Cutis

Extramammary Paget's disease (EMPD) is an uncommon clinical condition. However, cases of EMPD increasingly have been reported in recent years because of advancements in diagnostic technique and increased awareness of the disease. There are 3 patterns of EMPD: (1) cutaneous in situ epithelial with no associated underlying cancer; (2) epithelial with an associated underlying adnexal cancer; and (3) disease associated with underlying organ involvement (ie, genitourinary, gastrointestinal, or another distant site). Treatment of EMPD is problematic because the disease is associated with a high rate of recurrence. Preliminary results with topical imiquimod monotherapy demonstrate that this treatment may serve as a potential nonsurgical cure for the disease. We report a case of a patient who failed to respond to surgery or imiquimod monotherapy but who responded to imiquimod combination therapy with 5-fluorouracil (5-FU) and retinoic acid. 

Case Report
A 68-year-old Chinese man presented with a pruritic rash in the scrotal area of 7 years' duration (Figure 1). Results of a skin biopsy revealed diffuse clusters of malignant pagetoid intraepidermal epithelial proliferation that stained positive with colloidal iron, mucicarmine, and periodic acid-Schiff with diastase (Figure 2). The results were diagnostic for EMPD. Results of detailed clinical and laboratory examinations showed no evidence of malignancy in other sites.

The patient underwent a large surgical excision with skin flap repair. One year later, he complained of an itchy rash within the surgical scar. Results of a repeat biopsy confirmed EMPD. The patient refused further surgery. As an alternative treatment, imiquimod 5% cream was applied nightly (Monday through Friday) for 6 weeks; because of moderate irritation, the application was decreased to every other day for the next 4 weeks. In general, the patient tolerated the treatment well and only reported erythema, burning, and some tenderness in the affected area. At the end of the 10-week treatment, histologic evaluation results revealed residual epidermal EMPD. The patient was then treated with imiquimod, 5-FU, and retinoic acid combination chemotherapy. The protocol involved applying 5-FU 5% cream every morning, retinoic acid 0.1% gel every afternoon, and imiquimod every evening. After 12 days, the patient complained of severe burning and pain in the affected area, and results of an examination showed severe erosive erythema (Figure 3). At that point, topical chemotherapy was discontinued. Zinc oxide 2% and polysporin ointment were applied alternatively 4 times daily for 2 weeks.

In the third week after the topical chemotherapy, results of multiple punch biopsies on several sites revealed no residual malignancy. The patient remained asymptomatic, and the results of a repeat biopsy revealed no residual microscopic malignancy at the 2-year follow-up visit. 

Comment EMPD is a multifocal epidermal malignancy that possibly is related to the proliferation of pleuripotential epithelial stem cells. EMPD follows an unpredictable clinical course, ranging from indolent skin disease to aggressive malignancy. In general, EMPD appears in individuals aged 50 to 80 years, particularly in those who are white. Typical anatomic sites involve the vulvar, perianal, perineal, scrotal, and penile regions. Less common sites include the thighs, buttocks, axilla, eyelids, and external ear canal. The lesions of EMPD present as well-defined erythematous plaques that usually are accompanied by pruritus. The main differential diagnoses of EMPD include psoriasis, contact dermatitis, fungal infection, lichen sclerosis, atopic dermatitis, Bowen's disease, melanoma, histiocytosis, pagetoid basal cell carcinoma, and mycosis fungoides. The nonspecific presentation of EMPD often leads to a misdiagnosis, and an average of one year may pass before a biopsy is performed and a definitive diagnosis is made. Microscopically, the margins of EMPD are multicentric and vague, with skip areas that frequently extend beyond the clinically detectable lesion, which results in the high rate of recurrence of EMPD. In addition, there is a lack of clinical experience with cutaneous EMPD because the disease has a relatively rare occurrence. Case reports constitute the majority of literature on EMPD. The successful management of EMPD is compromised by the multifocal nature of the disease; recurrence of lesions after conventional surgical management is high, ranging from 44% to 75%. Even with Mohs micrographic surgery, the lesions have a reported recurrence rate of 27%.1-2 Imiquimod is an immodulator that stimulates the production of a wide range of cytokines, including interleukins 1, 6, 8, and 12; interferon; and tumor necrosis factor. Imiquimod activates B-cell responses by increasing the expression of class II major histocompatibility complex markers, which increase immunoglobulin production. Imiquimod also may enhance Langerhans cell migration from the skin to the lymph nodes, thus improving antigen presentation.3 An in vitro study has demonstrated that imiquimod inhibits tumor-associated angiogenesis and diminishes tumor burden in transplantable murine carcinoma.4 Results of a biopsy specimen from one melanoma patient also showed apoptosis after treatment with topical imiquimod cream and systemic dacarbazine.5 We identified 5 cases (in 4 reports) in which the effect of topical imiquimod monotherapy applied to the perianal/genital area of patients with EMPD was evaluated.6-9 All 5 cases showed a clinical and histologic cure, with minimal functional disturbance. In the study with the longest follow-up period, the patient remained disease free at the 14-month follow-up visit.7 In the study with the most frequent dosing interval, the medication was applied once daily.9 Treatment duration ranged from 6 to 16 weeks (Table).6-9

