonvulsants, antimalarials, antifungals, glucocorticoids, antihypertensives, and proton pump inhibitors also were implicated. They were identified with skin prick, intradermal, and patch tests (62.6%); lymphocyte transformation test (17.7%); oral rechallenge (5.6%); or without skin testing (6.5%). One quarter of patients with a high suspicion for drug allergy did not have a confirmed drug eruption in this study. Another study found that 10% to 20% of patients with reported penicillin allergy had confirmation via skin prick testing.¹⁴ These findings suggest that confirmation of suspected drug allergy may require more than one diagnostic test.

Tests for Adverse Drug Reactions

The following tests have been shown to aid in the identification of cutaneous drug eruptions: (1) patch tests^15-21; (2) intradermal tests^14,15,19,20; (3) drug provocation tests^15,20; and (4) lymphocyte transformation tests.²⁰ Intradermal or skin prick tests are most useful in urticarial eruptions but can be considered in nonurticarial eruptions with delayed inspection of test sites up to 1 week after testing. Drug provocation tests are considered the gold standard but involve patient risk. Lymphocyte transformation tests use the principle that T lymphocytes proliferate in the presence of drugs to which the patient is sensitized. Patch tests will be discussed in greater detail below. Immunohistochemistry can determine immunologic mechanisms of eruptions but cannot identify causative agents.^16,17,22

A retrospective study of patients referred for evaluation of adverse drug reactions between 1996 and 2006 found the collective negative predictive value (NPV)—the percentage of truly negative skin tests based on provocation or substitution testing—of cutaneous drug tests including patch, prick, and intradermal tests to be 89.6% (95% confidence interval, 85.9%-93.3%).²³ The NPVs of each test were not reported. Patients with negative cutaneous tests had subsequent oral rechallenge or substitution testing with medication from the same drug class.²³ Another study¹⁶ found the NPV of patch testing to be at least 79% after review of data from other studies using patch and provocation testing.^16,24 These studies suggest that cutaneous testing can be useful, albeit imperfect, in the evaluation and diagnosis of drug allergy.

Review of the Patch Test

Patch tests can be helpful in diagnosis of delayed hypersensitivities.¹⁸ Patch testing is most commonly and effectively used to diagnose allergic contact dermatitis, but its utility in other applications, such as diagnosis of cutaneous drug eruptions, has not been extensively studied.

The development of patch tests to diagnose systemic drug allergies is inhibited by the uncertainty of percutaneous drug penetration, a dearth of studies to determine the best test concentrations of active drug in the patch test, and the potential for nonimmunologic contact urticaria upon skin exposure. Furthermore, cutaneous metabolism of many antigens is well documented, but correlation to systemic metabolism often is unknown, which can confound patch test results and lead to false-negative results when the skin’s metabolic capacity does not match the body’s capacity to generate antigens capable of eliciting immunogenic responses.²¹ Additionally, the method used to suspend and disperse drugs in patch test vehicles is unfamiliar to most pharmacists, and standardized concentrations and vehicles are available only for some medications.²⁵ Studies sufficient to obtain US Food and Drug Administration approval of patch tests for systemic drug eruptions would be costly and therefore prohibitive to investigators. The majority of the literature consists of case reports and data extrapolated from reviews. Patch test results of many drugs have been reported in the literature, with the highest frequencies of positive results associated with anticonvulsants,²⁶ antibiotics, corticosteroids, calcium channel blockers, and benzodiazepines.²¹

Patch test placement affects the diagnostic value of the test. Placing patch tests on previously involved sites of fixed drug eruptions improves yield over placement on uninvolved skin.²⁷ Placing patch tests on previously involved sites of other drug eruptions such as toxic epidermal necrolysis also may aid in diagnosis, though the literature is sparse.^25,26,28

Patch Testing in Drug Eruptions

Morbilliform eruptions account for 48% to 91% of patients with adverse drug reactions.^4-6 Other drug eruptions include urticarial eruptions, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis, Stevens-Johnson syndrome, lichenoid drug eruption, symmetric drug-related intertriginous and flexural exanthema (SDRIFE), erythema multiforme (EM), and systemic contact dermatitis. The Table summarizes reports of positive patch tests with various medications for these drug eruptions.

