Urticaria

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Eosinophilic pustular folliculitis (EPF) was originally described in 1965 and has since evolved into 3 distinct subtypes: classic, immunosuppressed (IS), and infantile types. Immunosuppressed EPF can be further subdivided into human immunodeficiency virus (HIV) associated (IS-HIV) and non-HIV associated. Human immunodeficiency virus–seronegative cases have been associated with underlying malignancies (IS-heme) or chronic immunosuppression, such as that seen in transplant patients.

Case Report

A 52-year-old man with a medical history limited to prostate adenocarcinoma treated with a robotic prostatectomy presented with a pruritic red rash on the face, neck, shoulders, and chest of 1 month’s duration. The patient previously completed a course of azithromycin 250 mg, intramuscular triamcinolone, and oral prednisone with only minor improvement. Physical examination demonstrated multiple pink folliculocentric papules and pustules scattered on the head (Figure 1A), neck, and chest (Figure 1B), as well as edematous pink papules and plaques on the forehead (Figures 1C and 1D). The palms, soles, and oral mucosa were clear.

Initial biopsy of the right side of the chest was nonspecific and most consistent with a reaction to an arthropod bite. The patient was started on oral doxycycline 100 mg twice daily for 2 weeks. With no improvement seen, additional biopsies were obtained from the left side of the chest and forehead. The biopsy of the chest showed ruptured folliculitis with evidence of acute and chronic inflammation. The biopsy of the forehead demonstrated eosinophilic follicular spongiosis with intrafollicular Langerhans cell microgranulomas along with abundant eosinophils adjacent to follicles, consistent with EPF (Figure 2). Serum HIV testing was negative. Serum white blood cell count was normal at 6400/µL (reference range, 4500–11,000/µL) with mild elevation of eosinophils (8%). The remaining complete blood cell count and comprehensive metabolic panel were within reference range. The patient was subsequently started on oral indomethacin 25 mg twice daily and triamcinolone cream 0.1%. Within a few days he experienced initial improvement in his symptoms of pruritus and diminution in the number of inflammatory follicular papules.

Approximately 1 month after presentation, he began to experience symptoms of dysphagia and fatigue. In addition, tonsillar hypertrophy and palpable neck and axillary lymphadenopathy were present. Computed tomography of the neck, chest, and abdomen showed diffuse lymphadenopathy. Full-body positron emission tomography–computed tomography demonstrated extensive metabolically active lymphoma in multiple nodal groups above and below the diaphragm. There also was lymphomatous involvement of the spleen. An axillary lymph node biopsy was diagnostic for mantle cell lymphoma (CD4:CD8, 1:1; CD45 negative; CD20 positive; CD5 positive). He was subsequently initiated on a rituximab chemotherapeutic regimen via intravenous infusion and completed a total of 8 cycles. Although chemotherapy treatment improved the EPF, oral indomethacin and topical triamcinolone were useful in clearing disease.

Comment

Subtypes of EPF
Eosinophilic pustular folliculitis was first described in a Japanese female presenting with folliculocentric pustules distributed on the face, torso, and arms.¹ This noninfectious eosinophilic infiltration of hair follicles predominantly seen in the Japanese population is now regarded as the classic form. Three distinct subtypes of EPF now exist, including the originally described classic variant (Ofuji disease), an IS variant, and a rare infantile form.¹

All 3 subtypes of EPF are more commonly seen in men than women. The classic form has a peak incidence between the third and fourth decades of life. It presents as chronic annular papules and sterile pustules exhibiting peripheral extension, with individual lesions lasting for approximately 7 to 10 days with frequent relapses. The face is the most common area of involvement, followed by the trunk, extremities, and more rarely the palmoplantar surfaces. Concomitant leukocytosis with eosinophilia is seen in up to 35% of patients.¹ The infantile type represents the rarest EPF form. The average age of onset is 5 months, with most cases resolving by 14 months of age.¹

