Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: An Update

Roni P. Dodiuk-Gad; Wen-Hung Chung; Laurence Valeyrie-Allanore; Neil H. Shear

Disclosures

Am J Clin Dermatol. 2015;16(6):475-493. 

In This Article

3 Clinical Presentation

3.1 Acute Stage

Initially, SJS/TEN begins within 4 weeks (usually 4–28 days) after the onset of drug intake.[65] The disease can also occur a few days after the drug has been withdrawn in the case of long-half-life drugs. In very rare cases of rechallenge with the same drug, the disease appears more rapidly, within hours.[66]

Initial symptoms are usually non-specific and can precede cutaneous manifestations by a few days (1–3 days) in one third of cases. Painful mucous membranes, stinging eyes, headache, rhinitis, malaise, cough, sore throat, and myalgias are frequently noticed. In the absence of cutaneous manifestations, these symptoms may contribute to an erroneous initial diagnosis and delayed specific management. In other cases, the disease may begin with mucous membrane involvement and/or non-specific exanthema. However, the addition of new clinical signs, severe pain, and rapid progression should alert the physician and may lead to consideration of a severe disease.

3.1.1 Cutaneous Lesions. Early sites of cutaneous involvement are the presternal region of the trunk, the face, and proximal parts of the limbs. Palms and soles may also be initially involved. The rash may spread to distal parts of the limbs and the rest of the body within a few days. Individual cutaneous lesions appear as erythematous, dusky dark red purpuric macules, which are irregularly shaped (Fig. 3).[67,68] These atypical targets, with two concentric rings, have a necrotic center and may tend to coalesce.[68] At this stage, involvement of at least two mucous membrane sites is observed in up to 90 % of cases, and this feature may help in diagnosis.

Figure 3.

Erythematous dusky red macules on the trunk

In the absence of spontaneous detachment, a positive Nikolsky sign should be sought by exertion of lateral mechanical pressure with a finger on an erythematous zone.[67,68] This sign is considered positive if dermal–epidermal cleavage is induced and necrotic epidermis detachment on pressure points reveals large areas of exposed, red, sometimes oozing dermis. It can also be observed in autoimmune blistering diseases such as pemphigus. According to the percentage of epidermis that is detached or detachable, patients are classified into one of three groups: SJS involves <10 % of body surface area (BSA); SJS/TEN overlap involves between 10 % and 30 % of BSA; TEN involves >30 % of BSA.[68]

Despite the obvious differences from erythema multiforme, occasional typical target lesions may appear.[67,69] These lesions rapidly extend within 4 to 5 days. Skin involvement can be limited to the predilection sites at the SJS end of the spectrum (face, trunk) but are widespread in TEN. TEN displays areas of diffuse erythema, with individual macular lesions at the periphery. The epidermis detaches from the underlying dermis, leading to large, flaccid blisters (Fig. 4). The roofs of the blisters turn necrotic and display denudation of the epidermis in large sheets measuring >5 cm (Fig. 5). Tense bullous lesions are more frequently observed at the initial stage and on palmoplantar soles.

Figure 4.

Bullous lesions due to epidermal necrosis

Figure 5.

Blisters and epidermal detachment have led to large confluent Erosions

Thermal burn rules are currently used in SJS/TEN. Evaluation of the BSA involved may be difficult and is often overestimated, more particularly in the case of spotty lesions.

3.1.2 Mucous Membranes. Involvement of mucous membranes is noticed in more than 80 % of cases with at least two sites involved and may be inaugural in one third of cases.[68] Painful inflammation and erosions of mucosal surfaces occurs in 87 to 100 % of cases of TEN.[70,71] Lesions usually begin with painful, burning sensations of the lips, conjunctivae, and genitalia, followed by edematous, erythematous, and flaccid bullous lesions. Blisters rupture and tend to extend. Bullous lesions become very painful and hemorrhagic erosions, coated by greyish-white pseudo-membranes of the oral cavity (Fig. 6), leading to impaired alimentation and hypersalivation. Genital erosions most often include painful erosions of the glans penis, vulva, and vagina, and may lead to ''burning'' on micturition, urinary retention, and synechiae.[72] Anal lesions are less frequent. Ocular involvement is mainly represented by conjunctival involvement in 80 % of cases,[73,74] including photophobia, pain, lacrimation, chemosis, and redness.[73,74] However, more severe involvement leads to corneal ulceration, anterior uveitis, and purulent conjunctivitis. Ultimately, this can lead to blindness.

Figure 6.

