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Clinical Reviews in Allergy & Immunology

Published in:

01-02-2018

Current Perspectives on Erythema Multiforme

Authors: Marianne Lerch, Carlo Mainetti, Benedetta Terziroli Beretta-Piccoli, Thomas Harr

Published in: Clinical Reviews in Allergy & Immunology | Issue 1/2018

Abstract

Recognition and timely adequate treatment of erythema multiforme remain a major challenge. In this review, current diagnostic guidelines, potential pitfalls, and modern/novel treatment options are summarized with the aim to help clinicians with diagnostic and therapeutic decision-making. The diagnosis of erythema multiforme, that has an acute, self-limiting course, is based on its typical clinical picture of targetoid erythematous lesions with predominant acral localization as well as histological findings. Clinically, erythema multiforme can be differentiated into isolated cutaneous and combined mucocutaneous forms. Atypical erythema multiforme manifestations include lichenoid or granulomatous lesions as well as lesional infiltrates of T cell lymphoma and histiocytes. Herpes simplex virus infection being the most common cause, other infectious agents like—especially in children—Mycoplasma pneumoniae, hepatitis C virus, Coxsackie virus, and Epstein Barr virus may also trigger erythema multiforme. The second most frequently identified cause of erythema multiforme is drugs. In different studies, e.g., allopurinol, phenobarbital, phenytoin, valproic acid, antibacterial sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines, chlormezanone, acetylsalicylic acid, statins, as well as different TNF-α inhibitors such as adalimumab, infliximab, and etanercept were reported as possible implicated drugs. Recently, cases of erythema multiforme associated with vaccination, immunotherapy for melanoma, and even with topical drugs like imiquimod have been described. In patients with recurrent herpes simplex virus-associated erythema multiforme, the topical prophylactic treatment with acyclovir does not seem to prevent further episodes of erythema multiforme. In case of resistance to one virostatic drug, the switch to an alternative drug, and in patients non-responsive to virostatic agents, the use of dapsone as well as new treatment options, e.g., JAK-inhibitors or apremilast, might be considered.

Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC (1993) Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129(1):92–96. https://doi.org/10.1001/archderm.1993.01680220104023 CrossRefPubMed

Gossart R, Malthiery E, Aguilar F, Torres JH, Fauroux MA (2017) Fuchs syndrome: medical treatment of 1 case and literature review. Case Rep Dermatol 9(1):114–120. https://doi.org/10.1159/000468978 CrossRefPubMedPubMedCentral

Havliza K, Jakob A, Rompel R (2009) Erythema multiforme majus (Fuchs syndrome) associated with Mycoplasma pneumoniae infection in two patients. J Dtsch Dermatol Ges = J German Soc Dermatol: JDDG 7(5):445–448. https://doi.org/10.1111/j.1610-0387.2008.06978.x

Wetter DA, Davis MD (2010) 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 62(1):45–53. https://doi.org/10.1016/j.jaad.2009.06.046 CrossRefPubMed

Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC (2002) Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 138(8):1019–1024CrossRefPubMed

Assier H, Bastuji-Garin S, Revuz J, Roujeau JC (1995) Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 131(5):539–543. https://doi.org/10.1001/archderm.1995.01690170041005 CrossRefPubMed

Ng PP, Sun YJ, Tan HH, Tan SH (2003) Detection of herpes simplex virus genomic DNA in various subsets of erythema multiforme by polymerase chain reaction. Dermatology (Basel, Switzerland) 207(4):349–353. https://doi.org/10.1159/000074112 CrossRef

Aurelian L, Ono F, Burnett J (2003) Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J 9(1):1PubMed

Komorowski L, Mockenhaupt M, Sekula P, Roujeau JC, Probst C, Teegen B, Li W, Stocker W, Zillikens D (2013) Lack of a specific humoral autoreactivity in sera from patients with early erythema exsudativum multiforme majus. J Invest Dermatol 133(12):2799–2802. https://doi.org/10.1038/jid.2013.242 CrossRefPubMed

10.

