Dr. Jean Bolognia presented information about Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and diseases that mimic them. SJS and TEN are severe skin reactions that cause damage to the skin and mucus membranes and can be life-threatening. TEN typically involves the entire trunk.
Jean Bolognia, MD, professor of dermatology at the Yale University School of Medicine
First, Bolognia discussed the expanding differential diagnosis of SJS/TEN. Previously, dermatologists would be consulted to distinguish SJS/TEN from staphylococcal scalded skin syndrome. Currently, the differential diagnosis for SJS/TEN includes generalized bullous fixed drug eruption (FDE), TEN-like presentation of systemic lupus erythematosus, vancomycin-induced linear immunoglobulin A (IgA) bullous dermatosis, toxic erythema of chemotherapy (TEC), severe (grade IV) acute graft-versus-host disease, congenital candidiasis in premature infants (<1 kg), acute generalized exanthematous pustulosis, and autoimmune bullous diseases.
Bolognia emphasized that distinguishing between TEN and mimickers requires taking a step back and performing what she calls the “4X” clinical examination, looking at overall distribution patterns rather than the morphology of single lesions. While specific lesions may look like TEN, many of the TEN-mimickers can be identified based on lesion distribution (e.g. limited to major body folds) and areas of skin sparing (e.g. in generalized bullous FDE).
Next, Bolognia used patient cases to describe TEN mimickers and strategies to distinguish them. Generalized bullous FDE is an entity that can be misdiagnosed as TEN. Bolognia described a patient admitted four times for genital bullae and sloughing that was attributed to his worksite and then girlfriends. While the groin lesions resembled those seen in TEN, there were large areas of skin sparing, pointing to the diagnosis of generalized bullous FDE. In this patient, the generalized bullous FDE was caused by naproxen.
Bolognia noted that TEN and generalized bullous FDE can be confused with one another because they may share similar histological features (for ~50% of patients generalized disease is the initial presentation and therefore may lack melanophages), and the two disorders are caused by similar drugs, including non-steroidal anti-inflammatory agents and sulfonamide antibiotics. On the other hand, SJS often initially resembles a morbilliform eruption, but over time duskiness, fragility, vesicles or bullae followed by sloughing (“wet cigarette paper”), and mucosal erosions develop.
Some patients with vancomycin-induced linear IgA bullous dermatosis (LABD) can have a TEN-like presentation. This can even occur in patients previously diagnosed with TEN who initially improve then worsen as patients with an impaired skin barrier who develop a fever are routinely administered vancomycin. This is because the skin is presumed to be the source of an infection. Direct immunofluorescence of a skin biopsy specimen allows distinction.
TEC is an umbrella term for skin diseases that occur 2-4 weeks after chemotherapy. TEC has a distinct distribution pattern and may affect major body folds, hands and feet, and elbows and knees. It is bilateral, symmetrical, and usually associated with pain and burning rather than itching. Histological features of chemotherapy-treated skin include enlarged cell and nuclear size, nuclear pleomorphism, loss of polarity of epidermal cells, and keratinocyte crowding. In TEC, vacuolar degeneration and necrotic keratinocytes are additional histological findings and may be misinterpreted as changes of SJS.
TEC is commonly associated with the chemotherapy administered for acute myeloid leukemia, conditioning for an allogeneic hematopoietic stem cell transplant, and the antibody-drug conjugate enfortumab vedotin. TEC will recur if the same treatment dose is given again; therefore, optimal treatment involves collaborating with the hematology-oncology team and the pharmaceutical company to alter the regimen or reduce the dose if no other drug is available. Bolognia emphasized that severe TEC begins in the usual distribution pattern but generalizes rapidly, “like the worst sunburn you’ve ever seen.” Patients with severe TEC often become septic due to a similar process in the gastrointestinal tract and usually do not survive.
Immune checkpoint inhibitors (ICIs) can cause SJS/TEN or the related disorder, progressive immunotherapy-related mucocutaneous eruption (PIRME). PIRME tends to develop in the setting of a more “benign” rash (e.g. morbilliform, lichenoid) and evolves more slowly than SJS/TEN, is less severe with less mucosal disease, and occurs after an average of 4 cycles of therapy. Ipilimumab, pembrolizumab, and nivolumab are the most commonly used ICIs and are those most likely to cause SJS/TEN and PIRME.
Finally, Bolognia discussed treatments for SJS/TEN. Those for TEN include cyclosporine, IV immunoglobulin, a short course of high-dose corticosteroids, tumor necrosis factor inhibitors (e.g. etanercept), and Janus kinase inhibitors.
Generalized bullous FDE treatment is based on severity. Supportive care is sufficient if <20% of body surface area (BSA) is affected; corticosteroids can be used if >50% BSA is affected. Appropriate treatment for 25–50% BSA disease depends on the patient.
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