5-FU has selective toxicity in premalignant and malignant epithelial lesions. 5-FU is a chemotherapeutic drug that induces notable regression in advanced locally progressing EMPD.10,11 The mechanisms of action of 5-FU are based on the drug's steric similarity to uracil and its irreversible binding to thymidylate synthetase, which prevents the synthesis of thymidine from uridine. Consequently, RNA and DNA synthesis are inhibited, faulty RNA is produced, and cell toxicity ensues. Paget's cells have a high metabolic activity that requires abundant RNA. This high demand for RNA synthesis may be responsible for the sensitivity of Paget's cells to 5-FU. Six cases (in 6 reports) published in the English literature evaluated the effect of 5-FU monotherapy in the treatment of EMPD.11-16 Four reports showed clinical cure after treatment with 5-FU.12-14,16 In 2 of the reports, microscopic evidence of disease persisted after treatment12-13; in one report, no follow-up biopsy was performed14; in another report, no microscopic evidence of disease after treatment was identified.16 In the case report by Del Castillo et al,16 the patient applied topical 5-FU 5% intermittently (at the patient's discretion) to the affected axilla region for one year. The surgical removal of the lesion after one year of intermittent treatment showed no evidence of EMPD. In the case reports by Bewley et al11 and Eliezri et al,15 application of 5-FU 5% increased the disease margins. In summary, these reports demonstrate that topical 5-FU cannot be considered a safe and effective first-line choice of treatment due to its erosive feature and false impression of total clinical resolution. Retinoic acid has antiproliferative activity and induces apoptosis by its selective binding activity to the γ receptor in the nuclear receptor–independent pathway in neoplastic cells.17-18 We identified no published reports of topical retinoic acid for the treatment of EMPD. The most common use of retinoid antitumor agents is in the treatment of leukemia. In our case report, the tumor recurred after initial surgery and remained after 10 weeks of monotherapy with imiquimod. The reason imiquimod therapy failed in this case may relate to the presence of the tumor in the area of scar tissue; imiquimod by itself could not achieve adequate tissue penetration to induce the appropriate immune response. Consequently, we applied 5-FU cream in the morning to induce a selective toxicity in the Paget's cell, and retinoic acid gel in the afternoon to promote an antiproliferative apoptosis and to facilitate the penetration of imiquimod, which was applied in the evening. This combination therapy could potentiate a stronger stimulation of cytokines and interferon, which would then lead to the activation of T and B cells, natural killer cells, and a macrophage host response, all of which could be responsible for the destruction of the intraepithelial EMPD. In conclusion, we have demonstrated that a combination treatment of topical imiquimod, 5-FU, and retinoic acid may serve as an effective treatment option for patients who have failed imiquimod monotherapy. Acknowledgments—The authors would like to thank their colleagues John O'Dea, MD; Tony Chin, MD; Robert Uyeda, MD; and Simon Chan, MD, for reviewing and critiquing this manuscript. The authors also would like to thank Irma Marques for editing the manuscript.

Extramammary Paget's disease (EMPD) is an uncommon clinical condition. However, cases of EMPD increasingly have been reported in recent years because of advancements in diagnostic technique and increased awareness of the disease. There are 3 patterns of EMPD: (1) cutaneous in situ epithelial with no associated underlying cancer; (2) epithelial with an associated underlying adnexal cancer; and (3) disease associated with underlying organ involvement (ie, genitourinary, gastrointestinal, or another distant site). Treatment of EMPD is problematic because the disease is associated with a high rate of recurrence. Preliminary results with topical imiquimod monotherapy demonstrate that this treatment may serve as a potential nonsurgical cure for the disease. We report a case of a patient who failed to respond to surgery or imiquimod monotherapy but who responded to imiquimod combination therapy with 5-fluorouracil (5-FU) and retinoic acid. 

Case Report
A 68-year-old Chinese man presented with a pruritic rash in the scrotal area of 7 years' duration (Figure 1). Results of a skin biopsy revealed diffuse clusters of malignant pagetoid intraepidermal epithelial proliferation that stained positive with colloidal iron, mucicarmine, and periodic acid-Schiff with diastase (Figure 2). The results were diagnostic for EMPD. Results of detailed clinical and laboratory examinations showed no evidence of malignancy in other sites.

The patient underwent a large surgical excision with skin flap repair. One year later, he complained of an itchy rash within the surgical scar. Results of a repeat biopsy confirmed EMPD. The patient refused further surgery. As an alternative treatment, imiquimod 5% cream was applied nightly (Monday through Friday) for 6 weeks; because of moderate irritation, the application was decreased to every other day for the next 4 weeks. In general, the patient tolerated the treatment well and only reported erythema, burning, and some tenderness in the affected area. At the end of the 10-week treatment, histologic evaluation results revealed residual epidermal EMPD. The patient was then treated with imiquimod, 5-FU, and retinoic acid combination chemotherapy. The protocol involved applying 5-FU 5% cream every morning, retinoic acid 0.1% gel every afternoon, and imiquimod every evening. After 12 days, the patient complained of severe burning and pain in the affected area, and results of an examination showed severe erosive erythema (Figure 3). At that point, topical chemotherapy was discontinued. Zinc oxide 2% and polysporin ointment were applied alternatively 4 times daily for 2 weeks.

In the third week after the topical chemotherapy, results of multiple punch biopsies on several sites revealed no residual malignancy. The patient remained asymptomatic, and the results of a repeat biopsy revealed no residual microscopic malignancy at the 2-year follow-up visit. 

Comment EMPD is a multifocal epidermal malignancy that possibly is related to the proliferation of pleuripotential epithelial stem cells. EMPD follows an unpredictable clinical course, ranging from indolent skin disease to aggressive malignancy. In general, EMPD appears in individuals aged 50 to 80 years, particularly in those who are white. Typical anatomic sites involve the vulvar, perianal, perineal, scrotal, and penile regions. Less common sites include the thighs, buttocks, axilla, eyelids, and external ear canal. The lesions of EMPD present as well-defined erythematous plaques that usually are accompanied by pruritus. The main differential diagnoses of EMPD include psoriasis, contact dermatitis, fungal infection, lichen sclerosis, atopic dermatitis, Bowen's disease, melanoma, histiocytosis, pagetoid basal cell carcinoma, and mycosis fungoides. The nonspecific presentation of EMPD often leads to a misdiagnosis, and an average of one year may pass before a biopsy is performed and a definitive diagnosis is made. Microscopically, the margins of EMPD are multicentric and vague, with skip areas that frequently extend beyond the clinically detectable lesion, which results in the high rate of recurrence of EMPD. In addition, there is a lack of clinical experience with cutaneous EMPD because the disease has a relatively rare occurrence. Case reports constitute the majority of literature on EMPD. The successful management of EMPD is compromised by the multifocal nature of the disease; recurrence of lesions after conventional surgical management is high, ranging from 44% to 75%. Even with Mohs micrographic surgery, the lesions have a reported recurrence rate of 27%.1-2 Imiquimod is an immodulator that stimulates the production of a wide range of cytokines, including interleukins 1, 6, 8, and 12; interferon; and tumor necrosis factor. Imiquimod activates B-cell responses by increasing the expression of class II major histocompatibility complex markers, which increase immunoglobulin production. Imiquimod also may enhance Langerhans cell migration from the skin to the lymph nodes, thus improving antigen presentation.3 An in vitro study has demonstrated that imiquimod inhibits tumor-associated angiogenesis and diminishes tumor burden in transplantable murine carcinoma.4 Results of a biopsy specimen from one melanoma patient also showed apoptosis after treatment with topical imiquimod cream and systemic dacarbazine.5 We identified 5 cases (in 4 reports) in which the effect of topical imiquimod monotherapy applied to the perianal/genital area of patients with EMPD was evaluated.6-9 All 5 cases showed a clinical and histologic cure, with minimal functional disturbance. In the study with the longest follow-up period, the patient remained disease free at the 14-month follow-up visit.7 In the study with the most frequent dosing interval, the medication was applied once daily.9 Treatment duration ranged from 6 to 16 weeks (Table).6-9