Clinically, EPF is characterized by recurrent papules and pustules predominantly on the scalp without annular or polycyclic ring formation, as seen in the classic type. The palms and soles may be involved, which can clinically mimic infantile acropustulosis and scabies infection. Most patients exhibit a concomitant peripheral eosinophilia.^1,2

In the late 1980s, the IS variant of EPF was recognized in HIV-positive (IS-HIV) and HIV-negative malignancy-associated (IS-heme) populations.^1,3 This newly characterized form differs morphologically and biologically from the classic and infantile subtypes. The IS subtype has a unique presentation including intensely pruritic, discrete, erythematous, follicular papules with palmoplantar sparing and infrequent annular or circinate plaque forms.¹ Frequently, with the IS-HIV form, CD4⁺ T-cell counts are below 300 cells/mL, and 25% to 50% of patients have lymphopenia with eosinophilia.³ Highly active antiretroviral therapy has been associated with EPF resolution in HIV-positive individuals; however, it also has been shown to induce transient EPF during the first 3 to 6 months of initiation.^1,3,4

Unlike the IS-HIV form, the IS-heme form has occurred solely in males and is predominantly associated with hematologic malignancies (eg, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome) 30 to 90 days following bone marrow transplant, peripheral blood stem cell transplant, or chemotherapy treatment.^5,6 Unlike the chronic and persistent IS-HIV form, prior cases of IS-heme EPF have been predominantly self-limited. Interestingly, only 2 reported cases of EPF have occurred prior to the diagnosis of malignancy including B-cell leukemia and myelodysplastic syndrome.⁵

Histopathology
All 3 identified forms of EPF histopathologically show acute and chronic lymphoeosinophilic infiltrate concentrated at the follicular isthmus, which can lead to follicular destruction. Scattered mononuclear cells, eosinophils, and neutrophils are found within the pilar outer root sheath, sebaceous glands, and ducts. Approximately 40% of cases demonstrate follicular mucinosis.¹ Histopathology of lesional palmar skin in classic-type EPF demonstrates intraepidermal pustule formation with abundant eosinophils and neutrophils adjacent to the acrosyringium.^7,8

Pathogenesis
Although the pathophysiology of EPF is largely unknown, it is thought to represent a helper T cell (T_H2) response involving IL-4, IL-5, and IL-13 cytokines.⁹ Chemoattractant receptor homologous molecule 2, which is expressed on eosinophils and lymphocytes, is believed to play a role in the pruritus, edema, and inflammatory response seen adjacent to pilosebaceous units in EPF.¹⁰ Moreover, immunohistochemical and flow cytometry analysis has revealed a prevalence of prostaglandin D2 within the perisebocyte infiltrate in EPF.⁹ Prostaglandin D2 induces eotaxin-3 production within sebocytes via peroxisome proliferator-activated receptor γ, which enhances chemoattraction of eosinophils. This pathogenesis represents a prostaglandin-based mechanism and potentially explains the efficacy of indomethacin treatment of EPF through its cyclooxygenase inhibition and reduction of chemoattractant receptor homologous molecule 2 expression.^9-11

Treatment
Multiple therapeutic modalities have been reported for the treatment of EPF. For all 3 subtypes, moderate- to high-potency topical corticosteroids are considered first-line therapy. UVB phototherapy 2 to 3 times weekly remains the gold standard, given its consistent efficacy.^1,12 Indomethacin (50–75 mg daily) remains first-line treatment of classic EPF.^4,12 Previously reported cases of classic EPF and IS-EPF have responded well to oral prednisone (1 mg/kg daily).^12,13 In a retrospective review of EPF treatment data, the following treatments also have been reported to be successful: psoralen plus UVA, oral cetirizine (20–40 mg daily, particularly for IS-EPF cases), metronidazole (250 mg 3 times daily), minocycline (150 mg daily), itraconazole (200–400 mg daily, dapsone (50–200 mg daily), systemic retinoids, tacrolimus ointment 0.1%, and permethrin cream.^4,12

