Hubbry Logo
Stevens–Johnson syndromeStevens–Johnson syndromeMain
Open search
Stevens–Johnson syndrome
Community hub
Stevens–Johnson syndrome
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Stevens–Johnson syndrome
Stevens–Johnson syndrome
Stevens–Johnson syndrome
View on Wikipedia
from Wikipedia

Stevens–Johnson syndrome
Man with characteristic skin lesions of
Stevens–Johnson syndrome
SpecialtyDermatology
SymptomsFever, skin blisters, skin peeling, painful skin, red eyes[1]
ComplicationsDehydration, sepsis, pneumonia, multiple organ failure.[1]
Usual onsetAge < 30[2]
CausesCertain medications, certain infections, unknown[2][1]
Risk factorsHIV/AIDS, systemic lupus erythematosus,genetics, certain medications [1]
Diagnostic method<10% of the skin involved, skin biopsy[2]
Differential diagnosisChickenpox, staphylococcal epidermolysis, staphylococcal scalded skin syndrome, autoimmune bullous disease, Smallpox[3]
TreatmentHospitalization, stopping the cause[2]
MedicationPain medication, antihistamines, antibiotics, corticosteroids, intravenous immunoglobulins[2]
PrognosisMortality ~7.5%[1][4]
Frequency1–2 per million per year (together with TEN)[1]

Stevens–Johnson syndrome (SJS) is a type of severe skin reaction.[1] Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN) overlap, they are considered febrile mucocutaneous drug reactions and probably part of the same spectrum of disease, with SJS being less severe.[1][5][3] Erythema multiforme (EM) is generally considered a separate condition.[6] Early symptoms of SJS include fever and flu-like symptoms.[1] A few days later, the skin begins to blister and peel, forming painful raw areas.[1] Mucous membranes, such as the mouth, are also typically involved.[1] Complications include dehydration, sepsis, pneumonia and multiple organ failure.[1]

The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics and nevirapine.[1] Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus, or the cause may remain unknown.[2][1] Risk factors include HIV/AIDS and systemic lupus erythematosus.[1]

The diagnosis of Stevens–Johnson syndrome is based on involvement of less than 10% of the skin.[2] It is known as TEN when more than 30% of the skin is involved and considered an intermediate form when 10–30% is involved.[3] SJS/TEN reactions are believed to follow a type IV hypersensitivity mechanism.[7] It is also included with drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis in a group of conditions known as severe cutaneous adverse reactions (SCARs).[8]

Treatment typically takes place in hospital such as in a burn unit or intensive care unit.[2] Efforts may include stopping the cause, pain medication, antihistamines, antibiotics, intravenous immunoglobulins or corticosteroids.[2] Together with TEN, SJS affects 1 to 2 people per million per year.[1] Typical onset is under the age of 30.[2] Skin usually regrows over two to three weeks; however, complete recovery can take months.[2] Overall, the risk of death with SJS is 5 to 10%.[1][4]

Signs and symptoms

[edit]

SJS usually begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore treated with antibiotics. SJS, SJS/TEN, and TEN are often heralded by fever, sore throat, cough, and burning eyes for 1 to 3 days.[9] Patients with these disorders frequently experience burning pain of their skin at the start of disease.[9] Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips, but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis occurs in about 30% of children who develop SJS.[10] A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.[11]

Causes

[edit]

SJS is thought to arise from a disorder of the immune system.[11] The immune reaction can be triggered by drugs or infections.[12] Genetic factors are associated with a predisposition to SJS.[13] The cause of SJS is unknown in one-quarter to one-half of cases.[13] SJS, SJS/TEN, and TEN are considered a single disease with common causes and mechanisms.[9]

Individuals expressing certain[specify] human leukocyte antigen (i.e. HLA) serotypes (i.e. genetic alleles), genetical-based T cell receptors, or variations in their efficiency to absorb, distribute to tissues, metabolize, or excrete (this combination is termed ADME) a drug are predisposed to develop SJS.[citation needed]

Medications

[edit]
See also: List of SJS-inducing substances

Although SJS can be caused by viral infections and malignancies, the main cause is medications.[14] A leading cause appears to be the use of antibiotics, particularly sulfa drugs.[13][15] Between 100 and 200 different drugs may be associated with SJS.[16] No reliable test exists to establish a link between a particular drug and SJS for an individual case.[14] Determining what drug is the cause is based on the time interval between first use of the drug and the beginning of the skin reaction. Drugs discontinued more than 1 month prior to onset of mucocutaneous physical findings are highly unlikely to cause SJS and TEN.[9] SJS and TEN most often begin between 4 and 28 days after culprit drug administration.[9] A published algorithm (ALDEN) to assess drug causality gives structured assistance in identifying the responsible medication.[14][17]