5-FU has selective toxicity in premalignant and malignant epithelial lesions. 5-FU is a chemotherapeutic drug that induces notable regression in advanced locally progressing EMPD.10,11 The mechanisms of action of 5-FU are based on the drug's steric similarity to uracil and its irreversible binding to thymidylate synthetase, which prevents the synthesis of thymidine from uridine. Consequently, RNA and DNA synthesis are inhibited, faulty RNA is produced, and cell toxicity ensues. Paget's cells have a high metabolic activity that requires abundant RNA. This high demand for RNA synthesis may be responsible for the sensitivity of Paget's cells to 5-FU. Six cases (in 6 reports) published in the English literature evaluated the effect of 5-FU monotherapy in the treatment of EMPD.11-16 Four reports showed clinical cure after treatment with 5-FU.12-14,16 In 2 of the reports, microscopic evidence of disease persisted after treatment12-13; in one report, no follow-up biopsy was performed14; in another report, no microscopic evidence of disease after treatment was identified.16 In the case report by Del Castillo et al,16 the patient applied topical 5-FU 5% intermittently (at the patient's discretion) to the affected axilla region for one year. The surgical removal of the lesion after one year of intermittent treatment showed no evidence of EMPD. In the case reports by Bewley et al11 and Eliezri et al,15 application of 5-FU 5% increased the disease margins. In summary, these reports demonstrate that topical 5-FU cannot be considered a safe and effective first-line choice of treatment due to its erosive feature and false impression of total clinical resolution. Retinoic acid has antiproliferative activity and induces apoptosis by its selective binding activity to the γ receptor in the nuclear receptor–independent pathway in neoplastic cells.17-18 We identified no published reports of topical retinoic acid for the treatment of EMPD. The most common use of retinoid antitumor agents is in the treatment of leukemia. In our case report, the tumor recurred after initial surgery and remained after 10 weeks of monotherapy with imiquimod. The reason imiquimod therapy failed in this case may relate to the presence of the tumor in the area of scar tissue; imiquimod by itself could not achieve adequate tissue penetration to induce the appropriate immune response. Consequently, we applied 5-FU cream in the morning to induce a selective toxicity in the Paget's cell, and retinoic acid gel in the afternoon to promote an antiproliferative apoptosis and to facilitate the penetration of imiquimod, which was applied in the evening. This combination therapy could potentiate a stronger stimulation of cytokines and interferon, which would then lead to the activation of T and B cells, natural killer cells, and a macrophage host response, all of which could be responsible for the destruction of the intraepithelial EMPD. In conclusion, we have demonstrated that a combination treatment of topical imiquimod, 5-FU, and retinoic acid may serve as an effective treatment option for patients who have failed imiquimod monotherapy. Acknowledgments—The authors would like to thank their colleagues John O'Dea, MD; Tony Chin, MD; Robert Uyeda, MD; and Simon Chan, MD, for reviewing and critiquing this manuscript. The authors also would like to thank Irma Marques for editing the manuscript.

Extramammary Paget's disease (EMPD) is an uncommon clinical condition. However, cases of EMPD increasingly have been reported in recent years because of advancements in diagnostic technique and increased awareness of the disease. There are 3 patterns of EMPD: (1) cutaneous in situ epithelial with no associated underlying cancer; (2) epithelial with an associated underlying adnexal cancer; and (3) disease associated with underlying organ involvement (ie, genitourinary, gastrointestinal, or another distant site). Treatment of EMPD is problematic because the disease is associated with a high rate of recurrence. Preliminary results with topical imiquimod monotherapy demonstrate that this treatment may serve as a potential nonsurgical cure for the disease. We report a case of a patient who failed to respond to surgery or imiquimod monotherapy but who responded to imiquimod combination therapy with 5-fluorouracil (5-FU) and retinoic acid. 

Case Report
A 68-year-old Chinese man presented with a pruritic rash in the scrotal area of 7 years' duration (Figure 1). Results of a skin biopsy revealed diffuse clusters of malignant pagetoid intraepidermal epithelial proliferation that stained positive with colloidal iron, mucicarmine, and periodic acid-Schiff with diastase (Figure 2). The results were diagnostic for EMPD. Results of detailed clinical and laboratory examinations showed no evidence of malignancy in other sites.

The patient underwent a large surgical excision with skin flap repair. One year later, he complained of an itchy rash within the surgical scar. Results of a repeat biopsy confirmed EMPD. The patient refused further surgery. As an alternative treatment, imiquimod 5% cream was applied nightly (Monday through Friday) for 6 weeks; because of moderate irritation, the application was decreased to every other day for the next 4 weeks. In general, the patient tolerated the treatment well and only reported erythema, burning, and some tenderness in the affected area. At the end of the 10-week treatment, histologic evaluation results revealed residual epidermal EMPD. The patient was then treated with imiquimod, 5-FU, and retinoic acid combination chemotherapy. The protocol involved applying 5-FU 5% cream every morning, retinoic acid 0.1% gel every afternoon, and imiquimod every evening. After 12 days, the patient complained of severe burning and pain in the affected area, and results of an examination showed severe erosive erythema (Figure 3). At that point, topical chemotherapy was discontinued. Zinc oxide 2% and polysporin ointment were applied alternatively 4 times daily for 2 weeks.