In general, antimicrobials and NSAIDs were the most implicated drugs with positive patch test results in AGEP, DRESS syndrome, EM, fixed drug eruptions, and morbilliform eruptions. In AGEP, positive results also were reported for other drugs, including terbinafine and morphine.^29-38 In fixed drug eruptions, patch testing on involved skin showed positive results to NSAIDs, analgesics, platelet inhibitors, and antimicrobials.^27,52-55 Patch testing in DRESS syndrome has shown many positive reactions to antiepileptics and antipsychotics.^39-43 One study used patch tests in SDRIFE, reporting positive results with antimicrobials, antineoplastics, decongestants, and glucocorticoids.⁶¹ Nonsteroidal anti-inflammatory drugs, antimicrobials, calcium channel blockers, and histamine antagonists were implicated in EM.^47-51 Positive patch tests were seen in morbilliform eruptions with selective serotonin reuptake inhibitors, antiepileptics/benzodiazepines, NSAIDs, and antimicrobials.^28,57-60 In toxic epidermal necrolysis, diagnosis with patch testing was made using patches placed on previously involved skin with sulfamethoxazole.⁶²

Systemic Contact Dermatitis

Drugs historically recognized as causing allergic contact dermatitis (eg, topical gentamycin) can cause systemic contact dermatitis, which can be patch tested. In these situations, systemic contact dermatitis may be due to either the active drug or excipients in the medication formulation. Excipients are inactive ingredients in medications that provide a suitable consistency, appearance, or form. Often overlooked as culprits of drug hypersensitivity because they are theoretically inert, excipients are increasingly implicated in drug allergy. Swerlick and Campbell⁶³ described 11 cases in which chronic unexplained pruritus responded to medication changes to avoid coloring agents. The most common culprits were FD&C Blue No. 1 and FD&C Blue No. 2. Patch testing for allergies to dyes can be clinically useful, though a lack of commercially available patch tests makes diagnosis difficult.⁶⁴

Other excipients can cause cutaneous reactions. Propylene glycol, commonly implicated in allergic contact dermatitis, also can cause cutaneous eruptions upon systemic exposure.⁶⁵ Corticosteroid-induced systemic contact dermatitis has been reported, though it is less prevalent than allergic contact dermatitis.⁶⁶ These reactions usually are due to nonmethylated and nonhalogenated corticosteroids including budesonide, cortisone, hydrocortisone, prednisolone, and methylprednisolone.^67,68 Patch testing in these situations is complicated by the possibility of false-negative results due to the anti-inflammatory effects of the corticosteroids. Therefore, patch testing should be performed using standardized and not treatment concentrations.

In our clinic, we have anecdotally observed several patients with chronic dermatitis and suspected NSAID allergies have positive patch test results with propylene glycol and not the suspected drug. Excipients encountered in multiple drugs and foods are more likely to present as chronic dermatitis, while active drug ingredients started in hospital settings more often present as acute dermatitis.

Our Experience

We have patch tested a handful of patients with suspected drug eruptions (University Hospitals Cleveland Medical Center institutional review board #07-12-27). Medications, excipients, and their concentrations (in % weight per weight) and vehicles that were tested include ibuprofen (10% petrolatum), aspirin (10% petrolatum), hydrochlorothiazide (10% petrolatum), captopril (5% petrolatum), and propylene glycol (30% water or 5% petrolatum). Patch tests were read at 48 and 72 hours and scored according to the International Contact Dermatitis Research Group patch test scoring guidelines.⁶⁹ Two patients tested for ibuprofen reacted positively only to propylene glycol; the 3 other patients did not react to aspirin, hydrochlorothiazide, and captopril. Overall, we observed no positive patch tests to medications and 2 positive tests to propylene glycol in 5 patients tested (unpublished data).

Areas of Uncertainty

Although tests for immediate-type hypersensitivity reactions to drugs exist as skin prick tests, diagnostic testing for the majority of drug reactions does not exist. Drug allergy diagnosis is made with history and temporality, potentially resulting in unnecessary avoidance of helpful medications. Ideal patch test concentrations and vehicles as well as the sensitivity and specificity of these tests are unknown.

