TY - JOUR
AU1 - Newkirk, Russell E
AU2 - Fomin, Daren A
AU3 - Braden, Mary M
AB - Abstract Erythema multiforme and Stevens–Johnson syndrome/toxic epidermal necrolysis are immune-mediated epidermal conditions with variable clinical presentations. Although their clinical presentations often overlap, they have distinct etiologies and potential outcomes, which necessitate specific management strategies. This case is presented to highlight the subtle differences and review management given that Stevens–Johnson syndrome/toxic epidermal necrolysis can rapidly become life-threatening. The need for astute diagnostic work-up and accuracy is magnified in the military setting given operations in austere environments and availability of medical and medical evacuation resources. Herein, we present a less common case of bullous erythema-multiforme, the diagnostic approach, and clinical differential with special attention to the importance of the military physician. CASE PRESENTATION An 87-year-old Caucasian male presented to the Emergency Department of our tertiary care center with a blistering rash that developed 4 days before the presentation. Relevant dermatologic history includes two documented episodes of suspected erythema multiforme (EM) with negative herpes simplex virus (HSV) serologies. The patient stated that 5 days earlier he experienced pruritus on the dorsal surface of bilateral forearms (which was the same prodrome experienced in previous EM episodes) followed by “blister” formation to bilateral lower extremities, trunk, upper extremities, and lips. Because the most recent episode was seemingly more robust than previous episodes, he presented to an outside dermatologist for evaluation. The community dermatologist recommended immediate evaluation by an emergency physician for Stevens–Johnson syndrome (SJS) versus bullous pemphigoid (BP). He presented to our facility and was admitted to the medicine ward for observation with dermatology consultation. On admission, he had an elevated white blood cell count but was otherwise stable. Review of systems was negative for fevers, malaise, a history of recent upper respiratory infection, medication changes, antibiotic usage, eye complaints, dysuria, hematuria, and hematochezia. The patient had multiple medical comorbidities including hypertension, hyperlipidemia, type 2 diabetes, gout and congestive heart failure. Medications included allopurinol, furosemide, sacubitril/valsartan, and rosuvastatin. A full body skin exam revealed oral mucosal involvement with circumferential superficial erosion and sanguinous crusting of the superior and inferior vermillion only (Fig. 1). No other oral lesions were noted. Sclerae were grossly normal. There were numerous serous fluid-filled, tense bullae and erosions to the neck, distal upper extremities, back, left intergluteal cleft sparing the anus, and bilateral lower extremities to the ankles. A single bulla was observed on the left third finger on the ulnar side (Fig. 2). Otherwise, acral surfaces were spared. There was no evidence of scaling or desquamation. There were numerous dusky, erythematous, and slightly targetoid patches on the back and bilateral posterior legs (Fig. 3). Biopsies were obtained for histopathologic examination and direct immunofluorescence (DIF) which was negative. Histologic examination revealed focal epidermal necrosis with vacuolar/interface dermatitis and lichenoid inflammation. Negative DIF was useful to exclude BP from the differential diagnosis. FIGURE 1 Open in new tabDownload slide Oral mucosal involvement with circumferential superficial erosion and sanguinous crusting to the vermillion only. FIGURE 2 Open in new tabDownload slide Single bulla observed on the left third finger. FIGURE 3 Open in new tabDownload slide Dusky, erythematous, and slightly targetoid patches on the back and bilateral lower extremities with tense, fluid-filled bullae on bilateral lower extremities. Despite the presentation with lesions appearing more consistent with SJS/toxic epidermal necrolysis (TEN), because of the absence of constitutional symptoms, ocular involvement, and urethritis, the patient was diagnosed with the bullous variant of EM. He was started on an oral prednisone taper as well as a medium potency topical steroid. A robust viral panel was obtained and found to be negative. Although the exact etiology for bullous EM in this case remains uncertain, the