Ono F, Sharma BK, Smith CC, Burnett JW, Aurelian L (2005) CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol 124(6):1215–1224. https://doi.org/10.1111/j.0022-202X.2005.23712.x CrossRefPubMed

11.

Kampgen E, Burg G, Wank R (1988) Association of herpes simplex virus-induced erythema multiforme with the human leukocyte antigen DQw3. Arch Dermatol 124(9):1372–1375. https://doi.org/10.1001/archderm.1988.01670090028005 CrossRefPubMed

12.

Miller PK, Zain-Ul-Abideen M, Paul J, Perry AE, Linos K, Carter JB, Kurtzberg J, Mann JA (2017) A case of eczema coxsackium with erythema multiforme-like histopathology in a 14-year-old boy with chronic graft-versus-host disease. JAAD Case Rep 3(1):49–52. https://doi.org/10.1016/j.jdcr.2016.11.007 CrossRefPubMedPubMedCentral

13.

Siedner-Weintraub Y, Gross I, David A, Reif S, Molho-Pessach V (2017) Paediatric erythema multiforme: epidemiological, clinical and laboratory characteristics. Acta Derm Venereol 97(4):489–492. https://doi.org/10.2340/00015555-2569 CrossRefPubMed

14.

Schalock PC, Dinulos JG, Pace N, Schwarzenberger K, Wenger JK (2006) Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol 23(6):546–555. https://doi.org/10.1111/j.1525-1470.2006.00307.x CrossRefPubMed

15.

Canavan TN, Mathes EF, Frieden I, Shinkai K (2015) Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review. J Am Acad Dermatol 72(2):239–245. https://doi.org/10.1016/j.jaad.2014.06.026 CrossRefPubMed

16.

Messina MF, Cannavo SP, Aversa S, De Luca F (2011) Transient natural killer deficiency in a boy with herpes simplex virus-associated recurrent erythema multiforme. Scand J Infect Dis 43(6–7):550–552. https://doi.org/10.3109/00365548.2011.560185 CrossRefPubMed

17.

Turnbull N, Hawkins D, Atkins M, Francis N, Roberts N (2014) Persistent erythema multiforme associated with Epstein-Barr virus infection. Clin Exp Dermatol 39(2):154–157. https://doi.org/10.1111/ced.12243 CrossRefPubMed

18.

Drago F, Parodi A, Rebora A (1995) Persistent erythema multiforme: report of two new cases and review of literature. J Am Acad Dermatol 33(2 Pt 2):366–369. https://doi.org/10.1016/0190-9622(95)91435-8 CrossRefPubMed

19.

Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H, Walker AM (1990) The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 126(1):43–47. https://doi.org/10.1001/archderm.1990.01670250049006 CrossRefPubMed

20.

Shabahang L (2010) Characteristics of adult outpatients with erythema multiforme. Pak J Biol Sci: PJBS 13(22):1106–1109CrossRefPubMed

21.

Kaur S, Handa S (2008) Erythema multiforme following vaccination in an infant. Indian J Dermatol Venereol Leprol 74(3):251–253. https://doi.org/10.4103/0378-6323.41373 CrossRefPubMed

22.

Monastirli A, Pasmatzi E, Badavanis G, Tsambaos D (2017) Erythema multiforme following pneumococcal vaccination. Acta Dermatovenerol Alp Pannonica Adriat 26(1):25–26PubMed

23.

Ahdout J, Haley JC, Chiu MW (2010) Erythema multiforme during anti-tumor necrosis factor treatment for plaque psoriasis. J Am Acad Dermatol 62(5):874–879. https://doi.org/10.1016/j.jaad.2009.04.048 CrossRefPubMed

24.

Kimura T, Sowa-Osako J, Nakai T, Ohyama A, Kawaguchi T, Tsuruta D, Ohsawa M, Hirata K (2016) Alectinib-induced erythema multiforme and successful rechallenge with alectinib in a patient with anaplastic lymphoma kinase-rearranged lung cancer. Case Rep Oncol 9(3):826–832. https://doi.org/10.1159/000453314 CrossRefPubMedPubMedCentral

25.