In the third week after the topical chemotherapy, results of multiple punch biopsies on several sites revealed no residual malignancy. The patient remained asymptomatic, and the results of a repeat biopsy revealed no residual microscopic malignancy at the 2-year follow-up visit. 

Comment EMPD is a multifocal epidermal malignancy that possibly is related to the proliferation of pleuripotential epithelial stem cells. EMPD follows an unpredictable clinical course, ranging from indolent skin disease to aggressive malignancy. In general, EMPD appears in individuals aged 50 to 80 years, particularly in those who are white. Typical anatomic sites involve the vulvar, perianal, perineal, scrotal, and penile regions. Less common sites include the thighs, buttocks, axilla, eyelids, and external ear canal. The lesions of EMPD present as well-defined erythematous plaques that usually are accompanied by pruritus. The main differential diagnoses of EMPD include psoriasis, contact dermatitis, fungal infection, lichen sclerosis, atopic dermatitis, Bowen's disease, melanoma, histiocytosis, pagetoid basal cell carcinoma, and mycosis fungoides. The nonspecific presentation of EMPD often leads to a misdiagnosis, and an average of one year may pass before a biopsy is performed and a definitive diagnosis is made. Microscopically, the margins of EMPD are multicentric and vague, with skip areas that frequently extend beyond the clinically detectable lesion, which results in the high rate of recurrence of EMPD. In addition, there is a lack of clinical experience with cutaneous EMPD because the disease has a relatively rare occurrence. Case reports constitute the majority of literature on EMPD. The successful management of EMPD is compromised by the multifocal nature of the disease; recurrence of lesions after conventional surgical management is high, ranging from 44% to 75%. Even with Mohs micrographic surgery, the lesions have a reported recurrence rate of 27%.1-2 Imiquimod is an immodulator that stimulates the production of a wide range of cytokines, including interleukins 1, 6, 8, and 12; interferon; and tumor necrosis factor. Imiquimod activates B-cell responses by increasing the expression of class II major histocompatibility complex markers, which increase immunoglobulin production. Imiquimod also may enhance Langerhans cell migration from the skin to the lymph nodes, thus improving antigen presentation.3 An in vitro study has demonstrated that imiquimod inhibits tumor-associated angiogenesis and diminishes tumor burden in transplantable murine carcinoma.4 Results of a biopsy specimen from one melanoma patient also showed apoptosis after treatment with topical imiquimod cream and systemic dacarbazine.5 We identified 5 cases (in 4 reports) in which the effect of topical imiquimod monotherapy applied to the perianal/genital area of patients with EMPD was evaluated.6-9 All 5 cases showed a clinical and histologic cure, with minimal functional disturbance. In the study with the longest follow-up period, the patient remained disease free at the 14-month follow-up visit.7 In the study with the most frequent dosing interval, the medication was applied once daily.9 Treatment duration ranged from 6 to 16 weeks (Table).6-9

5-FU has selective toxicity in premalignant and malignant epithelial lesions. 5-FU is a chemotherapeutic drug that induces notable regression in advanced locally progressing EMPD.10,11 The mechanisms of action of 5-FU are based on the drug's steric similarity to uracil and its irreversible binding to thymidylate synthetase, which prevents the synthesis of thymidine from uridine. Consequently, RNA and DNA synthesis are inhibited, faulty RNA is produced, and cell toxicity ensues. Paget's cells have a high metabolic activity that requires abundant RNA. This high demand for RNA synthesis may be responsible for the sensitivity of Paget's cells to 5-FU. Six cases (in 6 reports) published in the English literature evaluated the effect of 5-FU monotherapy in the treatment of EMPD.11-16 Four reports showed clinical cure after treatment with 5-FU.12-14,16 In 2 of the reports, microscopic evidence of disease persisted after treatment12-13; in one report, no follow-up biopsy was performed14; in another report, no microscopic evidence of disease after treatment was identified.16 In the case report by Del Castillo et al,16 the patient applied topical 5-FU 5% intermittently (at the patient's discretion) to the affected axilla region for one year. The surgical removal of the lesion after one year of intermittent treatment showed no evidence of EMPD. In the case reports by Bewley et al11 and Eliezri et al,15 application of 5-FU 5% increased the disease margins. In summary, these reports demonstrate that topical 5-FU cannot be considered a safe and effective first-line choice of treatment due to its erosive feature and false impression of total clinical resolution. Retinoic acid has antiproliferative activity and induces apoptosis by its selective binding activity to the γ receptor in the nuclear receptor–independent pathway in neoplastic cells.17-18 We identified no published reports of topical retinoic acid for the treatment of EMPD. The most common use of retinoid antitumor agents is in the treatment of leukemia. In our case report, the tumor recurred after initial surgery and remained after 10 weeks of monotherapy with imiquimod. The reason imiquimod therapy failed in this case may relate to the presence of the tumor in the area of scar tissue; imiquimod by itself could not achieve adequate tissue penetration to induce the appropriate immune response. Consequently, we applied 5-FU cream in the morning to induce a selective toxicity in the Paget's cell, and retinoic acid gel in the afternoon to promote an antiproliferative apoptosis and to facilitate the penetration of imiquimod, which was applied in the evening. This combination therapy could potentiate a stronger stimulation of cytokines and interferon, which would then lead to the activation of T and B cells, natural killer cells, and a macrophage host response, all of which could be responsible for the destruction of the intraepithelial EMPD. In conclusion, we have demonstrated that a combination treatment of topical imiquimod, 5-FU, and retinoic acid may serve as an effective treatment option for patients who have failed imiquimod monotherapy. Acknowledgments—The authors would like to thank their colleagues John O'Dea, MD; Tony Chin, MD; Robert Uyeda, MD; and Simon Chan, MD, for reviewing and critiquing this manuscript. The authors also would like to thank Irma Marques for editing the manuscript.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis often noted as a skin rash with palpable petechiae or purpura. The rash of HSP usually is accompanied by arthralgia, abdominal pain, and renal disease.1-3 HSP affects children at a rate of 15 cases/100,000 individuals annually4; the disease is believed to occur less frequently in adults, in whom the natural course of the disease is not as well understood. In adults, HSP can be confused with other autoimmune diseases such as systemic lupus erythematous and hypersensitivity vasculitis. We present a case of adult-onset HSP and review the literature.