patient was taking allopurinol, a known cause of EM, SJS, and TEN. On previous episodes, he was counseled to discontinue this medication but did not. Each successive episode he experienced was worse than the previous episode. Following the latest episode, the patient was satisfactorily convinced to stop the medication. He has remained in remission since the time of submission of this article (approximately 8 months after diagnosis). DISCUSSION EM and SJS were once thought of as being on the same spectrum of disease. However, they are now considered separate entities and although their difference in presentation is subtle, the potential complications necessitate significant differences in management. This case was presented to help clinically distinguish EM from SJS and to highlight the current guidelines for management. This case had extremely subtle differences with significant impact to treatment strategy as SJS may progress to TEN. SJS and TEN are on the same spectrum of disease with SJS defined as <10% skin involvement and TEN representing >30% skin involvement, and 10–30% skin involvement representing an overlap of SJS/TEN.1–3 This patient’s presentation involved many clinical features shared by both EM and SJS/TEN. The lesions were more consistent with SJS/TEN given that they were flat versus raised, mucosal surfaces were involved, and blistering was present. However, the lack of a prodromal phase with constitutional symptoms such as fever and malaise and an elevated clinical suspicion from previous episodes were what ultimately led to the diagnosis and appropriate choice of management. This case illustrates the need to look at the totality of the clinical presentation and to avoid overreliance on any particular diagnostic feature of EM versus SJS/TEN. The pathologic trigger for EM is an immune-mediated response most commonly because of infection.4–8 The pathogenesis of EM and SJS/TEN are similar in that both involve cytotoxic lymphocyte responses against altered keratinocytes via direct cytotoxicity or soluble mediators (Fas ligand, granzymes).4 The alteration in keratinocytes in EM is secondary to viral processes for the vast majority of the time, most commonly HSV-1.4 In SJS/TEN the alteration in keratinocytes is most commonly because of medication.2–4 It should be noted that there is overlap for the pathogenesis and underlying etiology for these entities.4–6 Thus, distinguishing the two separate entities can be challenging. The diagnosis is clinical with emphasis on the morphology of the lesions and the presence or absence of constitutional symptoms.1,2 Histopathology is limited to confirming keratinocyte necrosis with vacuolar/interface alteration and is not sufficient for diagnosis as it cannot reliably distinguish between EM and SJS/TEN.1,2,4 The similarities and differences of EM and SJS/TEN are highlighted in Table I. TABLE I Erythema Multiforme Versus SJS/TEN1–10 . Erythema Multiforme . SJS/TEN . Hallmark lesion Raised, papular Typical target lesions: dusky edematous area surrounded by a darker, erythematous inflammatory zone further surrounded by a lighter edematous ring, enclosed by an erythematous zone +/− atypical targetoid lesions Flat, macular with ill-defined borders that may progress to vesicles and bullae followed by skin sloughing. Tender to palpation and diffusely erythematous. Typical target lesions +/− atypical targetoid lesions Distribution of lesions Face and extremities/acral Face and trunk Constitutional symptoms Uncommon Common Mucosal involvement 25–60% >87% Ocular involvement Uncommon Common Urethritis Uncommon Common Blister formation Uncommon Common Typical age 20–40 Elderly Gender M > F F > M Precipitating factors 1. Infectious (most commonly HSV-1)* 2. Drugs (NSAIDS, sulfonamides, antiepileptics and antibiotics) 3. Exposures (poison ivy) 4. Systemic disease (inflammatory bowel disease, Behcet disease) 5. Idiopathic Drugs: NSAIDS, sulfonamides, antiepileptics, antibiotics (especially penicillins), antimalarials and HAART Less commonly: infectious* Duration of symptoms 1–2 weeks 8–12 days acute phase, re-epitheliazation lasts 2–4 weeks Association with cancer, HIV, HLA type or collagen vascular disease No Yes . Erythema Multiforme . SJS/TEN . Hallmark lesion Raised, papular Typical target lesions: dusky edematous area surrounded by a darker, erythematous inflammatory zone further surrounded by a lighter edematous ring, enclosed