Unveiling the Spectrum of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Mimics

SSJ/NET

Stevens-Johnson syndrome (SJS) is a life-threatening skin condition that manifests on a spectrum of severity. It begins with a prodrome of high fever, flu-like symptoms, skin sensitivity, and blisters.

The characteristic rash is commonly described as a confluent erythematous macular rash with purpuric centers that blister and peel. SJS involves at least 10% of the body surface area; Toxic epidermal necrolysis (TEN) is diagnosed if the rash involves at least 30% of the body surface.

The characteristic mucosal involvement can cause symptoms such as conjunctival itching and pain when swallowing. The rash usually starts on the torso and face and spreads to the rest of the body, usually sparing the palms and soles. This rash has a positive Nikolsky sign , in which lateral pressure on intact skin causes detachment of the epidermis.

This is an important distinguishing feature to differentiate SJS/TEN from the other life-threatening rashes discussed below. Of these patients, 70 to 100% have mucosal involvement and up to 80% have ocular involvement that causes conjunctivitis and discharge. Given this fact, it is important to perform a thorough ocular and gynecological examination.

Risk factors for developing SJS/TEN include patients with active cancer, HIV, women, and receiving many medications. The most commonly involved medications include trimethoprim-sulfamethoxazole, phenobarbital, carbamazepine, lamotrigine, paracetamol, and chemotherapeutic agents.

Penicillins are cited as the most common antibiotic agent causing SJS/TEN. It is unclear whether this is due to the frequency with which penicillins are prescribed or whether the antibiotic was being used to treat an early cutaneous manifestation of SJS such as a bacterial infection. Therefore, a careful history and chronology must be performed to evaluate the true trigger.

The mainstay of SJS/TEN treatment is supportive treatment.

First, discontinue the causative agent. Local wound care, pain control, and intravenous fluid administration should be continued throughout the course of the illness, much as you would for a burn patient .

A retrospective analysis in 2010 recommended an initial intravenous fluid volume of 2 ml/kg body weight multiplied by the % body surface area with epidermal detachment in the first 24 hours.

They have a high clinical suspicion of secondary infections that are most commonly due to S. aureus and Pseudomonas aeruginosa . Although prophylactic antibiotics are not recommended, skin cultures can help guide therapy.

Studies have shown that, unfortunately, there was no survival benefit for those treated with systemic corticosteroids compared to those treated with usual care.

A useful decision tool for determining the most appropriate clinical setting for your patient’s treatment is the SCORTEN scale (seen below), which can assess disease severity; Those with a score greater than or equal to 2 are recommended for admission to the ICU or burn unit.

As SJS/TEN has a wide range of presentations and a potentially high mortality rate, it is important to distinguish it from other rashes that present similarly. In fact, when the term NET was first suggested in 1956, the document included patients with what has now been differentiated into fixed drug eruptions and staphylococcal scalded skin syndrome (SSSS). Various “mimics” of SJS/TEN that have different prognoses, causes, and management pathways are discussed below.

> Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) is a rare but serious skin reaction that is often confused with SJS/TEN. It is a pharmacological reaction that presents with sterile, non-follicular pustules on an erythematous and edematous base. It is most common on flexing surfaces and is often seen first in intertriginous areas extending to the trunk.

It usually develops quickly and occurs within 24 to 48 hours of starting a medication, unlike SJS, which can begin days or weeks after taking a medication. Oral mucosal involvement is seen in 25%, unlike the majority of people with SJS.

Many medications can cause this reaction, particularly penicillins, quinolones, sulfonamides, and hydroxychloroquine. Fever, leukocytosis, elevation of acute phase reactants, and eosinophilia are often seen. PEAG is usually a clinical diagnosis, but biopsy can confirm it. Additionally, after resolution, a patch test may be helpful in determining the causative agent.

Conveniently, management is very similar to SJS/TEN, consisting primarily of discontinuation of the causative agent and supportive care that generally leads to resolution of the rash within 2 weeks. Topical steroids are useful, but again systemic steroids have no clear benefit.

> Erythema multiforme

Erythema multiforme (EM) is an immune-mediated condition that presents with distinctive target lesions with or without mucosal involvement.

The target lesions are classic, but the rash has a varied presentation that evolves throughout the disease. A significant distinction is that MS lesions tend to be papular as opposed to atypical SJS target lesions which tend to be macular in nature.

When these lesions affect mucosal areas, it is generally called erythema multiforme major. When there is little or no mucosal involvement, it can be described as erythema multiforme minor. Lesions typically develop in 3 to 5 days and resolve within 2 weeks.

There are a variety of risk factors that contribute to the development of MS, including, but not limited to, infections, drugs, malignancies, and autoimmune diseases. However, infections account for approximately 90% of cases, with herpes simplex virus (HSV) being the most common in adults and mycoplasma in children.

Treatment of erythema multiforme is typically symptomatic care, with topical steroids and antihistamines . If mucosal involvement is present, intravenous or oral steroids should be considered.