Case Report
A 43-year-old Filipino man presented with a 2-day history of eruptions on his legs (Figure 1) and right arm that were mildly pruritic and burned. The lesions had been preceded by 2 weeks of severe arthralgia and myalgia. The patient noted he had experienced some low-grade fevers, and he complained of mild upper abdominal pain.

A few months prior to presentation, the patient had undergone a diagnostic workup by gastroenterology for an evaluation of abdominal pain and bright red blood from the rectum. Results of stool sampling noted the presence of white blood cells. He was evaluated with a barium enema; colonoscopy was not performed. He was diagnosed with acute gastroenteritis and prescribed levofloxacin for 7 days. During a visit to his primary care physician a few weeks prior to presentation, the patient had complained of significant arthralgia. The patient denied upper or lower respiratory tract symptoms. He also denied blood in his urine. The patient's medical history included migraines and a glucose-6-phosphate dehydrogenase deficiency. The only medication he took was sumatriptan for his migraines. The patient had no known allergies. He denied taking vitamins or herbal supplements and had no travel history or sick contacts. Results of a physical examination showed the patient had significant difficulty ambulating but otherwise was in no acute distress. His vital signs were within reference range. Multiple, nonblanching, erythematous papules and pustules were noted on both of the patient's legs and on his right arm. No truncal lesions were noted. Two 4-mm punch biopsy specimens were taken from the patient's left leg. Results of the histopathologic evaluation showed leukocytoclastic vasculitis (Figure 2). Results of direct immunofluorescence assays revealed granular staining (3+) of the superficial blood vessels focally for immunoglobulin A (IgA)(Figure 3). Results of a wound culture were negative. Laboratory examination results are listed in the Table. Results of a urinalysis revealed no protein, casts, or blood. Test results were negative for rheumatoid factor, hepatitis B and C, purified protein derivatives, extractable nuclear antigen antibodies, rapid plasma reagins, human immunodeficiency virus, cryoglobulins, antineutrophil cytoplasmic antibodies, and antinuclear antibodies; results of a throat culture were negative for β-hemolytic streptococcus. The results of a chest x-ray did not reveal abnormalities. The patient was diagnosed with HSP.

The patient was evaluated by the departments of internal medicine, rheumatology, nephrology, and gastroenterology. The patient initially was prescribed a therapeutic regimen of bed rest, acetaminophen, ranitidine, and diphenhydramine. He continued to have recurrent skin eruptions and developed more significant arthralgia and abdominal pain. The patient was given one dose of intramuscular methylprednisolone and oral prednisone. He continued to have occasional skin lesions and mild arthralgias for a few months but currently is clear and has no residual findings. 

Comment

HSP predominantly affects people younger than 20 years, and half of all affected children are younger than 5 years.1 The tetrad of rash, arthralgia, abdominal pain, and renal disease can occur in any order over any time period,1-3 and all 4 symptoms do not have to be present clinically. The rash can occur anywhere on the body but usually appears symmetrically on the lower extremities as red to purple lesions. The rash typically presents with palpable petechiae or purpura but has been noted to occur with pustules, vesicles, and bullae. Additionally, the rash can be urticarial, and the Köbner phenomenon can be present. HSP can be distinguished from other autoimmune processes by skin or kidney biopsy results that show IgA deposition. If a biopsy of a skin specimen is performed, immune complexes are found almost equally in the normal-appearing skin and in the lesions of the rash.5 Serum complement levels also can be elevated in patients with HSP. Kawana and Nishiyama6 noted that increased levels of serum C5b-9 could be correlated with increased activity of HSP; however, C3, C4, and CH50 levels should not be monitored because they were not shown to be elevated consistently in HSP and thus were not reliable.6 Gastrointestinal tract lesions have been seen when there is no evidence of characteristic skin findings7-10; the lesions usually are present in the stomach, descending duodenum, and colon.7,11,12 The lesions can be raised, erythematous, or intermittently spaced.10

In several reports, occult bleeding was seen in 50% of the patients with HSP, and 25% of the patients had visible bleeding.7,9,11-13 Endoscopy can be recommended for individuals with suspected HSP because the test may reveal gastrointestinal tract findings that appear without the classic rash.7,9 Renal involvement is common in patients with HSP. Hematuria with or without proteinuria is present in 30% to 70% of patients with HSP. Levy et al14 estimated that HSP nephritis is responsible for 15% of all glomerulopathies in children. A retrospective study by García-Porrúa et al15 noted that hematuria at the onset of HSP with persistence of the renal manifestations during the course of the disease, as well as anemia at disease onset (hemoglobin level <11 g/dL), onset in summer, and relapse, were positive useful predictors for renal sequelae in the adult patients. If a renal biopsy is performed, the percentage of glomeruli showing crescent formation can be correlated with outcome as well. It has been noted that patients with crescents in more than half of the glomeruli are more likely to progress to end-stage or chronic renal disease.16

The erythrocyte sedimentation rate also can be elevated in patients with HSP. Blanco et al17 believed that when comparing adults with children, an elevated erythrocyte sedimentation rate and joint pain more often were found in the adult population, whereas the children had a greater occurrence of abdominal pain, fever, and a preceding upper respiratory tract infection, usually with group A streptococci.