Nomura H, Takahashi H, Suzuki S, Kurihara Y, Chubachi S, Kawada I, Yasuda H, Betsuyaku T, Amagai M, Funakoshi T (2017) Unexpected recalcitrant course of drug-induced erythema multiforme-like eruption and interstitial pneumonia sequentially occurring after nivolumab therapy. J Dermatol 44(7):818–821. https://doi.org/10.1111/1346-8138.13810 CrossRefPubMed

26.

Rodriguez-Pazos L, Sanchez-Aguilar D, Rodriguez-Granados MT, Pereiro-Ferreiros MM, Toribio J (2010) Erythema multiforme photoinduced by statins. Photodermatol Photoimmunol Photomed 26(4):216–218. https://doi.org/10.1111/j.1600-0781.2010.00519.x CrossRefPubMed

27.

Yanes DA, Kaffenberger JA, Carr DR (2017) Erythema multiforme as a reaction to imiquimod 5% cream. Dermatol Online J 23(2)

28.

Gehanno JF, Priot AE, Balguerie X, Caillard JF (2006) Polyhexamethylenebiguanide hydrochloride exposure and erythema multiforme in a physician. Int J Occup Med Environ Health 19(1):81–82CrossRefPubMed

29.

Nasabzadeh TJ, Stefanato CM, Doole JE, Radfar A, Bhawan J, Venna S (2010) Recurrent erythema multiforme triggered by progesterone sensitivity. J Cutan Pathol 37(11):1164–1167. https://doi.org/10.1111/j.1600-0560.2010.01607.x CrossRefPubMed

30.

Grunnet KM, Powell KS, Miller IA, Davis LS (2017) Autoimmune progesterone dermatitis manifesting as mucosal erythema multiforme in the setting of HIV infection. JAAD Case Rep 3(1):22–24. https://doi.org/10.1016/j.jdcr.2016.10.010 CrossRefPubMed

31.

Elcin G, Gulseren D, Bayraktar M, Gunalp S, Gurgan T (2017) Autoimmune estrogen dermatitis in an infertile female. Cutan Ocul Toxicol 36(2):195–198. https://doi.org/10.1080/15569527.2016.1245197 CrossRefPubMed

32.

Begolli Gerqari AM, Ferizi M, Halimi S, Daka A, Hapciu S, Begolli IM, Begolli M, Hysen Gerqari I (2016) Erythema exsudativum multiforme induced by a taurine-containing energy drink. Acta Dermatovenerol Alp Pannonica Adriat 25(4):83–84PubMed

33.

Rowell NR, Beck JS, Anderson JR (1963) Lupus erythematosus and erythema multiforme-like lesions. A syndrome with characteristic immunological abnormalities. Arch Dermatol 88(2):176–180. https://doi.org/10.1001/archderm.1963.01590200064012 CrossRefPubMed

34.

Shteyngarts AR, Warner MR, Camisa C (1999) Lupus erythematosus associated with erythema multiforme: does Rowell’s syndrome exist? J Am Acad Dermatol 40(5 Pt 1):773–777. https://doi.org/10.1016/S0190-9622(99)70165-9 CrossRefPubMed

35.

Aydogan K, Karadogan S, Balaban Adim S, Tunali S (2005) Lupus erythematosus associated with erythema multiforme: report of two cases and review of the literature. J Eur Acad Dermatol Venereol: JEADV 19(5):621–627. https://doi.org/10.1111/j.1468-3083.2005.01233.x CrossRefPubMed

36.

Lee A, Batra P, Furer V, Cheung W, Wang N, Franks A Jr (2009) Rowell syndrome (systemic lupus erythematosus + erythema multiforme). Dermatol Online J 15(8):1PubMed

37.

Duarte AF, Mota A, Pereira M, Baudrier T, Azevedo F (2008) Rowell syndrome—case report and review of the literature. Dermatol Online J 14(3):15

38.

Parodi A, Drago EF, Varaldo G, Rebora A (1989) Rowell's syndrome. Report of a case. J Am Acad Dermatol 21(2 Pt 2):374–377. https://doi.org/10.1016/S0190-9622(89)80038-6 CrossRefPubMed

39.