Malignancy
Although the entity of IS-heme EPF is rare, the morphology and treatment are unique and can potentially unmask an underlying hematologic malignancy. In patients with EPF and associated malignancy, such as our patient, a differential diagnosis to consider is eosinophilic dermatosis of hematologic malignancy (EDHM). Eosinophilic dermatosis of hematologic malignancy is most commonly associated with chronic lymphocytic leukemia and can be differentiated from EPF clinically, histopathologically, and by treatment response. Eosinophilic dermatosis of hematologic malignancy clinically presents with nonspecific papules, pustules, and/or vesicles on the head, trunk, and extremities. On histopathology, EDHM shows a superficial and deep perivascular and interstitial lymphoeosinophilic infiltration. Furthermore, EDHM patients typically exhibit a poor treatment response to oral indomethacin.¹⁴

Conclusion

Eosinophilic pustular folliculitis is a noninfectious folliculocentric process comprised of 3 distinct types. The histopathology shows follicular spongiosis with increased eosinophils. The pathogenesis is most likely related to a multifactorial immune system dysregulation involving T_H2 T cells, prostaglandin D2, and eotaxin-3. The treatment of EPF may involve topical corticosteroids, UVB phototherapy, or most notably oral indomethacin. In patients with EPF and malignancy, EDHM is a differential diagnosis to consider. Our case serves as a reminder that rare eosinophilic dermatoses may represent manifestations of underlying hematopoietic malignancy and, when investigated early, can lead to appropriate life-saving treatment.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

ORLANDO – Using videoconferencing to assess patients for a reported penicillin allergy saved more than 2 hours of physician time for every patient, and resulted in almost every patient having their allergy label removed, researchers reported.

In what the researchers said was the first study showing the utility of telemedicine in evaluating patient-reported penicillin allergies, allergy and immunology physicians did a secure telemedicine consultation with patients after they underwent penicillin skin testing with a physician assistant; an approach which, on average, took 123 minutes fewer each time than if the physician had done the consultation face-to-face. The teleconference can be done on a laptop or smartphone.

Thomas R. Collins/Frontline Medical Communications

“This is so overlabeled,” Dr. Ramsey said. “Ten percent of the population thinks they’re allergic to penicillin, and 90% of them are not.”

A stark difference was found in the types of medicines administered before and after the evaluations, with aminopenicillin therapy jumping from 0 days of use to 188 days, and vancomycin – a more potent, but more costly alternative – dropping from 130 days of use to 16 days (P less than .05 for both).

Dr. Ramsey noted that, in part because of the time-consuming nature of the penicillin skin tests, they often are simply not done, so the false allergy labels are not caught, leading to pointless costs and exposure to more potent and potentially harmful forms of antibiotic therapy.

“Some hospitals don’t have allergists who will come in to do testing,” she said. “Sometimes patients are on medications that may interfere. And then a lot of times it’s just underrecognized – the implications of a penicillin allergy label. That is a very hot topic in our field and also in infectious disease.”

She hopes the telemedicine approach catches on more widely, which would help minimize the multitude of problems linked to penicillin allergy labels.

“Patients that avoid penicillin, they’re on more costly second-line antibiotics that are, in general, less effective, depending on which infection you’re talking about,” Dr. Ramsey said. “The [second-line antibiotics] have more side effects. And there’s data to show that patients with [a] penicillin allergy label have longer hospital stays, more costly hospital stays, are at risk for more resistant infections. And it breeds antimicrobial resistance in the long-term.”

Dr. Ramsey had no relevant financial disclosures.

SOURCE: Ramsey AC et al. AAAAI/WAO Joint Congress, Abstract 104.

ORLANDO – Using videoconferencing to assess patients for a reported penicillin allergy saved more than 2 hours of physician time for every patient, and resulted in almost every patient having their allergy label removed, researchers reported.

