Clinical Review & Education
JAMA Clinical Challenge
Recurrent Erythema Multiforme Jarad Levin, MD; Timothy Hofstra, MD
A
B
C
D
Figure. Lesions observed on case patient.
A 43-year-old African American woman with medical history of hepatitis C virus (HCV) infection was seen for a 2-year history of painful skin lesions on her legs and arms. Her lesions improved with prednisone but recurred when treatment was discontinued. No inciting factors were identified exQuiz at jama.com cept a possible relation to her menstrual cycle. She also reported concurrent painful oral lesions. Erythematous, hyperpigmented, annular papules with dusky centers and bullae were observed on her arms and legs bilaterally (Figure, A, B, C). Oral lesions were also observed and consisted of erythematous, crusted papules with superficial ulceration, gingival hyperplasia, and superimposed thrush (Figure, D). The patient had no history of oral or genital herpes lesions. Results of herpes simplex virus (HSV) 1 and 2 IgG serologic testing were positive. Test results for pemphigus antibody panel, antinuclear antibodies, human immunodeficiency virus, and rapid plasma reagin were negative. Biopsy findings were consistent with erythema multiforme.
426
WHAT WOULD YOU DO NEXT?
A. Check serum cryoglobulin level B. Administer intradermal progesterone challenge C. Prescribe interferon, ribavirin, and telaprevir D. Prescribe oral prednisone and HSV viral suppression therapy
JAMA July 23/30, 2014 Volume 312, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 05/24/2015
jama.com
JAMA Clinical Challenge Clinical Review & Education
Diagnosis HSV-associated recurrent erythema multiforme
What to Do Next D. Prescribe oral prednisone and HSV viral suppression therapy The key clinical feature in this case is recognizing the characteristic morphology of erythema multiforme and that HSV is the most common cause of recurrence.1 Given the positive HSV results, recurrent nature of the lesions, and biopsy results consistent with erythema multiforme, the patient was diagnosed with HSV-associated recurrent erythema multiforme. Although she did not have a history of oral or genital herpes lesions, HSV-associated erythema multiforme can occur in the absence of overt lesions and is likely attributable to subclinical infection or shedding.2 There was no need to test for cryoglobulins becausemorphologywasnotconsistentwithcryoglobulinemiavasculitis. Although HCV can be associated with erythema multiforme, the association between HSV and erythema multiforme is more common and the patient’s diagnosis was supported by positive HSV serology results. However, if she did not respond to antiviral agents for HSV, treating HCV infection would be a reasonable approach. Similarly, an intradermal progesterone challenge that involves injecting progesterone subcutaneously and observing for cutaneous reaction can be obtained if initial therapy fails. For recurrent erythema multiforme of unknown etiology, HSV suppression is first-line therapy but can be reconsidered in those with negative HSV serology results.
Discussion Erythema multiforme remains incompletely understood but appears to be the result of a TH1-mediated immune response to an inciting event, such as drug exposure or other infections such as HSV, HCV, and Mycoplasma pneumoniae.1,2 Drugs, including nonsteroidal antiinflammatory drugs, antibiotics, sulfonamides, and antiepileptics, as well as malignancies, menstruation, and inflammatory bowel disease, are all associated with erythema multiforme.1 The hallmark of erythema multiforme is targetoid lesions typically distributed acrally with symmetric involvement of extensor surfaces. Classic targetoid lesions are round and papular with a central duskiness or blister and have a clear ring of edema surrounded by an erythematous halo, giving the appearance of a target with 3 zones of color change.1 Lesions in acute erythema multiforme appear within a few days and resolve within 2 to 6 weeks.1 However, not all cases of erythema multiforme are self-limited. Like this patient, some patients experience multiple episodes yearly and are classified as having recurrent
erythema multiforme. Rarely, the lesions do not resolve despite therapy and are classified as persistent erythema multiforme. A thorough history and physical examination is often sufficient for diagnosis. However, a biopsy may be needed to exclude other conditions. Histopathology demonstrates an interface dermatitis with scattered epidermal necrosis, perivascular dermal lymphohistiocytic infiltrate with some eosinophils, edema in the upper dermis, and vacuolar degeneration of basal cells.1,3 Acute erythema multiforme is typically self-limited. Therapy consists of symptomatic treatment with topical corticosteroids and oral antihistamines. Oral corticosteroids may be necessary for severe mucocutaneous involvement.1 Drugs associated with erythema multiforme should be discontinued and infections should be treated. Compared with the acute form, recurrent erythema multiforme is more difficult to treat. The etiology can be difficult to identify, and recurrent erythema multiforme does not always respond to typical therapies.1,4 Oral steroids can be helpful in controlling recurrent cutaneous erythema multiforme, but the lesions often return or worsen when steroids are discontinued.4 This can lead to chronic steroid use, withitsassociatedadverseeffects.5 Therefore,steroidsarenotthemainstay of therapy for the recurrent form. In recurrent erythema multiforme, either of unknown etiology or HSV-associated, continuous HSV antiviral therapy is recommended for at least 6 months to prevent recurrence.1,4 Common oral regimens include acyclovir (400 mg twice daily), valacyclovir (500 mg twice daily), and famciclovir (250 mg twice daily).1 Immunomodulatory therapies with azathioprine, mycophenolate, dapsone, and thalidomide may be effective in cases with other etiologies or in patients who do not respond to antivirals.1,4 When initial therapy fails, alternative etiologies may be useful. A progesterone intradermal challenge can be considered, especially if there is an association with menstruation, to support a diagnosis of autoimmune progesterone-induced dermatitis presenting as erythema multiforme.6
Patient Outcome The patient started an oral prednisone taper, topical corticosteroids, and suppressive therapy with oral famciclovir. Skin lesions initially resolved but increased as the steroids were tapered, resulting in a need for lower-dose ongoing steroid therapy. The patient was not a candidate for HCV therapy. She was referred to a gynecologist for consideration of an intradermal progesterone challenge as well as contraception, needed because the patient will start thalidomide, a steroid-sparing agent that requires concomitant contraception.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: University of Texas Medical Branch, Galveston (Levin); Virginia Commonwealth University, Richmond (Hofstra).
1. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme. Int J Dermatol. 2012;51(8):889-902.
Corresponding Author: Jarad Levin, MD, Office of Internal Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 775550570 ([email protected]).
2. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM). Dermatol Online J. 2003;9(1):1.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Forms for Disclosure of Potential Conflicts of Interest and none were reported.
3. Kempf W, Hantschke M, Kutzner H, Burgdorf WHC. Interface dermatoses. In: Kempf et al, ed. Dermatopathology. Germany: Springer Science+Business Media; 2008:57-69.
4. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. 5. Sen P, Chua SH. A case of recurrent erythema multiforme and its therapeutic complications. Ann Acad Med Singapore. 2004;33(6):793-796. 6. Nasabzadeh TJ, Stefanato CM, Doole JE, Radfar A, Bhawan J, Venna S. Recurrent erythema multiforme triggered by progesterone sensitivity. J Cutan Pathol. 2010;37(11):1164-1167.
Additional Contributions: The authors would like to acknowledge Lindsey Hunter, dermatology resident, for her assistance in this case.
jama.com
JAMA July 23/30, 2014 Volume 312, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 05/24/2015
427
JAMA Clinical Challenge
Recurrent Erythema Multiforme Jarad Levin, MD; Timothy Hofstra, MD
A
B
C
D
Figure. Lesions observed on case patient.
A 43-year-old African American woman with medical history of hepatitis C virus (HCV) infection was seen for a 2-year history of painful skin lesions on her legs and arms. Her lesions improved with prednisone but recurred when treatment was discontinued. No inciting factors were identified exQuiz at jama.com cept a possible relation to her menstrual cycle. She also reported concurrent painful oral lesions. Erythematous, hyperpigmented, annular papules with dusky centers and bullae were observed on her arms and legs bilaterally (Figure, A, B, C). Oral lesions were also observed and consisted of erythematous, crusted papules with superficial ulceration, gingival hyperplasia, and superimposed thrush (Figure, D). The patient had no history of oral or genital herpes lesions. Results of herpes simplex virus (HSV) 1 and 2 IgG serologic testing were positive. Test results for pemphigus antibody panel, antinuclear antibodies, human immunodeficiency virus, and rapid plasma reagin were negative. Biopsy findings were consistent with erythema multiforme.
426
WHAT WOULD YOU DO NEXT?
A. Check serum cryoglobulin level B. Administer intradermal progesterone challenge C. Prescribe interferon, ribavirin, and telaprevir D. Prescribe oral prednisone and HSV viral suppression therapy
JAMA July 23/30, 2014 Volume 312, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 05/24/2015
jama.com
JAMA Clinical Challenge Clinical Review & Education
Diagnosis HSV-associated recurrent erythema multiforme
What to Do Next D. Prescribe oral prednisone and HSV viral suppression therapy The key clinical feature in this case is recognizing the characteristic morphology of erythema multiforme and that HSV is the most common cause of recurrence.1 Given the positive HSV results, recurrent nature of the lesions, and biopsy results consistent with erythema multiforme, the patient was diagnosed with HSV-associated recurrent erythema multiforme. Although she did not have a history of oral or genital herpes lesions, HSV-associated erythema multiforme can occur in the absence of overt lesions and is likely attributable to subclinical infection or shedding.2 There was no need to test for cryoglobulins becausemorphologywasnotconsistentwithcryoglobulinemiavasculitis. Although HCV can be associated with erythema multiforme, the association between HSV and erythema multiforme is more common and the patient’s diagnosis was supported by positive HSV serology results. However, if she did not respond to antiviral agents for HSV, treating HCV infection would be a reasonable approach. Similarly, an intradermal progesterone challenge that involves injecting progesterone subcutaneously and observing for cutaneous reaction can be obtained if initial therapy fails. For recurrent erythema multiforme of unknown etiology, HSV suppression is first-line therapy but can be reconsidered in those with negative HSV serology results.