by an erythematous zone +/− atypical targetoid lesions Flat, macular with ill-defined borders that may progress to vesicles and bullae followed by skin sloughing. Tender to palpation and diffusely erythematous. Typical target lesions +/− atypical targetoid lesions Distribution of lesions Face and extremities/acral Face and trunk Constitutional symptoms Uncommon Common Mucosal involvement 25–60% >87% Ocular involvement Uncommon Common Urethritis Uncommon Common Blister formation Uncommon Common Typical age 20–40 Elderly Gender M > F F > M Precipitating factors 1. Infectious (most commonly HSV-1)* 2. Drugs (NSAIDS, sulfonamides, antiepileptics and antibiotics) 3. Exposures (poison ivy) 4. Systemic disease (inflammatory bowel disease, Behcet disease) 5. Idiopathic Drugs: NSAIDS, sulfonamides, antiepileptics, antibiotics (especially penicillins), antimalarials and HAART Less commonly: infectious* Duration of symptoms 1–2 weeks 8–12 days acute phase, re-epitheliazation lasts 2–4 weeks Association with cancer, HIV, HLA type or collagen vascular disease No Yes *Other infectious etiologies include: Parapoxvirus, Vaccinia (smallpox vaccine), Varicella zoster virus, Adenovirus, Epstein-Barr virus, Cyomegalovirus, Hepatitis virus, Coxsackievirus, Parvovirus B19, HIV, Mycoplasma pneumonia (most common cause in children), Chlamydophila psittaci, Salmonella, Mycobacterium tuberculosis, Histoplasma capsulatum and Dermatophytes. Open in new tab TABLE I Erythema Multiforme Versus SJS/TEN1–10 . Erythema Multiforme . SJS/TEN . Hallmark lesion Raised, papular Typical target lesions: dusky edematous area surrounded by a darker, erythematous inflammatory zone further surrounded by a lighter edematous ring, enclosed by an erythematous zone +/− atypical targetoid lesions Flat, macular with ill-defined borders that may progress to vesicles and bullae followed by skin sloughing. Tender to palpation and diffusely erythematous. Typical target lesions +/− atypical targetoid lesions Distribution of lesions Face and extremities/acral Face and trunk Constitutional symptoms Uncommon Common Mucosal involvement 25–60% >87% Ocular involvement Uncommon Common Urethritis Uncommon Common Blister formation Uncommon Common Typical age 20–40 Elderly Gender M > F F > M Precipitating factors 1. Infectious (most commonly HSV-1)* 2. Drugs (NSAIDS, sulfonamides, antiepileptics and antibiotics) 3. Exposures (poison ivy) 4. Systemic disease (inflammatory bowel disease, Behcet disease) 5. Idiopathic Drugs: NSAIDS, sulfonamides, antiepileptics, antibiotics (especially penicillins), antimalarials and HAART Less commonly: infectious* Duration of symptoms 1–2 weeks 8–12 days acute phase, re-epitheliazation lasts 2–4 weeks Association with cancer, HIV, HLA type or collagen vascular disease No Yes . Erythema Multiforme . SJS/TEN . Hallmark lesion Raised, papular Typical target lesions: dusky edematous area surrounded by a darker, erythematous inflammatory zone further surrounded by a lighter edematous ring, enclosed by an erythematous zone +/− atypical targetoid lesions Flat, macular with ill-defined borders that may progress to vesicles and bullae followed by skin sloughing. Tender to palpation and diffusely erythematous. Typical target lesions +/− atypical targetoid lesions Distribution of lesions Face and extremities/acral Face and trunk Constitutional symptoms Uncommon Common Mucosal involvement 25–60% >87% Ocular involvement Uncommon Common Urethritis Uncommon Common Blister formation Uncommon Common Typical age 20–40 Elderly Gender M > F F > M Precipitating factors 1. Infectious (most commonly HSV-1)* 2. Drugs (NSAIDS, sulfonamides, antiepileptics and antibiotics) 3. Exposures (poison ivy) 4. Systemic disease (inflammatory bowel disease, Behcet disease) 5. Idiopathic Drugs: NSAIDS, sulfonamides, antiepileptics, antibiotics (especially penicillins), antimalarials and HAART Less commonly: infectious* Duration of symptoms 1–2 weeks 8–12 days acute phase, re-epitheliazation lasts 2–4 weeks Association with cancer, HIV, HLA type or collagen vascular disease No Yes *Other infectious etiologies include: Parapoxvirus, Vaccinia (smallpox vaccine), Varicella zoster virus, Adenovirus, Epstein-Barr virus, Cyomegalovirus, Hepatitis virus, Coxsackievirus, Parvovirus B19, HIV, Mycoplasma pneumonia (most common cause in children), Chlamydophila psittaci, Salmonella, Mycobacterium tuberculosis, Histoplasma capsulatum