As mentioned previously, HSP easily can be confused with other autoimmune diseases. Thus, the condition should be confirmed with a biopsy specimen from the affected area, which would show leukocytoclastic vasculitis and IgA deposition in the skin or kidney under immunofluorescence microscopy. In many cases, patients with HSP have a history of infection that precedes the symptoms by a few days to 2 weeks. These antecedent infections include streptococcal pharyngitis, viral pharyngitis, sinusitis, urinary tract infection, bronchitis, and diverticulitis.18 Hepatitis B also has been implicated as a cause of HSP.19-21

In a retrospective study comparing the clinical course of patients with HSP who were older than 20 years (adults) with those who were younger than 20 years (children), it was noted that the adults had renal involvement more frequently than the children, with 85% of the adults having a nephropathy versus 25% of the children.17 Of those patients with a nephropathy, the adults developed nephrotic syndrome more often than did the children (13% vs 3%, respectively). Additionally, 13% of the adults with HSP subsequently developed renal insufficiency; however, none of the children with HSP developed this complication. Corticosteroids were given for unresponsive lesions or nephritic involvement. Therapy was required by 63% of the adults and approximately 40% of the children, but 22% of the adults and none of the children needed cytotoxic drugs.17

The overall outcome is favorable in most patients diagnosed with HSP; one study showed a complete recovery in 89% of the adults and 94% of the children with this condition.17 Significant morbidity, however, was seen in a retrospective study of 250 patients aged 15 to 86 years who had enough renal involvement from HSP to require a biopsy. After 15 years, 11% of the patients were dependent on dialysis, and 13% had severe renal failure.22 In rare cases, patients with adult-onset HSP had fatal complications because of arrhythmia from vasculitis, which affected the right atrium, and because of massive pulmonary hemorrhage secondary to extensive petechial bleeding, which was refractory to intravenous steroids.23 Recurrences of HSP tend to be less severe than the original outbreak and usually happen within 4 months of the original symptoms. In children, HSP recurrences have been noted in approximately 33% of patients3,14 and seem to be more likely in the subset of patients with nephritis.3

Most patients do not receive therapy; however, those patients with a higher percentage of crescent formation in the kidneys usually require treatment. Renal transplantation also is an option for patients with HSP with end-stage renal disease, but recurrence is seen after 5 years posttransplantation in 35% of patients.24

In summary, our patient was diagnosed with HSP based on the results of a biopsy, direct immunofluorescence, and laboratory workup. His gastrointestinal tract symptoms are resolved, and he continues to have normal urinalysis results and blood chemistries levels within reference range. He occasionally notes a few new skin lesions and has episodes of mild arthralgia. The patient will continue to be followed up closely to ensure that he does not develop renal abnormalities.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis often noted as a skin rash with palpable petechiae or purpura. The rash of HSP usually is accompanied by arthralgia, abdominal pain, and renal disease.1-3 HSP affects children at a rate of 15 cases/100,000 individuals annually4; the disease is believed to occur less frequently in adults, in whom the natural course of the disease is not as well understood. In adults, HSP can be confused with other autoimmune diseases such as systemic lupus erythematous and hypersensitivity vasculitis. We present a case of adult-onset HSP and review the literature.

Case Report
A 43-year-old Filipino man presented with a 2-day history of eruptions on his legs (Figure 1) and right arm that were mildly pruritic and burned. The lesions had been preceded by 2 weeks of severe arthralgia and myalgia. The patient noted he had experienced some low-grade fevers, and he complained of mild upper abdominal pain.

A few months prior to presentation, the patient had undergone a diagnostic workup by gastroenterology for an evaluation of abdominal pain and bright red blood from the rectum. Results of stool sampling noted the presence of white blood cells. He was evaluated with a barium enema; colonoscopy was not performed. He was diagnosed with acute gastroenteritis and prescribed levofloxacin for 7 days. During a visit to his primary care physician a few weeks prior to presentation, the patient had complained of significant arthralgia. The patient denied upper or lower respiratory tract symptoms. He also denied blood in his urine. The patient's medical history included migraines and a glucose-6-phosphate dehydrogenase deficiency. The only medication he took was sumatriptan for his migraines. The patient had no known allergies. He denied taking vitamins or herbal supplements and had no travel history or sick contacts. Results of a physical examination showed the patient had significant difficulty ambulating but otherwise was in no acute distress. His vital signs were within reference range. Multiple, nonblanching, erythematous papules and pustules were noted on both of the patient's legs and on his right arm. No truncal lesions were noted. Two 4-mm punch biopsy specimens were taken from the patient's left leg. Results of the histopathologic evaluation showed leukocytoclastic vasculitis (Figure 2). Results of direct immunofluorescence assays revealed granular staining (3+) of the superficial blood vessels focally for immunoglobulin A (IgA)(Figure 3). Results of a wound culture were negative. Laboratory examination results are listed in the Table. Results of a urinalysis revealed no protein, casts, or blood. Test results were negative for rheumatoid factor, hepatitis B and C, purified protein derivatives, extractable nuclear antigen antibodies, rapid plasma reagins, human immunodeficiency virus, cryoglobulins, antineutrophil cytoplasmic antibodies, and antinuclear antibodies; results of a throat culture were negative for β-hemolytic streptococcus. The results of a chest x-ray did not reveal abnormalities. The patient was diagnosed with HSP.

The patient was evaluated by the departments of internal medicine, rheumatology, nephrology, and gastroenterology. The patient initially was prescribed a therapeutic regimen of bed rest, acetaminophen, ranitidine, and diphenhydramine. He continued to have recurrent skin eruptions and developed more significant arthralgia and abdominal pain. The patient was given one dose of intramuscular methylprednisolone and oral prednisone. He continued to have occasional skin lesions and mild arthralgias for a few months but currently is clear and has no residual findings. 

Comment

HSP predominantly affects people younger than 20 years, and half of all affected children are younger than 5 years.1 The tetrad of rash, arthralgia, abdominal pain, and renal disease can occur in any order over any time period,1-3 and all 4 symptoms do not have to be present clinically. The rash can occur anywhere on the body but usually appears symmetrically on the lower extremities as red to purple lesions. The rash typically presents with palpable petechiae or purpura but has been noted to occur with pustules, vesicles, and bullae. Additionally, the rash can be urticarial, and the Köbner phenomenon can be present. HSP can be distinguished from other autoimmune processes by skin or kidney biopsy results that show IgA deposition. If a biopsy of a skin specimen is performed, immune complexes are found almost equally in the normal-appearing skin and in the lesions of the rash.5 Serum complement levels also can be elevated in patients with HSP. Kawana and Nishiyama6 noted that increased levels of serum C5b-9 could be correlated with increased activity of HSP; however, C3, C4, and CH50 levels should not be monitored because they were not shown to be elevated consistently in HSP and thus were not reliable.6 Gastrointestinal tract lesions have been seen when there is no evidence of characteristic skin findings7-10; the lesions usually are present in the stomach, descending duodenum, and colon.7,11,12 The lesions can be raised, erythematous, or intermittently spaced.10