Discussion Erythema multiforme remains incompletely understood but appears to be the result of a TH1-mediated immune response to an inciting event, such as drug exposure or other infections such as HSV, HCV, and Mycoplasma pneumoniae.1,2 Drugs, including nonsteroidal antiinflammatory drugs, antibiotics, sulfonamides, and antiepileptics, as well as malignancies, menstruation, and inflammatory bowel disease, are all associated with erythema multiforme.1 The hallmark of erythema multiforme is targetoid lesions typically distributed acrally with symmetric involvement of extensor surfaces. Classic targetoid lesions are round and papular with a central duskiness or blister and have a clear ring of edema surrounded by an erythematous halo, giving the appearance of a target with 3 zones of color change.1 Lesions in acute erythema multiforme appear within a few days and resolve within 2 to 6 weeks.1 However, not all cases of erythema multiforme are self-limited. Like this patient, some patients experience multiple episodes yearly and are classified as having recurrent
erythema multiforme. Rarely, the lesions do not resolve despite therapy and are classified as persistent erythema multiforme. A thorough history and physical examination is often sufficient for diagnosis. However, a biopsy may be needed to exclude other conditions. Histopathology demonstrates an interface dermatitis with scattered epidermal necrosis, perivascular dermal lymphohistiocytic infiltrate with some eosinophils, edema in the upper dermis, and vacuolar degeneration of basal cells.1,3 Acute erythema multiforme is typically self-limited. Therapy consists of symptomatic treatment with topical corticosteroids and oral antihistamines. Oral corticosteroids may be necessary for severe mucocutaneous involvement.1 Drugs associated with erythema multiforme should be discontinued and infections should be treated. Compared with the acute form, recurrent erythema multiforme is more difficult to treat. The etiology can be difficult to identify, and recurrent erythema multiforme does not always respond to typical therapies.1,4 Oral steroids can be helpful in controlling recurrent cutaneous erythema multiforme, but the lesions often return or worsen when steroids are discontinued.4 This can lead to chronic steroid use, withitsassociatedadverseeffects.5 Therefore,steroidsarenotthemainstay of therapy for the recurrent form. In recurrent erythema multiforme, either of unknown etiology or HSV-associated, continuous HSV antiviral therapy is recommended for at least 6 months to prevent recurrence.1,4 Common oral regimens include acyclovir (400 mg twice daily), valacyclovir (500 mg twice daily), and famciclovir (250 mg twice daily).1 Immunomodulatory therapies with azathioprine, mycophenolate, dapsone, and thalidomide may be effective in cases with other etiologies or in patients who do not respond to antivirals.1,4 When initial therapy fails, alternative etiologies may be useful. A progesterone intradermal challenge can be considered, especially if there is an association with menstruation, to support a diagnosis of autoimmune progesterone-induced dermatitis presenting as erythema multiforme.6
Patient Outcome The patient started an oral prednisone taper, topical corticosteroids, and suppressive therapy with oral famciclovir. Skin lesions initially resolved but increased as the steroids were tapered, resulting in a need for lower-dose ongoing steroid therapy. The patient was not a candidate for HCV therapy. She was referred to a gynecologist for consideration of an intradermal progesterone challenge as well as contraception, needed because the patient will start thalidomide, a steroid-sparing agent that requires concomitant contraception.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: University of Texas Medical Branch, Galveston (Levin); Virginia Commonwealth University, Richmond (Hofstra).
1. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme. Int J Dermatol. 2012;51(8):889-902.
Corresponding Author: Jarad Levin, MD, Office of Internal Medicine, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 775550570 ([email protected]).
2. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM). Dermatol Online J. 2003;9(1):1.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Forms for Disclosure of Potential Conflicts of Interest and none were reported.
3. Kempf W, Hantschke M, Kutzner H, Burgdorf WHC. Interface dermatoses. In: Kempf et al, ed. Dermatopathology. Germany: Springer Science+Business Media; 2008:57-69.
4. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. 5. Sen P, Chua SH. A case of recurrent erythema multiforme and its therapeutic complications. Ann Acad Med Singapore. 2004;33(6):793-796. 6. Nasabzadeh TJ, Stefanato CM, Doole JE, Radfar A, Bhawan J, Venna S. Recurrent erythema multiforme triggered by progesterone sensitivity. J Cutan Pathol. 2010;37(11):1164-1167.
Additional Contributions: The authors would like to acknowledge Lindsey Hunter, dermatology resident, for her assistance in this case.
jama.com
JAMA July 23/30, 2014 Volume 312, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 05/24/2015
427