and Dermatophytes. Open in new tab Both EM and SJS may present with erythematous, targetoid lesions.2,3,5 The key difference with EM is that the lesions are typically raised or papular.1,5,9 EM lesions are round, erythematous, edematous papules that are surrounded by areas of blanching.1,4,5 The central papules can enlarge and develop surrounding alterations in features, which results in the hallmark target lesions.5 This lesion typically consists of a central region of epidermal necrosis that can either appear as a dusky area or blister as in bullous EM.5 This is surrounded by a darker, erythematous inflammatory zone further surrounded by a lighter edematous ring, enclosed by an erythematous zone.1,5,9 Of note, there is significant variability in morphology (hence the term, “multiforme”) to include papules or plaques with only two zones of color, bullae, and hemorrhagic papules/plaques (typically on mucosae).5,9 Mucosal involvement is not uncommon and EM minor is differentiated from EM major by the absence of mucosal lesions.1,5,9 Lesions can develop at nearly any cutaneous site, including most commonly acral surfaces, and are generally asymptomatic or pruritic/burning in nature.5,9 Systemic involvement is extremely unlikely and patients are generally stable in condition, although they may report a viral prodrome before disease onset.5,9 Lab abnormalities are variable and nonspecific, in severe cases potentially showing an elevated erythrocyte sedimentation rate, white blood cell count, and liver function tests.5 The typical lesions in SJS/TEN are flat/macular, often beginning as ill-defined erythematous macules and progressing to vesicles and bullae followed by skin sloughing.1,3,5 The lesions can also be diffusely erythematous and are usually tender to palpation.1,3 The key difference from EM is that SJS/TEN presents with a clinically unwell patient. Appearance of the lesions in SJS/TEN is typically proceeded by a prodromal phase with fever, fatigue, and malaise.1–5 Patients may also have flu-like symptoms, skin tenderness, photophobia, malaise, myalgia, arthralgia, and corneal symptoms at the time of presentation.3–6 Mucositis may lead to intolerance of oral intake and patients may present with genitourinary problems including erosions and strictures of the urethra.3 One study demonstrated that approximately 80% of patients have ocular involvement ranging from uveitis to corneal ulceration and panophtlamitits.6 Common lab abnormalities include anemia and neutropenia (an indication of poor prognosis).2 More severe cases show markers of massive fluid shift (ie, elevated glucose and blood urea nitrogen, and electrolyte disturbances as indicated per the objective score of toxic epidermal necrosis (SCORTEN)).3 Although similar in clinical appearance, treatment and prognosis become the greatest differences between EM and SJS/TEN. EM is often self-limiting, especially in mild cases.1,9 It can be treated with oral corticosteroids, 40–60 mg by mouth daily tapered over 2–3 weeks.1,5,9,10 Dosage and duration can be adjusted based on disease severity with some cases requiring month long tapers.9,10 Topical steroids may also be beneficial as they were in this case.1,5,6,9 Antivirals (acyclovir) are often useful in resistant cases as the most common cause is HSV.5,9 Recently, small studies have shown modest-to-significant efficacy of treatment with nonsteroidal alternatives including dapsone, rituximab, and Apremilast.7,8,11 One study suggests that in prolonged cases of EM that fail to respond to antiviral and immunosuppressive agents, apremilast may be an effective alternative as it showed complete clearance in three individuals including one pediatric patient who tolerated doses of 1 mg/kg.8 SJS/TEN management is much more involved with significant complication risk, including sepsis, gastrointestinal bleeding, pulmonary edema, pulmonary embolism, myocardial infarction, and death in severe cases.3 Treatment includes withdrawal of any offending agent, supportive wound care including fluids, nutrition, pain control and prevention, and treatment of infection.1,3 One objective measure used to determine severity and management of SJS/TEN is the SCORTEN. Scores of two or greater should be managed in an intensive care unit or burn unit.1–4 The appearance of blistering lesions with oral mucosal involvement in an elderly patient initially raised concern for BP. The community