SJS may be caused by the medications rivaroxaban,[18] vancomycin, allopurinol, valproate, levofloxacin, diclofenac, etravirine, isotretinoin, fluconazole,[19] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,[20] lamotrigine, nevirapine,[9] pyrimethamine, ibuprofen,[21] ethosuximide, carbamazepine, bupropion, telaprevir,[22][23] and nystatin.[24][25]

Medications that have traditionally been known to lead to SJS, erythema multiforme, and toxic epidermal necrolysis include sulfonamide antibiotics,[9] penicillin antibiotics, cefixime (antibiotic), barbiturates (sedatives), lamotrigine, phenytoin (e.g., Dilantin) (anticonvulsants) and trimethoprim. Combining lamotrigine with sodium valproate increases the risk of SJS.[26]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a rare cause of SJS in adults; the risk is higher for older patients, women, and those initiating treatment.[27] Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. Similar to NSAIDs, paracetamol (acetaminophen) has also caused rare cases[28][29] of SJS. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.[11]

Infections

[edit]

The second most common cause of SJS and TEN is infection, particularly in children. This includes upper respiratory infections, otitis media, pharyngitis, and Epstein–Barr virus, Mycoplasma pneumoniae and cytomegalovirus infections. The routine use of medicines such as antibiotics, antipyretics and analgesics to manage infections can make it difficult to identify if cases were caused by the infection or medicines taken.[30]

Viral diseases reported to cause SJS include: herpes simplex virus (possibly; is debated), AIDS, coxsackievirus, influenza, hepatitis, and mumps.[13]

In pediatric cases, Epstein–Barr virus and enteroviruses have been associated with SJS.[13]

Recent upper respiratory tract infections have been reported by more than half of patients with SJS.[13]

Bacterial infections linked to SJS include group A beta-hemolytic streptococci, diphtheria, brucellosis, lymphogranuloma venereum, mycobacteria, Mycoplasma pneumoniae, rickettsial infections, tularemia, and typhoid.[13]

Fungal infections with coccidioidomycosis, dermatophytosis and histoplasmosis are also considered possible causes.[13] Malaria and trichomoniasis, protozoal infections, have also been reported as causes.[13]

Pathophysiology

[edit]

SJS is a type IV hypersensitivity reaction in which a drug or its metabolite stimulates cytotoxic T cells (i.e. CD8+ T cells) and T helper cells (i.e. CD4+ T cells) to initiate autoimmune reactions that attack self tissues. In particular, it is a type IV, subtype IVc, delayed hypersensitivity reaction dependent in part on the tissue-injuring actions of natural killer cells.[31] This contrasts with the other types of SCARs disorders, i.e., the DRESS syndrome which is a Type IV, Subtype IVb, hypersensitivity drug reaction dependent in part on the tissue-injuring actions of eosinophils[31][32] and acute generalized exanthematous pustulosis which is a Type IV, subtype IVd, hypersensitivity reaction dependent in part on the tissue-injuring actions of neutrophils.[31][33]

Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8+ T cells or CD4+ T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the antigen presentation pathways of the innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell (APC) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC); and presents the MHC-associated peptides to T-cell receptors on CD8+ T cells or CD4+ T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms (HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR) can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. In all these cases, however, a non-self epitope must bind to a specific HLA serotype (i.e. variation) in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite.[34][35] Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes:[36] Studies have identified several HLA serotypes associated with development of SJS, SJS/TEN, or TEN in response to certain drugs.[31][37] In general, these associations are restricted to the cited populations.[38]

In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15.[39][40][41] A study in Europe suggested the gene marker is only relevant for East Asians.[42][43] This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered.[9]

Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (phenotype frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."[44]

Other HLA associations with the development of SJS, SJS/TEN, or TEN and the intake of specific drugs as determined in certain populations are given in HLA associations with SCARs.