In several reports, occult bleeding was seen in 50% of the patients with HSP, and 25% of the patients had visible bleeding.7,9,11-13 Endoscopy can be recommended for individuals with suspected HSP because the test may reveal gastrointestinal tract findings that appear without the classic rash.7,9 Renal involvement is common in patients with HSP. Hematuria with or without proteinuria is present in 30% to 70% of patients with HSP. Levy et al14 estimated that HSP nephritis is responsible for 15% of all glomerulopathies in children. A retrospective study by García-Porrúa et al15 noted that hematuria at the onset of HSP with persistence of the renal manifestations during the course of the disease, as well as anemia at disease onset (hemoglobin level <11 g/dL), onset in summer, and relapse, were positive useful predictors for renal sequelae in the adult patients. If a renal biopsy is performed, the percentage of glomeruli showing crescent formation can be correlated with outcome as well. It has been noted that patients with crescents in more than half of the glomeruli are more likely to progress to end-stage or chronic renal disease.16

The erythrocyte sedimentation rate also can be elevated in patients with HSP. Blanco et al17 believed that when comparing adults with children, an elevated erythrocyte sedimentation rate and joint pain more often were found in the adult population, whereas the children had a greater occurrence of abdominal pain, fever, and a preceding upper respiratory tract infection, usually with group A streptococci.

As mentioned previously, HSP easily can be confused with other autoimmune diseases. Thus, the condition should be confirmed with a biopsy specimen from the affected area, which would show leukocytoclastic vasculitis and IgA deposition in the skin or kidney under immunofluorescence microscopy. In many cases, patients with HSP have a history of infection that precedes the symptoms by a few days to 2 weeks. These antecedent infections include streptococcal pharyngitis, viral pharyngitis, sinusitis, urinary tract infection, bronchitis, and diverticulitis.18 Hepatitis B also has been implicated as a cause of HSP.19-21

In a retrospective study comparing the clinical course of patients with HSP who were older than 20 years (adults) with those who were younger than 20 years (children), it was noted that the adults had renal involvement more frequently than the children, with 85% of the adults having a nephropathy versus 25% of the children.17 Of those patients with a nephropathy, the adults developed nephrotic syndrome more often than did the children (13% vs 3%, respectively). Additionally, 13% of the adults with HSP subsequently developed renal insufficiency; however, none of the children with HSP developed this complication. Corticosteroids were given for unresponsive lesions or nephritic involvement. Therapy was required by 63% of the adults and approximately 40% of the children, but 22% of the adults and none of the children needed cytotoxic drugs.17

The overall outcome is favorable in most patients diagnosed with HSP; one study showed a complete recovery in 89% of the adults and 94% of the children with this condition.17 Significant morbidity, however, was seen in a retrospective study of 250 patients aged 15 to 86 years who had enough renal involvement from HSP to require a biopsy. After 15 years, 11% of the patients were dependent on dialysis, and 13% had severe renal failure.22 In rare cases, patients with adult-onset HSP had fatal complications because of arrhythmia from vasculitis, which affected the right atrium, and because of massive pulmonary hemorrhage secondary to extensive petechial bleeding, which was refractory to intravenous steroids.23 Recurrences of HSP tend to be less severe than the original outbreak and usually happen within 4 months of the original symptoms. In children, HSP recurrences have been noted in approximately 33% of patients3,14 and seem to be more likely in the subset of patients with nephritis.3

Most patients do not receive therapy; however, those patients with a higher percentage of crescent formation in the kidneys usually require treatment. Renal transplantation also is an option for patients with HSP with end-stage renal disease, but recurrence is seen after 5 years posttransplantation in 35% of patients.24

In summary, our patient was diagnosed with HSP based on the results of a biopsy, direct immunofluorescence, and laboratory workup. His gastrointestinal tract symptoms are resolved, and he continues to have normal urinalysis results and blood chemistries levels within reference range. He occasionally notes a few new skin lesions and has episodes of mild arthralgia. The patient will continue to be followed up closely to ensure that he does not develop renal abnormalities.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis often noted as a skin rash with palpable petechiae or purpura. The rash of HSP usually is accompanied by arthralgia, abdominal pain, and renal disease.1-3 HSP affects children at a rate of 15 cases/100,000 individuals annually4; the disease is believed to occur less frequently in adults, in whom the natural course of the disease is not as well understood. In adults, HSP can be confused with other autoimmune diseases such as systemic lupus erythematous and hypersensitivity vasculitis. We present a case of adult-onset HSP and review the literature.

Case Report
A 43-year-old Filipino man presented with a 2-day history of eruptions on his legs (Figure 1) and right arm that were mildly pruritic and burned. The lesions had been preceded by 2 weeks of severe arthralgia and myalgia. The patient noted he had experienced some low-grade fevers, and he complained of mild upper abdominal pain.

A few months prior to presentation, the patient had undergone a diagnostic workup by gastroenterology for an evaluation of abdominal pain and bright red blood from the rectum. Results of stool sampling noted the presence of white blood cells. He was evaluated with a barium enema; colonoscopy was not performed. He was diagnosed with acute gastroenteritis and prescribed levofloxacin for 7 days. During a visit to his primary care physician a few weeks prior to presentation, the patient had complained of significant arthralgia. The patient denied upper or lower respiratory tract symptoms. He also denied blood in his urine. The patient's medical history included migraines and a glucose-6-phosphate dehydrogenase deficiency. The only medication he took was sumatriptan for his migraines. The patient had no known allergies. He denied taking vitamins or herbal supplements and had no travel history or sick contacts. Results of a physical examination showed the patient had significant difficulty ambulating but otherwise was in no acute distress. His vital signs were within reference range. Multiple, nonblanching, erythematous papules and pustules were noted on both of the patient's legs and on his right arm. No truncal lesions were noted. Two 4-mm punch biopsy specimens were taken from the patient's left leg. Results of the histopathologic evaluation showed leukocytoclastic vasculitis (Figure 2). Results of direct immunofluorescence assays revealed granular staining (3+) of the superficial blood vessels focally for immunoglobulin A (IgA)(Figure 3). Results of a wound culture were negative. Laboratory examination results are listed in the Table. Results of a urinalysis revealed no protein, casts, or blood. Test results were negative for rheumatoid factor, hepatitis B and C, purified protein derivatives, extractable nuclear antigen antibodies, rapid plasma reagins, human immunodeficiency virus, cryoglobulins, antineutrophil cytoplasmic antibodies, and antinuclear antibodies; results of a throat culture were negative for β-hemolytic streptococcus. The results of a chest x-ray did not reveal abnormalities. The patient was diagnosed with HSP.