Guidelines From Professional Societies

Drug allergy testing guidelines are available from the British Society for Allergy and Clinical Immunology⁷⁰ and American Academy of Allergy, Asthma and Immunology.⁷¹ The guidelines recommend diagnosis by history and temporality, and it is stated that patch testing is potentially useful in maculopapular rashes, AGEP, fixed drug eruptions, and DRESS syndrome.

Conclusion

Case reports in the literature suggest the utility of patch testing in some drug allergies. We suggest testing excipients such as propylene glycol and benzoic acid to rule out systemic contact dermatitis when patch testing with active drugs to confirm cause of suspected adverse cutaneous reactions to medications.

Adverse drug reactions account for 3% to 6% of hospital admissions in the United States and occur in 10% to 15% of hospitalized patients.^1,2 The most common culprits are antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).^3-12 In most cases, diagnoses are made clinically without diagnostic testing. To identify drug allergies associated with diagnostic testing, one center selected patients with suspected cutaneous drug reactions (2006-2010) for further evaluation.¹³ Of 612 patients who were evaluated, 141 had a high suspicion of drug allergy and were included in the analysis. The excluded patients had pseudoallergic reactions, reactive exanthemas due to infection, histopathologic exclusion of drug allergy, angioedema, or other dermatological conditions such as contact dermatitis and eczema. Of the included patients, 107 were diagnosed with drug reactions, while the remainder had non–drug-related exanthemas or unknown etiology after testing. Identified culprit drugs were predominantly antibiotics (39.8%) and NSAIDs (21.2%); contrast media, anticoagulants, anticonvulsants, antimalarials, antifungals, glucocorticoids, antihypertensives, and proton pump inhibitors also were implicated. They were identified with skin prick, intradermal, and patch tests (62.6%); lymphocyte transformation test (17.7%); oral rechallenge (5.6%); or without skin testing (6.5%). One quarter of patients with a high suspicion for drug allergy did not have a confirmed drug eruption in this study. Another study found that 10% to 20% of patients with reported penicillin allergy had confirmation via skin prick testing.¹⁴ These findings suggest that confirmation of suspected drug allergy may require more than one diagnostic test.

Tests for Adverse Drug Reactions

The following tests have been shown to aid in the identification of cutaneous drug eruptions: (1) patch tests^15-21; (2) intradermal tests^14,15,19,20; (3) drug provocation tests^15,20; and (4) lymphocyte transformation tests.²⁰ Intradermal or skin prick tests are most useful in urticarial eruptions but can be considered in nonurticarial eruptions with delayed inspection of test sites up to 1 week after testing. Drug provocation tests are considered the gold standard but involve patient risk. Lymphocyte transformation tests use the principle that T lymphocytes proliferate in the presence of drugs to which the patient is sensitized. Patch tests will be discussed in greater detail below. Immunohistochemistry can determine immunologic mechanisms of eruptions but cannot identify causative agents.^16,17,22

A retrospective study of patients referred for evaluation of adverse drug reactions between 1996 and 2006 found the collective negative predictive value (NPV)—the percentage of truly negative skin tests based on provocation or substitution testing—of cutaneous drug tests including patch, prick, and intradermal tests to be 89.6% (95% confidence interval, 85.9%-93.3%).²³ The NPVs of each test were not reported. Patients with negative cutaneous tests had subsequent oral rechallenge or substitution testing with medication from the same drug class.²³ Another study¹⁶ found the NPV of patch testing to be at least 79% after review of data from other studies using patch and provocation testing.^16,24 These studies suggest that cutaneous testing can be useful, albeit imperfect, in the evaluation and diagnosis of drug allergy.

Review of the Patch Test

Patch tests can be helpful in diagnosis of delayed hypersensitivities.¹⁸ Patch testing is most commonly and effectively used to diagnose allergic contact dermatitis, but its utility in other applications, such as diagnosis of cutaneous drug eruptions, has not been extensively studied.