dermatologist appropriately sought to rule out this disorder to determine appropriate management. BP is an autoimmune immune disease that results in erythematous and tense, fluid-filled plaques with bullae that may involve the oral mucosa.5,9 The lesions may also be pruritic.9 In addition to the differences in the morphology of the lesions, BP can be definitively distinguished from EM and SJS/TEN with histologic findings augmented with DIF.5 BP demonstrates IgG and C3 linear deposition on the epidermal basement membrane and subepidermal bullae with numerous eosinophils.5 CONCLUSIONS It is recommended that efforts to distinguish between EM (specifically the bullous variant) and SJS/TEN be increased. This is especially critical in the military setting where operations in austere environments may significantly limit treatment options. Distinguishing between the two may ultimately be the deciding factor in determining medical evacuation (MEDEVAC) or local treatment, with significant impact to assets and operations at stake. Novel treatment modalities with sound scientific backing have been shown to be efficacious in limited trials with success clearing the illness but the mainstay of therapy for EM involves oral steroids and antivirals.1,5,7–11 The views expressed are solely those of the authors and do not reflect the official policy or position of the U.S. Army, U.S. Navy, U.S. Air Force, the Department of Defense, or the U.S. Government. References 1. Paulino L , Hamblin D, Osondu N, Amini R: Varients of erythema Multiforme: a case report and literature review . Cureus 2018 ; 10 : 3459 . Available at . https://www.cureus.com/articles/15082-variants-of-erythema-multiforme-a-case-report-and-literature-review accessed December 8, 2019 . Google Scholar OpenURL Placeholder Text WorldCat 2. Chia-Chun A , Young-Kwang T: Hematological abnormalities and the use of granulocyte-colony-stimulating factor in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis . Int J Dermatol 2011 ; 50 ( 10 ): 1570 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 3. Schwartz RA , McDonough PH, Lee BW: Toxic epidermal Necrolysis . J Am Acad Dermatol 2013 ; 69 ( 2 ): 187.e1 – 187.e16 . Google Scholar Crossref Search ADS WorldCat 4. Yager J : Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: a comparative review . Vet Dermatol 2014 ; 25 : 406 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Sokumbi O , Wetter DA: Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist . Int J Dermatol 2012 ; 51 : 889 – 902 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Chang YS , Huang FC, Tsen SH, et al. : Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management . Cornea 2007 ; 26 : 123 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Oak AS , Seminario-Vidal L, Sami N: Treatment of antiviral-resistant recurrent erythema multiforme with dapsone . Dermatol Online J 2017 ; 30 ( 2 ): 12449 . Available at . https://onlinelibrary.wiley.com/doi/abs/10.1111/dth.12449 accessed December 8, 2019 . Google Scholar OpenURL Placeholder Text WorldCat 8. Chen T , Levitt J, Geller L: Apremilast for treatment of recurrent erythema multiforme . Dermatol Online J 2017 ; 23 ( 1 ): 14 . Available at . https://escholarship.org/uc/item/15s432gx accessed December 8, 2019 . Google Scholar OpenURL Placeholder Text WorldCat 9. Trayes KP , Love G, Studdiford JS: Erythema multiforme: recognition and management . Am Fam Physician 2019 ; 100 ( 2 ): 82 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 10. 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 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Hirsch G , Ingen-Housz-Oro S, Fite C, et al. : Rituximab, a new treatment fo difficult-to-treat chronic erythema multiforme major? Five cases . J Eur Acad Dermatol Venereol 2016 ; 30 ( 7 ): 1140 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US. This work is written by US Government employees and is in the public domain in the US. Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.
TI - Erythema Multiforme Versus Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis: Subtle Difference in Presentation, Major Difference in Management
JF - Military Medicine
DO - 10.1093/milmed/usaa029
DA - 2020-09-18
UR - https://www.deepdyve.com/lp/oxford-university-press/erythema-multiforme-versus-stevens-johnson-syndrome-toxic-epidermal-EwhEeBDgZ9
SP - e1847
EP - e1850
VL - 185
IS - 9-10
DP - DeepDyve
ER -