The patient was evaluated by the departments of internal medicine, rheumatology, nephrology, and gastroenterology. The patient initially was prescribed a therapeutic regimen of bed rest, acetaminophen, ranitidine, and diphenhydramine. He continued to have recurrent skin eruptions and developed more significant arthralgia and abdominal pain. The patient was given one dose of intramuscular methylprednisolone and oral prednisone. He continued to have occasional skin lesions and mild arthralgias for a few months but currently is clear and has no residual findings. 

Comment

HSP predominantly affects people younger than 20 years, and half of all affected children are younger than 5 years.1 The tetrad of rash, arthralgia, abdominal pain, and renal disease can occur in any order over any time period,1-3 and all 4 symptoms do not have to be present clinically. The rash can occur anywhere on the body but usually appears symmetrically on the lower extremities as red to purple lesions. The rash typically presents with palpable petechiae or purpura but has been noted to occur with pustules, vesicles, and bullae. Additionally, the rash can be urticarial, and the Köbner phenomenon can be present. HSP can be distinguished from other autoimmune processes by skin or kidney biopsy results that show IgA deposition. If a biopsy of a skin specimen is performed, immune complexes are found almost equally in the normal-appearing skin and in the lesions of the rash.5 Serum complement levels also can be elevated in patients with HSP. Kawana and Nishiyama6 noted that increased levels of serum C5b-9 could be correlated with increased activity of HSP; however, C3, C4, and CH50 levels should not be monitored because they were not shown to be elevated consistently in HSP and thus were not reliable.6 Gastrointestinal tract lesions have been seen when there is no evidence of characteristic skin findings7-10; the lesions usually are present in the stomach, descending duodenum, and colon.7,11,12 The lesions can be raised, erythematous, or intermittently spaced.10

In several reports, occult bleeding was seen in 50% of the patients with HSP, and 25% of the patients had visible bleeding.7,9,11-13 Endoscopy can be recommended for individuals with suspected HSP because the test may reveal gastrointestinal tract findings that appear without the classic rash.7,9 Renal involvement is common in patients with HSP. Hematuria with or without proteinuria is present in 30% to 70% of patients with HSP. Levy et al14 estimated that HSP nephritis is responsible for 15% of all glomerulopathies in children. A retrospective study by García-Porrúa et al15 noted that hematuria at the onset of HSP with persistence of the renal manifestations during the course of the disease, as well as anemia at disease onset (hemoglobin level <11 g/dL), onset in summer, and relapse, were positive useful predictors for renal sequelae in the adult patients. If a renal biopsy is performed, the percentage of glomeruli showing crescent formation can be correlated with outcome as well. It has been noted that patients with crescents in more than half of the glomeruli are more likely to progress to end-stage or chronic renal disease.16

The erythrocyte sedimentation rate also can be elevated in patients with HSP. Blanco et al17 believed that when comparing adults with children, an elevated erythrocyte sedimentation rate and joint pain more often were found in the adult population, whereas the children had a greater occurrence of abdominal pain, fever, and a preceding upper respiratory tract infection, usually with group A streptococci.

As mentioned previously, HSP easily can be confused with other autoimmune diseases. Thus, the condition should be confirmed with a biopsy specimen from the affected area, which would show leukocytoclastic vasculitis and IgA deposition in the skin or kidney under immunofluorescence microscopy. In many cases, patients with HSP have a history of infection that precedes the symptoms by a few days to 2 weeks. These antecedent infections include streptococcal pharyngitis, viral pharyngitis, sinusitis, urinary tract infection, bronchitis, and diverticulitis.18 Hepatitis B also has been implicated as a cause of HSP.19-21

In a retrospective study comparing the clinical course of patients with HSP who were older than 20 years (adults) with those who were younger than 20 years (children), it was noted that the adults had renal involvement more frequently than the children, with 85% of the adults having a nephropathy versus 25% of the children.17 Of those patients with a nephropathy, the adults developed nephrotic syndrome more often than did the children (13% vs 3%, respectively). Additionally, 13% of the adults with HSP subsequently developed renal insufficiency; however, none of the children with HSP developed this complication. Corticosteroids were given for unresponsive lesions or nephritic involvement. Therapy was required by 63% of the adults and approximately 40% of the children, but 22% of the adults and none of the children needed cytotoxic drugs.17

The overall outcome is favorable in most patients diagnosed with HSP; one study showed a complete recovery in 89% of the adults and 94% of the children with this condition.17 Significant morbidity, however, was seen in a retrospective study of 250 patients aged 15 to 86 years who had enough renal involvement from HSP to require a biopsy. After 15 years, 11% of the patients were dependent on dialysis, and 13% had severe renal failure.22 In rare cases, patients with adult-onset HSP had fatal complications because of arrhythmia from vasculitis, which affected the right atrium, and because of massive pulmonary hemorrhage secondary to extensive petechial bleeding, which was refractory to intravenous steroids.23 Recurrences of HSP tend to be less severe than the original outbreak and usually happen within 4 months of the original symptoms. In children, HSP recurrences have been noted in approximately 33% of patients3,14 and seem to be more likely in the subset of patients with nephritis.3

Most patients do not receive therapy; however, those patients with a higher percentage of crescent formation in the kidneys usually require treatment. Renal transplantation also is an option for patients with HSP with end-stage renal disease, but recurrence is seen after 5 years posttransplantation in 35% of patients.24

In summary, our patient was diagnosed with HSP based on the results of a biopsy, direct immunofluorescence, and laboratory workup. His gastrointestinal tract symptoms are resolved, and he continues to have normal urinalysis results and blood chemistries levels within reference range. He occasionally notes a few new skin lesions and has episodes of mild arthralgia. The patient will continue to be followed up closely to ensure that he does not develop renal abnormalities.