The development of patch tests to diagnose systemic drug allergies is inhibited by the uncertainty of percutaneous drug penetration, a dearth of studies to determine the best test concentrations of active drug in the patch test, and the potential for nonimmunologic contact urticaria upon skin exposure. Furthermore, cutaneous metabolism of many antigens is well documented, but correlation to systemic metabolism often is unknown, which can confound patch test results and lead to false-negative results when the skin’s metabolic capacity does not match the body’s capacity to generate antigens capable of eliciting immunogenic responses.²¹ Additionally, the method used to suspend and disperse drugs in patch test vehicles is unfamiliar to most pharmacists, and standardized concentrations and vehicles are available only for some medications.²⁵ Studies sufficient to obtain US Food and Drug Administration approval of patch tests for systemic drug eruptions would be costly and therefore prohibitive to investigators. The majority of the literature consists of case reports and data extrapolated from reviews. Patch test results of many drugs have been reported in the literature, with the highest frequencies of positive results associated with anticonvulsants,²⁶ antibiotics, corticosteroids, calcium channel blockers, and benzodiazepines.²¹

Patch test placement affects the diagnostic value of the test. Placing patch tests on previously involved sites of fixed drug eruptions improves yield over placement on uninvolved skin.²⁷ Placing patch tests on previously involved sites of other drug eruptions such as toxic epidermal necrolysis also may aid in diagnosis, though the literature is sparse.^25,26,28

Patch Testing in Drug Eruptions

Morbilliform eruptions account for 48% to 91% of patients with adverse drug reactions.^4-6 Other drug eruptions include urticarial eruptions, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis, Stevens-Johnson syndrome, lichenoid drug eruption, symmetric drug-related intertriginous and flexural exanthema (SDRIFE), erythema multiforme (EM), and systemic contact dermatitis. The Table summarizes reports of positive patch tests with various medications for these drug eruptions.

In general, antimicrobials and NSAIDs were the most implicated drugs with positive patch test results in AGEP, DRESS syndrome, EM, fixed drug eruptions, and morbilliform eruptions. In AGEP, positive results also were reported for other drugs, including terbinafine and morphine.^29-38 In fixed drug eruptions, patch testing on involved skin showed positive results to NSAIDs, analgesics, platelet inhibitors, and antimicrobials.^27,52-55 Patch testing in DRESS syndrome has shown many positive reactions to antiepileptics and antipsychotics.^39-43 One study used patch tests in SDRIFE, reporting positive results with antimicrobials, antineoplastics, decongestants, and glucocorticoids.⁶¹ Nonsteroidal anti-inflammatory drugs, antimicrobials, calcium channel blockers, and histamine antagonists were implicated in EM.^47-51 Positive patch tests were seen in morbilliform eruptions with selective serotonin reuptake inhibitors, antiepileptics/benzodiazepines, NSAIDs, and antimicrobials.^28,57-60 In toxic epidermal necrolysis, diagnosis with patch testing was made using patches placed on previously involved skin with sulfamethoxazole.⁶²

Systemic Contact Dermatitis

Drugs historically recognized as causing allergic contact dermatitis (eg, topical gentamycin) can cause systemic contact dermatitis, which can be patch tested. In these situations, systemic contact dermatitis may be due to either the active drug or excipients in the medication formulation. Excipients are inactive ingredients in medications that provide a suitable consistency, appearance, or form. Often overlooked as culprits of drug hypersensitivity because they are theoretically inert, excipients are increasingly implicated in drug allergy. Swerlick and Campbell⁶³ described 11 cases in which chronic unexplained pruritus responded to medication changes to avoid coloring agents. The most common culprits were FD&C Blue No. 1 and FD&C Blue No. 2. Patch testing for allergies to dyes can be clinically useful, though a lack of commercially available patch tests makes diagnosis difficult.⁶⁴

Other excipients can cause cutaneous reactions. Propylene glycol, commonly implicated in allergic contact dermatitis, also can cause cutaneous eruptions upon systemic exposure.⁶⁵ Corticosteroid-induced systemic contact dermatitis has been reported, though it is less prevalent than allergic contact dermatitis.⁶⁶ These reactions usually are due to nonmethylated and nonhalogenated corticosteroids including budesonide, cortisone, hydrocortisone, prednisolone, and methylprednisolone.^67,68 Patch testing in these situations is complicated by the possibility of false-negative results due to the anti-inflammatory effects of the corticosteroids. Therefore, patch testing should be performed using standardized and not treatment concentrations.