Zeitouni NC, Funaro D, Cloutier RA, Gagne E, Claveau J (2000) Redefining Rowell’s syndrome. Br J Dermatol 142(2):343–346. https://doi.org/10.1046/j.1365-2133.2000.03306.x CrossRefPubMed

40.

Fraser-Andrews EA, Morris-Jones R, Novakovic L, Hawk JL (2005) Erythema multiforme following polymorphic light eruption: a report of two cases. Clin Exp Dermatol 30(3):232–234. https://doi.org/10.1111/j.1365-2230.2004.01707.x CrossRefPubMed

41.

Czarnecka-Operacz M, Jenerowicz D, Szulczynska-Gabor J, Teresiak-Mikolajczak E, Szyfter-Harris J, Bowszyc-Dmochowska M (2016) Vesicular contact reaction may progress into erythema multiforme. Acta Dermatovenerol Croat: ADC 24(4):307–309PubMed

42.

Wolf R, Stander S, Well O, Frey L, Klier I, Brunner S, Flaig M, Wollenberg A, Ruzicka T (2017) Pustular erythema multiforme major associated with atypical pneumonia. J Eur Acad Dermatol Venereol: JEADV 31(11):e502–e503. https://doi.org/10.1111/jdv.14356 CrossRefPubMed

43.

Behera B, Kumari R, Gochhait D, Thappa DM (2017) Generalized lichen planus developing at the healed sites of erythema multiforme in a human immunodeficiency virus-seropositive patient. Indian J Dermatol Venereol Leprol 83(4):485–489. https://doi.org/10.4103/ijdvl.IJDVL_268_16 CrossRefPubMed

44.

Elm MK, Murchland MR (2012) Multifocal, fixed-drug eruption masquerading as recurrent erythema multiforme. J Drugs Dermatol: JDD 11(2):244–246PubMed

45.

Beer K, Beer MS, Appelbaum D (2013) Granuloma annulare masquerading as erythema multiforme. J Drugs Dermatol: JDD 12(6):694–697PubMed

46.

Ohtani T, Deguchi M, Aiba S (2008) Erythema multiforme-like lesions associated with lesional infiltration of tumor cells occurring with adult T-cell lymphoma/leukemia. Int J Dermatol 47(4):390–392. https://doi.org/10.1111/j.1365-4632.2008.03535.x CrossRefPubMed

47.

Michigami M, Kabashima K, Nonaka Y, Kamoda Y, Yoshinaga T, Kudo H (2012) Kikuchi-Fujimoto disease with recurrent fever and erythema multiforme-like lesions. Eur J Dermatol: EJD 22(2):263–264. https://doi.org/10.1684/ejd.2011.1628 PubMed

48.

Chua SH, Giam YC, Sim CS (1996) Systemic lupus erythematosus with erythema multiforme-like lesions and histiocytic necrotizing lymphadenitis—a case report. Ann Acad Med Singap 25(4):599–601PubMed

49.

Sebastian A, Patterson C, Zaenglein AL, Ioffreda MD, Helm KF (2009) Histiocytic erythema multiforme. J Cutan Pathol 36(12):1323–1325. https://doi.org/10.1111/j.1600-0560.2009.01287.x CrossRefPubMed

50.

Rzany B, Mockenhaupt M, Baur S, Schroder W, Stocker U, Mueller J, Hollander N, Bruppacher R, Schopf E (1996) Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Clin Epidemiol 49(7):769–773. https://doi.org/10.1016/0895-4356(96)00035-2 CrossRefPubMed

51.

Ackerman AB, Penneys NS, Clark WH (1971) Erythema multiforme exudativum: distinctive pathological process. Br J Dermatol 84(6):554–566CrossRefPubMed

52.

Ackerman AB, Ragaz A (1985) Erythema multiforme. Am J Dermatopathol 7(2):133–139CrossRefPubMed

53.

Lever WF (1985) My concept of erythema multiforme. Am J Dermatopathol 7(2):141–142. https://doi.org/10.1097/00000372-198504000-00008 CrossRefPubMed

54.