Severe involvement of the mucous membranes, as occurs with multiforme major, may require hospitalization and a consultation with the ophthalmologist should be considered if ocular involvement is present. It is important to note that treatment of an underlying causative infection does not affect the severity or duration of MS.

> Drug reaction with eosinophilia and systemic symptoms (DRESS)

As the name suggests, it is another serious drug-induced reaction that can be difficult to differentiate.

This syndrome presents with fever, eosinophilia or elevation of atypical lymphocytes, lymphadenopathy, facial edema and generalized discomfort.

This rash usually does not occur until 2 to 8 weeks after drug exposure and may continue or even worsen after withdrawal of the causative agent. Include liver function when ordering laboratory studies, as organ involvement is usually present; most commonly the liver, lungs or kidneys.

Some of the most common drugs that cause DRESS include aromatic anticonvulsants (for example, phenytoin, carbamazepine, and phenobarbital), sulfonamides, allopurinol, and vancomycin. DRESS usually presents with a morbilliform rash beginning on the trunk and upper extremities.

The rash becomes edematous causing periorbital edema of the face. It can take many forms and present with pustules, folliculitis or peeling or even a rare form with mucosal involvement. Therefore, it can be very difficult to diagnose and differentiate from other rashes and requires a high index of suspicion.

Treatment involves topical steroids. Systemic steroids tapered over 6 to 8 weeks are indicated for patients with systemic signs such as hepatitis, pleuritis, pneumonia, and kidney damage. For refractory cases, IVIg and plasmapheresis have been used.

> Pemphigus vulgaris

Pemphigus vulgaris is a chronic autoimmune disease characterized by acantholysis. Destruction of desmosomes in the epidermis results in loss of adhesion between keratinocytes, resulting in painful blisters. These blisters are a positive Nikolsky sign.

The important distinctions of this rash from the others previously discussed are that pruritus is generally absent and there is almost always mucosal involvement, primarily the oral mucosa.

Risk factors include ultraviolet light and medications. Certain thiol drugs, such as penicillamine and captopril, are the most common causative agents. Systemic glucocorticoids are the treatment of choice and are responsible for the rapid control of this disease.

There are also emerging studies investigating the use of rituximab, a monoclonal antibody, or combinations of nonsteroidal systemic immunomodulatory medications such as azathioprine or mycophenolate as an adjunct to glucocorticoids with positive results.

Using these supplements reduces the amount of steroids needed and therefore results in fewer adverse events. For severe refractory cases, IV immunoglobulin may also be beneficial. In these cases, consult a rheumatologist or dermatologist.

> Meningococcemia

One of the first symptoms of meningitis to present is a classic rash that can progress from nonspecific to petechial to hemorrhagic in a matter of hours.

The rash begins as 1-2 mm petechiae on the trunk and lower extremities. Approximately 50% of patients with meningococcemia will present with petechiae.

The degree of thrombocytopenia can be estimated by the presence of these petechiae and therefore raises concern for possible hemorrhagic complications secondary to DIC. These petechiae can merge into a larger purpura. Purpura fulminans is a serious complication that can occur in approximately 15-25% of people with diagnosed meningococcemia.

It is characterized by the acute onset of cutaneous hemorrhage, DIC, and vascular thrombosis. Blisters and vesicles form and can eventually lead to gangrenous necrosis. Unlike many of the rashes we have discussed so far, a meningococcemia rash is a symptom of a pathological process much more extensive than the disease itself.

> Staphylococcal scalded skin syndrome (SSE)

Staphylococcal scalded skin syndrome is a life-threatening skin condition caused by a Staphylococcus aureus bacterial toxin that undergoes hematogenous dissemination from the skin.

It presents with painful erythematous skin that begins primarily in high-friction areas such as skin folds. Flaccid bullae, scaling, and a positive Nikolsky sign characterize the rash.

It is important to note that, unlike SJS/TEN, there is no mucosal involvement and the rash is more superficial. This rash most commonly affects infants and children and may present early with irritability and poor oral intake. If observed in adults, the mortality rate is high, often up to 60% due to the high infection burden, while the mortality rate in infants is 5%.

Treatment is supportive, with antibiotics that cover the staphylococcal infection. Nafcillin, oxacillin, and vancomycin are common options, since most bacteria that cause SEPE are resistant to penicillin. Steroids are contraindicated due to immunosuppression.

> Erythroderma

Erythroderma, also called exfoliative dermatitis, is a rare rash identified by widespread peeling that covers most surfaces of the skin.

It is seen more frequently in the elderly male population. Many causes can cause the rash, including underlying skin conditions, drug reactions, HIV, and cutaneous T-cell lymphoma. The skin is red, hot, itchy, and painful.

The patient often trembles due to heat loss from cutaneous vasodilation. There may be other examination findings that correlate with the underlying cause, such as nail psoriasis; Lymphadenopathy and splenomegaly may be seen in T-cell lymphomas.

The rash has a rapid onset if it is caused by drugs, while it may take longer to develop when it is due to other etiologies. Treatment consists of discontinuation of possible causative medications, supportive care, and topical steroids.