In our clinic, we have anecdotally observed several patients with chronic dermatitis and suspected NSAID allergies have positive patch test results with propylene glycol and not the suspected drug. Excipients encountered in multiple drugs and foods are more likely to present as chronic dermatitis, while active drug ingredients started in hospital settings more often present as acute dermatitis.

Our Experience

We have patch tested a handful of patients with suspected drug eruptions (University Hospitals Cleveland Medical Center institutional review board #07-12-27). Medications, excipients, and their concentrations (in % weight per weight) and vehicles that were tested include ibuprofen (10% petrolatum), aspirin (10% petrolatum), hydrochlorothiazide (10% petrolatum), captopril (5% petrolatum), and propylene glycol (30% water or 5% petrolatum). Patch tests were read at 48 and 72 hours and scored according to the International Contact Dermatitis Research Group patch test scoring guidelines.⁶⁹ Two patients tested for ibuprofen reacted positively only to propylene glycol; the 3 other patients did not react to aspirin, hydrochlorothiazide, and captopril. Overall, we observed no positive patch tests to medications and 2 positive tests to propylene glycol in 5 patients tested (unpublished data).

Areas of Uncertainty

Although tests for immediate-type hypersensitivity reactions to drugs exist as skin prick tests, diagnostic testing for the majority of drug reactions does not exist. Drug allergy diagnosis is made with history and temporality, potentially resulting in unnecessary avoidance of helpful medications. Ideal patch test concentrations and vehicles as well as the sensitivity and specificity of these tests are unknown.

Guidelines From Professional Societies

Drug allergy testing guidelines are available from the British Society for Allergy and Clinical Immunology⁷⁰ and American Academy of Allergy, Asthma and Immunology.⁷¹ The guidelines recommend diagnosis by history and temporality, and it is stated that patch testing is potentially useful in maculopapular rashes, AGEP, fixed drug eruptions, and DRESS syndrome.

Conclusion

Case reports in the literature suggest the utility of patch testing in some drug allergies. We suggest testing excipients such as propylene glycol and benzoic acid to rule out systemic contact dermatitis when patch testing with active drugs to confirm cause of suspected adverse cutaneous reactions to medications.

Adverse drug reactions account for 3% to 6% of hospital admissions in the United States and occur in 10% to 15% of hospitalized patients.^1,2 The most common culprits are antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).^3-12 In most cases, diagnoses are made clinically without diagnostic testing. To identify drug allergies associated with diagnostic testing, one center selected patients with suspected cutaneous drug reactions (2006-2010) for further evaluation.¹³ Of 612 patients who were evaluated, 141 had a high suspicion of drug allergy and were included in the analysis. The excluded patients had pseudoallergic reactions, reactive exanthemas due to infection, histopathologic exclusion of drug allergy, angioedema, or other dermatological conditions such as contact dermatitis and eczema. Of the included patients, 107 were diagnosed with drug reactions, while the remainder had non–drug-related exanthemas or unknown etiology after testing. Identified culprit drugs were predominantly antibiotics (39.8%) and NSAIDs (21.2%); contrast media, anticoagulants, anticonvulsants, antimalarials, antifungals, glucocorticoids, antihypertensives, and proton pump inhibitors also were implicated. They were identified with skin prick, intradermal, and patch tests (62.6%); lymphocyte transformation test (17.7%); oral rechallenge (5.6%); or without skin testing (6.5%). One quarter of patients with a high suspicion for drug allergy did not have a confirmed drug eruption in this study. Another study found that 10% to 20% of patients with reported penicillin allergy had confirmation via skin prick testing.¹⁴ These findings suggest that confirmation of suspected drug allergy may require more than one diagnostic test.

