Stevens-Johnson syndrome - Oral Mucosal Lesion
SJS was previously referred to as erythema multiforme major but is now considered a separate entity, having different precipitating factors from erythema multiforme (EM), which is associated with reactivated herpes simplex virus infection. EM is no longer considered to be part of SJS/TEN. Similarly, the entity of reactive infectious mucocutaneous eruption (RIME) should be distinguished from SJS (see Differential Diagnosis section).
While the molecular events and etiology of SJS and TEN are incompletely understood, a medication history is strongly associated with their development in greater than 80% of cases. The primary medications most frequently implicated include allopurinol, NSAIDs, antibiotics, and anticonvulsants. Newer culprits include the immune checkpoint inhibitors and enfortumab vedotin. Additional causes, albeit rare, include immunizations and infections.
Investigations over the past decade have provided strong evidence that SJS and TEN are secondary to the host's inability to detoxify the culprit drug and its metabolites. This results in a cell-mediated immune response that activates cytotoxic T-cells and induces keratinocyte apoptosis via cell surface death receptor signaling.
Photodistributed SJS/TEN is a rarely reported phenomenon. Almost all reported patients have been women on an antibiotic, an anticonvulsant, or NSAID therapy who developed SJS/TEN limited to photoexposed areas 24-72 hours after sun or tanning bed exposure. Sun-covered mucosal surfaces were also affected.
SJS/TEN can affect all ages and races, with a slight preponderance seen in women (1.5:1) and an increasing incidence with age. Studies have linked certain HLA haplotypes and genetic p450 polymorphisms to increased risk of SJS/TEN when exposed to specific medications. AIDS is associated with a thousandfold increased risk of SJS/TEN.
SJS may run an unpredictable clinical course. The onset of disease occurs 1-3 weeks after the ingestion of an antibiotic or within the first 2 months of anticonvulsant treatment. It is typically preceded by nonspecific prodromal symptoms followed by characteristic skin and mucosal lesions.
Prodromal symptoms include fevers, malaise, arthralgias / myalgias, ocular irritation, upper respiratory tract symptoms, and oropharyngeal pain and may precede skin / mucosal findings by 1-3 days. Importantly, cutaneous pain or burning skin is a prominent early feature of SJS/TEN, and its presence could signify an ominous sign of impending necrolysis.
Cutaneous lesions may begin as a more typical exanthematous eruption that evolves to dusky, irregular, ill-defined coalescing macules with purpuric or detached centers. Lesions typically appear first on the central trunk, palms, and soles and then spread to involve the face and proximal extremities. As the disease progresses, large areas of serous blistering and sloughing may occur. Skin is typically painful and tender.
Mucosal lesions: Oral mucosal sloughing and crusting is present in more than 90% of cases and ocular involvement in more than 80%. Urogenital and, more rarely, respiratory and gastrointestinal (GI) mucosa may also be involved.
With secondary infection or severe involvement of the eyes, photophobia, uveitis, panophthalmitis, ulceration, pseudomembrane formation, and scarring may occur. Corneal perforation, lacrimal scarring, xerophthalmia, immobile eyelids, symblepharon, entropion, trichiasis, and blindness may result. An estimated 50%-90% of patients will experience chronic ocular sequelae that may develop as long as 8 years following acute SJS/TEN.
Esophageal, anal, vaginal, and urethral meatal stenosis may be seen. GI bleeding, hepatitis, urinary retention, nephritis, anuria from dehydration and genitourinary injury, myocarditis, pneumothorax, obtundation, and seizures are rare complications. Other involvement includes GI lesions with diarrhea, cystitis, splenic inflammation, arthritis, pneumonitis, otitis media, paronychia, and nail shedding.
Prognosis: SJS carries a 1%-5% mortality risk, may or may not have systemic symptoms, and involves the trunk and face with many isolated lesions. TEN carries a 25%-35% mortality risk, invariably has systemic symptoms, and the lesions on the trunk and face are largely coalesced. Secondary infection of denuded skin plays a significant role in mortality, as does respiratory compromise from mucositis.
Risk factors that confer a worse prognosis include extent of BSA involved, older age, malignancy, number of medications, leukopenias and elevated serum urea, glucose, and creatinine levels. SCORTEN is a prognostic scoring system for patients with epidermal necrolysis that contemplates many of the above-mentioned risk factors and several others.
Rapid identification and withdrawal of the offending drug and transfer to a burn unit with aggressive supportive care are the most critical steps in management.
Long-term ocular and genitourinary follow-up is vital in mitigating complications.
Related topic: postacute sequelae of SJS and TEN
L51.1 – Stevens-Johnson syndrome
73442001 – Stevens-Johnson syndrome
- Erythema multiforme (EM) – Histologic features may not differentiate EM from SJS/TEN. Clinically, however, EM has characteristic target lesions (3 concentric colors that are round and well demarcated) that occur on the extremities more often than the trunk. Precipitating factors are usually infectious (typically herpes simplex virus) but may include medications. Lesions may be papular or vesicular but do not result in widespread desquamation. Note that EM is not considered within the same disease spectrum as SJS/TEN and confers no risk in progressing to TEN. Nikolsky sign is negative. Other implicated infections include influenza, hepatitis, Epstein-Barr viruses, Yersinia, tuberculosis, histoplasmosis, and coccidioidomycosis.
- RIME – Mucositis accompanied by no or mild cutaneous involvement, usually of vesicles or tense bullae secondary to mycoplasma or other infection. Oral and usually ocular mucositis is pronounced relative to skin findings.
- Paraneoplastic pemphigus – Patients often have a history of previously diagnosed lymphoid malignancy such as chronic lymphocytic leukemia or lymphoma. This condition is generally present for longer than SJS.
- Pemphigus vulgaris – This immunobullous disease usually has a more insidious onset than SJS, and cutaneous lesions often will not appear for months after the oral lesions have developed.
- Acute graft-versus-host disease – There is a history of hematopoietic cell transplantation within the past 100 days.
- Hand-foot-and-mouth disease – The oral ulcers and erythematous cutaneous macular lesions in this condition are much smaller compared with those of SJS and the disease is not necrolytic but will often show palmar lesions.
- Bullous pemphigoid – This tends to affect an older population than SJS, and oral involvement is seen in only 20% of cases without the hemorrhagic lip crusts.
- Methotrexate-induced mucocutaneous toxicity