T-cell receptors

[edit]

In addition to acting through HLA proteins to bind with a T-cell receptor, a drug or its metabolite may bypass HLA proteins to bind directly to a T-cell receptor and thereby stimulate CD8+ T or CD4+ T cells to initiate autoimmune responses. In either case, this binding appears to develop only on certain T cell receptors. Since the genes for these receptors are highly edited, i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) T-cell receptors while an individual express only a fraction of these, a drug's or its metabolite's ability to induce the DRESS syndrome by interacting with a T cell receptor is limited to those individuals whose T cells express a T cell receptor(s) that can interact with the drug or its metabolite.[34][45] Thus, only rare individuals are predisposed to develop SJS in response to a particular drug on the bases of their expression of specific T-cell receptor types.[36] While the evidence supporting this T-cell receptor selectivity is limited, one study identified the preferential presence of the TCR-V-b and complementarity-determining region 3 in T-cell receptors found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T cell receptors are involved in the development of specific drug-induced SCARs.[37]

ADME

[edit]

Variations in ADME, i.e. an individual's efficiency in absorbing, tissue-distributing, metabolizing, or excreting a drug, have been found to occur in various severe cutaneous adverse reactions (SCARS) as well as other types of adverse drug reactions.[46] These variations influence the levels and duration of a drug or its metabolite in tissues and thereby impact the drug's or metabolite's ability to evoke these reactions.[8] For example, CYP2C9 is an important drug-metabolizing cytochrome P450; it metabolizes and thereby inactivates phenytoin. Taiwanese, Japanese, and Malaysian individuals expressing the CYP2C9*3[47] variant of CYP2C9, which has reduced metabolic activity compared to the wild type (i.e. CYP2c9*1) cytochrome, have increased blood levels of phenytoin and a high incidence of SJS (as well as SJS/TEN and TEN) when taking the drug.[8][48] In addition to abnormalities in drug-metabolizing enzymes, dysfunctions of the kidney, liver, or GI tract which increase a SCARs-inducing drug or metabolite levels are suggested to promote SCARs responses.[8][4] These ADME abnormalities, it is also suggested, may interact with particular HLA proteins and T cell receptors to promote a SCARs disorder.[8][49]

Diagnosis

[edit]

The diagnosis is based on involvement of less than 10% of the skin.[2] It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] A positive Nikolsky's sign is helpful in the diagnosis of SJS and TEN.[9] A skin biopsy is helpful, but not required, to establish a diagnosis of SJS and TEN.[9]

Pathology

[edit]
Micrograph showing full-thickness epidermal necrosis with a basket weave-like stratum corneum and separation of the dermis and epidermis, skin biopsy, H&E stain

SJS, like TEN and erythema multiforme, is characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum.

Classification

[edit]

Stevens–Johnson syndrome (SJS) is a milder form of toxic epidermal necrolysis (TEN).[50] These conditions were first recognized in 1922.[27] A classification first published in 1993, that has been adopted as a consensus definition, identifies Stevens–Johnson syndrome, toxic epidermal necrolysis, and SJS/TEN overlap. All three are part of a spectrum of severe cutaneous reactions (SCAR) which affect skin and mucous membranes.[14] The distinction between SJS, SJS/TEN overlap, and TEN is based on the type of lesions and the amount of the body surface area with blisters and erosions.[14] It is agreed that the most reliable method to classify EM, SJS, and TEN is based on lesion morphology and extent of epidermal detachment.[9] Blisters and erosions cover between 3% and 10% of the body in SJS, 11–30% in SJS/TEN overlap, and over 30% in TEN.[14] The skin pattern most commonly associated with SJS is widespread, often joined or touching (confluent), papuric spots (macules) or flat small blisters or large blisters which may also join.[14] These occur primarily on the torso.[14]

SJS, TEN, and SJS/TEN overlap can be mistaken for erythema multiforme.[51] Erythema multiforme, which is also within the SCAR spectrum, differs in clinical pattern and etiology.[14]

Prevention

[edit]

Screening individuals for certain predisposing gene variants before initiating treatment with particular SJS-, TEN/SJS-, or TEN-inducing drugs is recommended or under study. These recommendations are typically limited to specific populations that show a significant chance of having the indicated gene variant since screening of populations with extremely low incidences of expressing the variant is considered cost-ineffective.[52] Individuals expressing the HLA allele associated with sensitivity to an indicated drug should not be treated with the drug. These recommendations include the following.[8][53] Before treatment with carbamazepine, the Taiwan and USA Food and Drug Administrations recommend screening for HLA-B*15:02 in certain Asian groups. This has been implemented in Taiwan, Hong Kong, Singapore, and many medical centers in Thailand and Mainland China. Before treatment with allopurinol, the American College of Rheumatology guidelines for managing gout recommend HLA-B*58:01 screening. This is provided in many medical centers in Taiwan, Hong Kong, Thailand, and Mainland China. Before treatment with abacavir, the USA Food and Drug Administration recommends screening for HLA-B*57:01 in Caucasian populations. This screening is widely implemented.[citation needed] It has also been suggested[by whom?] that all individuals found to express this HLA serotype avoid treatment with abacovir. Current trials are underway in Taiwan to define the cost-effectiveness of avoiding phenytoin in SJS, SJS/TEN, and TEN for individuals expressing the CYP2C9*3 allele of CYP2C9.[53]