Extensive erosions of the lips and oral mucosa

3.1.3 Systemic Manifestations. SJS/TEN corresponds to an acute skin failure associated with severe weakness, pain, and prolonged high fever.[75] Internal epithelial organ involvement is rare and mainly concerns the respiratory and gastrointestinal tracts. Early pulmonary dysfunction is observed in 25 % of cases, and the respiratory rate and blood oxygenation must be systematically evaluated.[76] Pulmonary involvement includes breathing difficulties, cough, bronchial obstruction, and respiratory distress. A recent retrospective study reported that 39 % of patients with SJS/TEN had specific endobronchial lesions and 25 % required mechanical ventilation.[77] Initial bronchial hypersecretion, laryngeal involvement, and dyspnea should alert the physician.

Less commonly, gastrointestinal involvement has been reported, including diarrhea, abdominal distention, and excretion of colonic intestinal epithelium, which can lead to bowel perforation.[78,79]

Renal involvement is currently observed in the acute phase, mainly represented by acute renal failure, proximal acute tubular necrosis, hematuria, and microalbuminemia.[80] Anemia, mild elevation in hepatic enzymes and amylase (mostly of salivary origin) are frequent, without any impact on prognosis. Neutropenia is rare and is considered a severity marker but is too rare to have an impact on the Severity of Illness Score for TEN (SCORTEN) (Table 2).

3.1.4 Prognosis. Progression lasts for about 4–5 days following admission. Next, patients enter a plateau phase, which corresponds to progressive re-epithelialization. Complete healing can take a few days to several weeks. This phase is associated with life-threatening complications such as sepsis due to epithelial loss.[81,82]Staphylococcus aureus and Pseudomonas are the most frequent pathogens involved, both usually present in the skin and blood. Multisystem organ failure and pneumonitis are important causes of morbidity, with prevalence rates of 24 and 23.1 %, respectively.[82]

In Europe, according to the RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions) results, the mortality rate was 23 % at 6 weeks and 34 % at 1 year.[83] The severity of the reaction was a risk factor for mortality only in the 3 months after onset, whereas serious comorbidities and age influenced mortality beyond 90 days and up to 1 year after the onset of the reaction.[83]

In parallel, it has already been demonstrated that prompt withdrawal of the offending agent may reduce the risk of death by 30 %.[84]

A SJS/TEN-specific severity-of-illness score is proposed (SCORTEN), in which seven variables remain independent prognosis factors of death: age >40 years, heart rate >120 beats/min, cancer or hemopathy, BSA involvement >10 %, serum urea level >10 mmol/L, serum bicarbonate level <20 mmol/L, and serum glucose level >14 mmol/L (Table 2).[85] The score's ability to predict outcome and usefulness has been confirmed by several teams,[86,87] and a simplified score has recently been proposed for cases with missing laboratory data.[88] The prognostic value of SCORTEN is more accurate at day 3 of hospitalization.[89]

3.2 Chronic Stage

During the past few decades, SJS/TEN has no longer been considered as only an acute disease. Specific follow-up of sequelae should be systematically planned and studied for better understanding of the pathophysiology, detection, and prevention of the reaction, and to reduce the health burden.[90] Dermatological sequelae frequently include hyper-and hypopigmentation (72 %), hypertrophic scars, and nail dystrophies (pigmentation in the nail bed, ridging, and permanent anonychia).

In 65–89 % of cases, patients develop late ocular complications, including dry eye syndrome, trichiasis, photophobia, symblepharon, corneal inflammation and neovascularization, and, in the most severe cases, reduced visual acuity and blindness.[73,91]

Buccal and dental complications in a study of 16 patients with TEN reported gingival synechiae, gingival recession, dental alteration, xerostomia, and increased saliva acidity.[92]

Long-term follow-up of SJS/TEN patients can identify chronic lung disease, mostly bronchiolitis obliterans. Pulmonary function tests performed during the usual followup display abnormalities presenting mainly as asymptomatic diffusion impairment, with a risk proportional to BSA involvement.[93]

Male genitalia synechiae may require circumcision. Strictures of vaginal mucosa and/or birth-canal stenosis[72] may be responsible for dyspareunia or vaginal dryness, and can complicate spontaneous vaginal delivery and sexual intercourse. Surgical, topical, physical, and laser treatments are often required.

The results of our recent study assessing the long-term emotional and physical sequelae of SJS/TEN[94] demonstrated major emotional complications (symptoms of anxiety, depression, and post-traumatic stress), impaired healthrelated quality of life, and long-term physical complications (most commonly cutaneous and ophthalmic).

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