Tests for Adverse Drug Reactions

The following tests have been shown to aid in the identification of cutaneous drug eruptions: (1) patch tests^15-21; (2) intradermal tests^14,15,19,20; (3) drug provocation tests^15,20; and (4) lymphocyte transformation tests.²⁰ Intradermal or skin prick tests are most useful in urticarial eruptions but can be considered in nonurticarial eruptions with delayed inspection of test sites up to 1 week after testing. Drug provocation tests are considered the gold standard but involve patient risk. Lymphocyte transformation tests use the principle that T lymphocytes proliferate in the presence of drugs to which the patient is sensitized. Patch tests will be discussed in greater detail below. Immunohistochemistry can determine immunologic mechanisms of eruptions but cannot identify causative agents.^16,17,22

A retrospective study of patients referred for evaluation of adverse drug reactions between 1996 and 2006 found the collective negative predictive value (NPV)—the percentage of truly negative skin tests based on provocation or substitution testing—of cutaneous drug tests including patch, prick, and intradermal tests to be 89.6% (95% confidence interval, 85.9%-93.3%).²³ The NPVs of each test were not reported. Patients with negative cutaneous tests had subsequent oral rechallenge or substitution testing with medication from the same drug class.²³ Another study¹⁶ found the NPV of patch testing to be at least 79% after review of data from other studies using patch and provocation testing.^16,24 These studies suggest that cutaneous testing can be useful, albeit imperfect, in the evaluation and diagnosis of drug allergy.

Review of the Patch Test

Patch tests can be helpful in diagnosis of delayed hypersensitivities.¹⁸ Patch testing is most commonly and effectively used to diagnose allergic contact dermatitis, but its utility in other applications, such as diagnosis of cutaneous drug eruptions, has not been extensively studied.

The development of patch tests to diagnose systemic drug allergies is inhibited by the uncertainty of percutaneous drug penetration, a dearth of studies to determine the best test concentrations of active drug in the patch test, and the potential for nonimmunologic contact urticaria upon skin exposure. Furthermore, cutaneous metabolism of many antigens is well documented, but correlation to systemic metabolism often is unknown, which can confound patch test results and lead to false-negative results when the skin’s metabolic capacity does not match the body’s capacity to generate antigens capable of eliciting immunogenic responses.²¹ Additionally, the method used to suspend and disperse drugs in patch test vehicles is unfamiliar to most pharmacists, and standardized concentrations and vehicles are available only for some medications.²⁵ Studies sufficient to obtain US Food and Drug Administration approval of patch tests for systemic drug eruptions would be costly and therefore prohibitive to investigators. The majority of the literature consists of case reports and data extrapolated from reviews. Patch test results of many drugs have been reported in the literature, with the highest frequencies of positive results associated with anticonvulsants,²⁶ antibiotics, corticosteroids, calcium channel blockers, and benzodiazepines.²¹

Patch test placement affects the diagnostic value of the test. Placing patch tests on previously involved sites of fixed drug eruptions improves yield over placement on uninvolved skin.²⁷ Placing patch tests on previously involved sites of other drug eruptions such as toxic epidermal necrolysis also may aid in diagnosis, though the literature is sparse.^25,26,28

Patch Testing in Drug Eruptions

Morbilliform eruptions account for 48% to 91% of patients with adverse drug reactions.^4-6 Other drug eruptions include urticarial eruptions, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis, Stevens-Johnson syndrome, lichenoid drug eruption, symmetric drug-related intertriginous and flexural exanthema (SDRIFE), erythema multiforme (EM), and systemic contact dermatitis. The Table summarizes reports of positive patch tests with various medications for these drug eruptions.

In general, antimicrobials and NSAIDs were the most implicated drugs with positive patch test results in AGEP, DRESS syndrome, EM, fixed drug eruptions, and morbilliform eruptions. In AGEP, positive results also were reported for other drugs, including terbinafine and morphine.^29-38 In fixed drug eruptions, patch testing on involved skin showed positive results to NSAIDs, analgesics, platelet inhibitors, and antimicrobials.^27,52-55 Patch testing in DRESS syndrome has shown many positive reactions to antiepileptics and antipsychotics.^39-43 One study used patch tests in SDRIFE, reporting positive results with antimicrobials, antineoplastics, decongestants, and glucocorticoids.⁶¹ Nonsteroidal anti-inflammatory drugs, antimicrobials, calcium channel blockers, and histamine antagonists were implicated in EM.^47-51 Positive patch tests were seen in morbilliform eruptions with selective serotonin reuptake inhibitors, antiepileptics/benzodiazepines, NSAIDs, and antimicrobials.^28,57-60 In toxic epidermal necrolysis, diagnosis with patch testing was made using patches placed on previously involved skin with sulfamethoxazole.⁶²

