When a Rare Disease Is Missed: Misdiagnosis of Stevens–Johnson Syndrome and Why It Matters

Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare, life-threatening reactions, most often triggered by medications. Despite their severity, early SJS/TEN is frequently misdiagnosed, delaying withdrawal of the offending drug and appropriate care. For a condition where hours and days matter, misrecognition can significantly worsen outcomes.

As we recognize Rare Disease Month, it is important to examine why SJS/TEN is so often missed, what it is commonly mistaken for, and how diagnostic challenges may intersect with broader health inequities.

Why SJS/TEN Is Commonly Misdiagnosed

SJS/TEN is rare, and many clinicians will encounter few cases during their careers. As a result, early presentations are often interpreted as more common and less severe conditions.

A major review on severe cutaneous drug reactions notes that approximately one-third of patients referred to specialist centers with suspected SJS/TEN ultimately receive a different diagnosis, highlighting the diagnostic uncertainty surrounding this disease¹. This uncertainty is partly driven by the nonspecific nature of early symptoms, which often include fever, malaise, sore throat, and eye discomfort.

At this stage, SJS/TEN may resemble viral illness, allergic drug eruptions, or other more common rashes.

Common Conditions Mistaken for SJS/TEN

The differential diagnosis of SJS/TEN is broad. According to Bachot and Roujeau, the most frequent misdiagnoses include erythema multiforme major, acute generalized exanthematous pustulosis, staphylococcal scalded skin syndrome, autoimmune blistering diseases, and exfoliative dermatitis¹.

This diagnostic overlap is clinically important. Prompt recognition and immediate discontinuation of the causative medication remains the most critical intervention in reducing morbidity and mortality. Delays caused by misdiagnosis allow disease progression and increase the risk of complications.

When SJS Presents Before Skin Detachment

Misdiagnosis is especially likely when SJS/TEN presents before classic skin findings appear.

A published case report describes a young woman who initially presented with fever, conjunctivitis, and superficial keratitis, and was treated for presumed infectious eye disease before developing mucosal erosions and skin involvement consistent with SJS². In this case, ocular symptoms preceded cutaneous findings, delaying diagnosis.

This example illustrates an important point: SJS/TEN may begin with ocular or mucosal symptoms alone, and clinicians outside of dermatology may be the first to encounter the disease.

Rare Disease Status and System-Level Misclassification

Misdiagnosis is not limited to bedside evaluation. Large electronic health record studies demonstrate that accurately identifying true SJS/TEN cases within health systems is challenging.

An analysis of electronic health records covering nearly 60 million individuals found that only a small proportion of cases initially coded as SJS/TEN were confirmed after detailed chart review by dermatologists³. This finding reflects ongoing difficulties in distinguishing SJS/TEN from other severe skin reactions, even at the population level.

For patients, misclassification can lead to delayed referrals, inconsistent documentation, and barriers to long-term follow-up care.

Racial Disparities and Risk Considerations

While SJS/TEN affects individuals of all backgrounds, risk is not evenly distributed across populations.

A large U.S. hospitalization study examining drug-associated SJS/TEN found that Asian and Black patients were disproportionately represented among hospitalized cases, compared with White patients⁴. These disparities were strongly associated with known genetic risk factors, including HLA variants linked to severe drug reactions.

Although this study focuses on incidence rather than misdiagnosis, it raises an important concern: communities at higher risk for SJS/TEN may also be vulnerable to delayed recognition, particularly when combined with underrepresentation in medical education and structural barriers to specialist care.

Why Early Recognition Matters

SJS/TEN carries a substantial risk of mortality, particularly in TEN, and survivors often experience long-term complications affecting the skin, eyes, and mucous membranes.

Across studies, early diagnosis and rapid withdrawal of the offending drug remain the most important factors influencing outcomes¹. Even short delays can allow limited disease to progress to extensive epidermal necrolysis.

The Takeaway

SJS/TEN is rare, but misdiagnosis is common. Early symptoms may resemble benign illnesses, and delayed recognition can have devastating consequences. As we reflect during Rare Disease Month, improving awareness, diagnostic accuracy, and equity in recognition is essential to improving outcomes for all individuals affected by SJS/TEN.

References

1. Bachot N, Roujeau JC. Differential diagnosis of severe cutaneous drug eruptions. American Journal of Clinical Dermatology. 2003;4(8):561–572.

   
   

2. Chan F, Benson MD, Plemel DJA, Mahmood MN, Chan SM. A diagnosis of Stevens–Johnson syndrome in a patient presenting with superficial keratitis. American Journal of Ophthalmology Case Reports. 2018;11:167–169.

   
   

3. Davis RL, Gallagher MA, Asgari MM, et al. Identification of Stevens–Johnson syndrome and toxic epidermal necrolysis in electronic health record databases. Pharmacoepidemiology and Drug Safety. 2015;24(7):684–692.

   
   

4. Lu N, Rai SK, Terkeltaub R, et al. Racial disparities in the risk of Stevens–Johnson syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States. Seminars in Arthritis and Rheumatism. 2016;46(2):253–258.