In what the researchers said was the first study showing the utility of telemedicine in evaluating patient-reported penicillin allergies, allergy and immunology physicians did a secure telemedicine consultation with patients after they underwent penicillin skin testing with a physician assistant; an approach which, on average, took 123 minutes fewer each time than if the physician had done the consultation face-to-face. The teleconference can be done on a laptop or smartphone.

Thomas R. Collins/Frontline Medical Communications

“This is so overlabeled,” Dr. Ramsey said. “Ten percent of the population thinks they’re allergic to penicillin, and 90% of them are not.”

A stark difference was found in the types of medicines administered before and after the evaluations, with aminopenicillin therapy jumping from 0 days of use to 188 days, and vancomycin – a more potent, but more costly alternative – dropping from 130 days of use to 16 days (P less than .05 for both).

Dr. Ramsey noted that, in part because of the time-consuming nature of the penicillin skin tests, they often are simply not done, so the false allergy labels are not caught, leading to pointless costs and exposure to more potent and potentially harmful forms of antibiotic therapy.

“Some hospitals don’t have allergists who will come in to do testing,” she said. “Sometimes patients are on medications that may interfere. And then a lot of times it’s just underrecognized – the implications of a penicillin allergy label. That is a very hot topic in our field and also in infectious disease.”

She hopes the telemedicine approach catches on more widely, which would help minimize the multitude of problems linked to penicillin allergy labels.

“Patients that avoid penicillin, they’re on more costly second-line antibiotics that are, in general, less effective, depending on which infection you’re talking about,” Dr. Ramsey said. “The [second-line antibiotics] have more side effects. And there’s data to show that patients with [a] penicillin allergy label have longer hospital stays, more costly hospital stays, are at risk for more resistant infections. And it breeds antimicrobial resistance in the long-term.”

Dr. Ramsey had no relevant financial disclosures.

SOURCE: Ramsey AC et al. AAAAI/WAO Joint Congress, Abstract 104.

ORLANDO – Using videoconferencing to assess patients for a reported penicillin allergy saved more than 2 hours of physician time for every patient, and resulted in almost every patient having their allergy label removed, researchers reported.

In what the researchers said was the first study showing the utility of telemedicine in evaluating patient-reported penicillin allergies, allergy and immunology physicians did a secure telemedicine consultation with patients after they underwent penicillin skin testing with a physician assistant; an approach which, on average, took 123 minutes fewer each time than if the physician had done the consultation face-to-face. The teleconference can be done on a laptop or smartphone.

Thomas R. Collins/Frontline Medical Communications

“This is so overlabeled,” Dr. Ramsey said. “Ten percent of the population thinks they’re allergic to penicillin, and 90% of them are not.”

A stark difference was found in the types of medicines administered before and after the evaluations, with aminopenicillin therapy jumping from 0 days of use to 188 days, and vancomycin – a more potent, but more costly alternative – dropping from 130 days of use to 16 days (P less than .05 for both).

Dr. Ramsey noted that, in part because of the time-consuming nature of the penicillin skin tests, they often are simply not done, so the false allergy labels are not caught, leading to pointless costs and exposure to more potent and potentially harmful forms of antibiotic therapy.

“Some hospitals don’t have allergists who will come in to do testing,” she said. “Sometimes patients are on medications that may interfere. And then a lot of times it’s just underrecognized – the implications of a penicillin allergy label. That is a very hot topic in our field and also in infectious disease.”

She hopes the telemedicine approach catches on more widely, which would help minimize the multitude of problems linked to penicillin allergy labels.

“Patients that avoid penicillin, they’re on more costly second-line antibiotics that are, in general, less effective, depending on which infection you’re talking about,” Dr. Ramsey said. “The [second-line antibiotics] have more side effects. And there’s data to show that patients with [a] penicillin allergy label have longer hospital stays, more costly hospital stays, are at risk for more resistant infections. And it breeds antimicrobial resistance in the long-term.”