Systemic Contact Dermatitis

Drugs historically recognized as causing allergic contact dermatitis (eg, topical gentamycin) can cause systemic contact dermatitis, which can be patch tested. In these situations, systemic contact dermatitis may be due to either the active drug or excipients in the medication formulation. Excipients are inactive ingredients in medications that provide a suitable consistency, appearance, or form. Often overlooked as culprits of drug hypersensitivity because they are theoretically inert, excipients are increasingly implicated in drug allergy. Swerlick and Campbell⁶³ described 11 cases in which chronic unexplained pruritus responded to medication changes to avoid coloring agents. The most common culprits were FD&C Blue No. 1 and FD&C Blue No. 2. Patch testing for allergies to dyes can be clinically useful, though a lack of commercially available patch tests makes diagnosis difficult.⁶⁴

Other excipients can cause cutaneous reactions. Propylene glycol, commonly implicated in allergic contact dermatitis, also can cause cutaneous eruptions upon systemic exposure.⁶⁵ Corticosteroid-induced systemic contact dermatitis has been reported, though it is less prevalent than allergic contact dermatitis.⁶⁶ These reactions usually are due to nonmethylated and nonhalogenated corticosteroids including budesonide, cortisone, hydrocortisone, prednisolone, and methylprednisolone.^67,68 Patch testing in these situations is complicated by the possibility of false-negative results due to the anti-inflammatory effects of the corticosteroids. Therefore, patch testing should be performed using standardized and not treatment concentrations.

In our clinic, we have anecdotally observed several patients with chronic dermatitis and suspected NSAID allergies have positive patch test results with propylene glycol and not the suspected drug. Excipients encountered in multiple drugs and foods are more likely to present as chronic dermatitis, while active drug ingredients started in hospital settings more often present as acute dermatitis.

Our Experience

We have patch tested a handful of patients with suspected drug eruptions (University Hospitals Cleveland Medical Center institutional review board #07-12-27). Medications, excipients, and their concentrations (in % weight per weight) and vehicles that were tested include ibuprofen (10% petrolatum), aspirin (10% petrolatum), hydrochlorothiazide (10% petrolatum), captopril (5% petrolatum), and propylene glycol (30% water or 5% petrolatum). Patch tests were read at 48 and 72 hours and scored according to the International Contact Dermatitis Research Group patch test scoring guidelines.⁶⁹ Two patients tested for ibuprofen reacted positively only to propylene glycol; the 3 other patients did not react to aspirin, hydrochlorothiazide, and captopril. Overall, we observed no positive patch tests to medications and 2 positive tests to propylene glycol in 5 patients tested (unpublished data).

Areas of Uncertainty

Although tests for immediate-type hypersensitivity reactions to drugs exist as skin prick tests, diagnostic testing for the majority of drug reactions does not exist. Drug allergy diagnosis is made with history and temporality, potentially resulting in unnecessary avoidance of helpful medications. Ideal patch test concentrations and vehicles as well as the sensitivity and specificity of these tests are unknown.

Guidelines From Professional Societies

Drug allergy testing guidelines are available from the British Society for Allergy and Clinical Immunology⁷⁰ and American Academy of Allergy, Asthma and Immunology.⁷¹ The guidelines recommend diagnosis by history and temporality, and it is stated that patch testing is potentially useful in maculopapular rashes, AGEP, fixed drug eruptions, and DRESS syndrome.

Conclusion

Case reports in the literature suggest the utility of patch testing in some drug allergies. We suggest testing excipients such as propylene glycol and benzoic acid to rule out systemic contact dermatitis when patch testing with active drugs to confirm cause of suspected adverse cutaneous reactions to medications.

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.