Orfanos CE, Schaumburg-Lever G, Lever WF (1974) Dermal and epidermal types of erythema multiforme. A histopathologic study of 24 cases. Arch Dermatol 109(5):682–688. https://doi.org/10.1001/archderm.1974.01630050028006 CrossRefPubMed

55.

Cote B, Wechsler J, Bastuji-Garin S, Assier H, Revuz J, Roujeau JC (1995) Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol 131(11):1268–1272. https://doi.org/10.1001/archderm.1995.01690230046008 CrossRefPubMed

56.

Tatnall FM, Schofield JK, Leigh IM (1995) A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 132(2):267–270CrossRefPubMed

57.

Lemak MA, Duvic M, Bean SF (1986) Oral acyclovir for the prevention of herpes-associated erythema multiforme. J Am Acad Dermatol 15(1):50–54. https://doi.org/10.1016/S0190-9622(86)70141-2 CrossRefPubMed

58.

Fawcett HA, Wansbrough-Jones MH, Clark AE, Leigh IM (1983) Prophylactic topical acyclovir for frequent recurrent herpes simplex infection with and without erythema multiforme. Br Med J (Clin Res Ed) 287(6395):798–799. https://doi.org/10.1136/bmj.287.6395.798-a CrossRef

59.

Staikuniene J, Staneviciute J (2015) Long-term valacyclovir treatment and immune modulation for herpes-associated erythema multiforme. Cen Eur J Immunol 40(3):387–390. https://doi.org/10.5114/ceji.2015.54604 CrossRef

60.

Routt E, Levitt J (2014) Famciclovir for recurrent herpes-associated erythema multiforme: a series of three cases. J Am Acad Dermatol 71(4):e146–e147. https://doi.org/10.1016/j.jaad.2014.05.029 CrossRefPubMed

61.

Kieny A, Lipsker D (2016) Efficacy of interferon in recurrent valaciclovir-refractory erythema multiforme in a patient not infected with hepatitis C virus. Clin Exp Dermatol 41(6):648–650. https://doi.org/10.1111/ced.12871 CrossRefPubMed

62.

Oak AS, Seminario-Vidal L, Sami N (2017) Treatment of antiviral-resistant recurrent erythema multiforme with dapsone. Dermatol Ther 30(2). https://doi.org/10.1111/dth.12449

63.

Sen P, Chua SH (2004) A case of recurrent erythema multiforme and its therapeutic complications. Ann Acad Med Singap 33(6):793–796PubMed

64.

Bakis S, Zagarella S (2005) Intermittent oral cyclosporin for recurrent herpes simplex-associated erythema multiforme. Australas J Dermatol 46(1):18–20. https://doi.org/10.1111/j.1440-0960.2004.00130.x CrossRefPubMed

65.

Baillis B, Maize JC Sr (2017) Treatment of recurrent erythema multiforme with adalimumab as monotherapy. JAAD Case Rep 3(2):95–97. https://doi.org/10.1016/j.jdcr.2016.11.009 CrossRefPubMedPubMedCentral

66.

Chen CW, Tsai TF, Chen YF, Hung CM (2008) Persistent erythema multiforme treated with thalidomide. Am J Clin Dermatol 9(2):123–127. https://doi.org/10.2165/00128071-200809020-00006 CrossRefPubMed

67.

Damsky W, King BA (2016) Idiopathic erythema multiforme: evidence of underlying Janus kinase-signal transducer and activator of transcription activation and successful treatment with tofacitinib. JAAD Case Rep 2(6):502–504. https://doi.org/10.1016/j.jdcr.2016.10.009 CrossRefPubMedPubMedCentral

68.

Chen T, Levitt J, Geller L (2017) Apremilast for treatment of recurrent erythema multiforme. Dermatol Online J 23(1)

Title: Current Perspectives on Erythema Multiforme
Authors: Marianne Lerch
Carlo Mainetti
Benedetta Terziroli Beretta-Piccoli
Thomas Harr
Publication date: 01-02-2018
Publisher: Springer US
Published in: Clinical Reviews in Allergy & Immunology / Issue 1/2018
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-017-8667-7

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