Dr. Ramsey had no relevant financial disclosures.

SOURCE: Ramsey AC et al. AAAAI/WAO Joint Congress, Abstract 104.

GENEVA – Omalizumab for treatment of chronic spontaneous urticaria brings about a profound improvement in angioedema-related quality of life, a widely underappreciated dimension of the impairment caused by this disease, Karsten Weller, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Weller K et al. EADV Congress 2017.

GENEVA – Omalizumab for treatment of chronic spontaneous urticaria brings about a profound improvement in angioedema-related quality of life, a widely underappreciated dimension of the impairment caused by this disease, Karsten Weller, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Weller K et al. EADV Congress 2017.

GENEVA – Omalizumab for treatment of chronic spontaneous urticaria brings about a profound improvement in angioedema-related quality of life, a widely underappreciated dimension of the impairment caused by this disease, Karsten Weller, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Weller K et al. EADV Congress 2017.

GENEVA – In real-world clinical practice, roughly two-thirds of patients with chronic spontaneous urticaria treated with the approved dose of omalizumab will achieve good disease control – and for those who don’t, three-quarters will respond upon updosing to 450 or 600 mg every 4 weeks.

That’s the key message of an open-label study of 286 patients with chronic spontaneous urticaria (CSU) conducted at 15 hospitals by the Catalan and Balearic Chronic Urticaria Network (XUrCB), Jorge Spertino, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Spertino J et al. EADV Congress

GENEVA – In real-world clinical practice, roughly two-thirds of patients with chronic spontaneous urticaria treated with the approved dose of omalizumab will achieve good disease control – and for those who don’t, three-quarters will respond upon updosing to 450 or 600 mg every 4 weeks.

That’s the key message of an open-label study of 286 patients with chronic spontaneous urticaria (CSU) conducted at 15 hospitals by the Catalan and Balearic Chronic Urticaria Network (XUrCB), Jorge Spertino, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Spertino J et al. EADV Congress

GENEVA – In real-world clinical practice, roughly two-thirds of patients with chronic spontaneous urticaria treated with the approved dose of omalizumab will achieve good disease control – and for those who don’t, three-quarters will respond upon updosing to 450 or 600 mg every 4 weeks.

That’s the key message of an open-label study of 286 patients with chronic spontaneous urticaria (CSU) conducted at 15 hospitals by the Catalan and Balearic Chronic Urticaria Network (XUrCB), Jorge Spertino, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/Frontline Medical News

[email protected]

SOURCE: Spertino J et al. EADV Congress

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

A low-histamine diet could decrease symptoms and improve the quality of life for people with chronic spontaneous urticaria (CsU), according to Nicola Wagner, MD, of the department of dermatology at the Clinical Center Darmstadt (Germany) GmbH, Darmstadt, and her coauthors.

In their prospective study of 56 patients with a 3-month history of CsU (average 25 months) who followed a low-histamine diet for 3 weeks, 42 (75%) showed improvements in the urticaria activity score (UAS), compared to baseline. In nine patients (16%), disease activity remained the same, and five patients (9%) experienced worsening symptoms.

The primary endpoint, which was at least a three-point improvement in urticaria activity score, was reached by 34 patients (61%). Among these 34 patients, the average reduction in the UAS score during the last 4 days of the diet compared with the 4 days before starting the diet was 8.59 points (P less than .001), and dropped from 9.05 to 4.23 (P = .004) across the entire group (J Eur Acad Dermatol Venereol. 2017 Apr;31[4]:650-5).

The low-histamine diet omitted food such as cheese, preserved meats, strawberries, raspberries, citrus fruit, bananas, kiwis, plums, papaya, and alcohol, and included foods such as dairy, vegetables, fresh meat, eggs, bread, pasta, rice, and certain varieties of fish. “Many patients with CsU complain of worsening of symptoms by consuming histamine-rich food, like red wine or matured cheese, but to the best of our knowledge, until now no studies were available supporting these observations,” the authors wrote.

The low-histamine diet was also associated with an average improvement in Dermatological Life Quality Instrument Questionnaire from baseline of 2.08 points across all participants, while Chronic Urticaria Quality of Life Questionnaire scores improved by an average of 5.46 score points in the 52 patients for whom these evaluations were available.

“Quality of life showed an improvement by a low-histamine diet, which was surprising, because dieting may decrease quality of life,” the authors noted.

There was also a reduction in antihistamine use among participants taking antihistamines at baseline, with 39% (22 of 56) reducing their intake and just over half of these patients (12 of the 22) stopping antihistamines altogether.

The study measured levels of diamine oxidase – the enzyme responsible for disintegrating histamine – both before and after, and saw no significant change across the patient group. However, patients with higher urticaria activity scores at baseline did show a decline in diamine oxidase activity with the diet.

Addressing concerns that these improvements could simply reflect spontaneous remission of the disease, the authors pointed out that a previous study had found a remission rate of just 3.4% over 6 months.

Based on the results, they concluded that a low-histamine diet “might be recommended for a period of 3-4 weeks in CsU patients in order to reduce symptoms and antihistamine intake as well as to improve quality of life.”

The authors had no funding source or conflicts of interest to declare.

A low-histamine diet could decrease symptoms and improve the quality of life for people with chronic spontaneous urticaria (CsU), according to Nicola Wagner, MD, of the department of dermatology at the Clinical Center Darmstadt (Germany) GmbH, Darmstadt, and her coauthors.

In their prospective study of 56 patients with a 3-month history of CsU (average 25 months) who followed a low-histamine diet for 3 weeks, 42 (75%) showed improvements in the urticaria activity score (UAS), compared to baseline. In nine patients (16%), disease activity remained the same, and five patients (9%) experienced worsening symptoms.

The primary endpoint, which was at least a three-point improvement in urticaria activity score, was reached by 34 patients (61%). Among these 34 patients, the average reduction in the UAS score during the last 4 days of the diet compared with the 4 days before starting the diet was 8.59 points (P less than .001), and dropped from 9.05 to 4.23 (P = .004) across the entire group (J Eur Acad Dermatol Venereol. 2017 Apr;31[4]:650-5).

The low-histamine diet omitted food such as cheese, preserved meats, strawberries, raspberries, citrus fruit, bananas, kiwis, plums, papaya, and alcohol, and included foods such as dairy, vegetables, fresh meat, eggs, bread, pasta, rice, and certain varieties of fish. “Many patients with CsU complain of worsening of symptoms by consuming histamine-rich food, like red wine or matured cheese, but to the best of our knowledge, until now no studies were available supporting these observations,” the authors wrote.

The low-histamine diet was also associated with an average improvement in Dermatological Life Quality Instrument Questionnaire from baseline of 2.08 points across all participants, while Chronic Urticaria Quality of Life Questionnaire scores improved by an average of 5.46 score points in the 52 patients for whom these evaluations were available.

“Quality of life showed an improvement by a low-histamine diet, which was surprising, because dieting may decrease quality of life,” the authors noted.

There was also a reduction in antihistamine use among participants taking antihistamines at baseline, with 39% (22 of 56) reducing their intake and just over half of these patients (12 of the 22) stopping antihistamines altogether.

The study measured levels of diamine oxidase – the enzyme responsible for disintegrating histamine – both before and after, and saw no significant change across the patient group. However, patients with higher urticaria activity scores at baseline did show a decline in diamine oxidase activity with the diet.

Addressing concerns that these improvements could simply reflect spontaneous remission of the disease, the authors pointed out that a previous study had found a remission rate of just 3.4% over 6 months.

Based on the results, they concluded that a low-histamine diet “might be recommended for a period of 3-4 weeks in CsU patients in order to reduce symptoms and antihistamine intake as well as to improve quality of life.”

The authors had no funding source or conflicts of interest to declare.

A low-histamine diet could decrease symptoms and improve the quality of life for people with chronic spontaneous urticaria (CsU), according to Nicola Wagner, MD, of the department of dermatology at the Clinical Center Darmstadt (Germany) GmbH, Darmstadt, and her coauthors.

In their prospective study of 56 patients with a 3-month history of CsU (average 25 months) who followed a low-histamine diet for 3 weeks, 42 (75%) showed improvements in the urticaria activity score (UAS), compared to baseline. In nine patients (16%), disease activity remained the same, and five patients (9%) experienced worsening symptoms.

The primary endpoint, which was at least a three-point improvement in urticaria activity score, was reached by 34 patients (61%). Among these 34 patients, the average reduction in the UAS score during the last 4 days of the diet compared with the 4 days before starting the diet was 8.59 points (P less than .001), and dropped from 9.05 to 4.23 (P = .004) across the entire group (J Eur Acad Dermatol Venereol. 2017 Apr;31[4]:650-5).

The low-histamine diet omitted food such as cheese, preserved meats, strawberries, raspberries, citrus fruit, bananas, kiwis, plums, papaya, and alcohol, and included foods such as dairy, vegetables, fresh meat, eggs, bread, pasta, rice, and certain varieties of fish. “Many patients with CsU complain of worsening of symptoms by consuming histamine-rich food, like red wine or matured cheese, but to the best of our knowledge, until now no studies were available supporting these observations,” the authors wrote.

The low-histamine diet was also associated with an average improvement in Dermatological Life Quality Instrument Questionnaire from baseline of 2.08 points across all participants, while Chronic Urticaria Quality of Life Questionnaire scores improved by an average of 5.46 score points in the 52 patients for whom these evaluations were available.

“Quality of life showed an improvement by a low-histamine diet, which was surprising, because dieting may decrease quality of life,” the authors noted.

There was also a reduction in antihistamine use among participants taking antihistamines at baseline, with 39% (22 of 56) reducing their intake and just over half of these patients (12 of the 22) stopping antihistamines altogether.

The study measured levels of diamine oxidase – the enzyme responsible for disintegrating histamine – both before and after, and saw no significant change across the patient group. However, patients with higher urticaria activity scores at baseline did show a decline in diamine oxidase activity with the diet.

Addressing concerns that these improvements could simply reflect spontaneous remission of the disease, the authors pointed out that a previous study had found a remission rate of just 3.4% over 6 months.

Based on the results, they concluded that a low-histamine diet “might be recommended for a period of 3-4 weeks in CsU patients in order to reduce symptoms and antihistamine intake as well as to improve quality of life.”

The authors had no funding source or conflicts of interest to declare.

WAILEA, HAWAII – New drugs can mean new drug reactions affecting the skin, notably those associated with hepatitis C therapies and new cancer drugs, according to J. Mark Jackson, MD, of the University of Louisville (Ky.).

When dermatologists recognize the side effects from hepatitis C and cancer drugs, they can monitor patients appropriately and initiate the correct treatments, Dr. Jackson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/ Skin Disease Education Foundation.

WAILEA, HAWAII – New drugs can mean new drug reactions affecting the skin, notably those associated with hepatitis C therapies and new cancer drugs, according to J. Mark Jackson, MD, of the University of Louisville (Ky.).

When dermatologists recognize the side effects from hepatitis C and cancer drugs, they can monitor patients appropriately and initiate the correct treatments, Dr. Jackson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/ Skin Disease Education Foundation.

WAILEA, HAWAII – New drugs can mean new drug reactions affecting the skin, notably those associated with hepatitis C therapies and new cancer drugs, according to J. Mark Jackson, MD, of the University of Louisville (Ky.).

When dermatologists recognize the side effects from hepatitis C and cancer drugs, they can monitor patients appropriately and initiate the correct treatments, Dr. Jackson said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/ Skin Disease Education Foundation.