Treatment

[edit]

SJS constitutes a dermatological emergency. Patients with documented Mycoplasma infections can be treated with oral macrolide or oral doxycycline.[11]

Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g., intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.[11]

Beyond this kind of supportive care, no treatment for SJS is accepted. Treatment with corticosteroids is controversial. Early retrospective studies suggested corticosteroids increased hospital stays and complication rates. No randomized trials of corticosteroids have been conducted for SJS, and it can be managed successfully without them.[11]

Other agents have been used, including cyclophosphamide and ciclosporin, but none have exhibited much therapeutic success. Intravenous immunoglobulin treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics.

An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision, and a host of other ocular problems. Those with chronic ocular surface disease caused by SJS may find some improvement with PROSE treatment (prosthetic replacement of the ocular surface ecosystem treatment).[54]

Prognosis

[edit]

SJS (with less than 10% of body surface area involved) has a mortality rate of around 5%. The mortality for toxic epidermal necrolysis (TEN) is 30–40%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account.[55] It is helpful to calculate a SCORTEN within the first 3 days of hospitalization.[9] Other outcomes include organ damage/failure, ocular morbidity, and blindness.[56][57] Restrictive lung disease may develop in patients with SJS and TEN after initial acute pulmonary involvement.[9] Patients with SJS or TEN caused by a drug have a better prognosis the earlier the causative drug is withdrawn.[9]

Epidemiology

[edit]

SJS is a rare condition, with a reported incidence of around 2.6[11] to 6.1[27] cases per million people per year. In the United States, about 300 new diagnoses are made each year. The condition is more common in adults than in children.

History

[edit]

SJS is named for Albert Mason Stevens and Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in the American Journal of Diseases of Children in 1922.[58][59]

Notable cases

[edit]

Research

[edit]

In 2015, the NIH and the Food and Drug Administration (FDA) organized a workshop entitled "Research Directions in Genetically-Mediated Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis".[9]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Stevens–Johnson syndrome

View on Grokipedia
from Grokipedia
Stevens–Johnson syndrome (SJS) is a rare, severe, and potentially fatal mucocutaneous reaction characterized by widespread epidermal , leading to skin and detachment, typically involving less than 10% of the . It is part of a spectrum that includes SJS/ (TEN) overlap (10–30% detachment) and TEN (>30% detachment), both of which can result in significant morbidity and mortality due to complications like and multiorgan failure. The condition often begins with flu-like prodromal symptoms such as fever, , and , followed by a painful erythematous that progresses to blisters, erosions, and sloughing of the skin and mucous membranes in areas like the , eyes, and genitals. The primary cause of SJS is an adverse reaction to medications, accounting for over 80% of cases, with common culprits including anticonvulsants (e.g., , ), sulfonamide antibiotics, , and nonsteroidal anti-inflammatory drugs (NSAIDs); symptoms usually appear 1–3 weeks after drug initiation. Less frequently, infections such as or , particularly in children, or rarely vaccinations and , can trigger the syndrome. Genetic factors play a role, with associations like the HLA-B*1502 allele increasing risk in certain populations exposed to specific drugs like . Epidemiologically, SJS affects 2–7 individuals per million annually worldwide, with higher incidence in women, older adults, and those with (up to 1 in 1,000 cases), though overall it remains uncommon. Diagnosis is primarily clinical, based on history of recent exposure, characteristic distribution, and positive Nikolsky sign (epidermal detachment with gentle pressure), often confirmed by showing full-thickness epidermal . Severity is assessed using the SCORTEN score, which predicts mortality based on factors like age, heart rate, and levels. requires immediate hospitalization, preferably in an intensive care or burn unit, with discontinuation of the suspected agent as the cornerstone; supportive measures include fluid resuscitation, wound care, pain control, and infection prevention. Immunomodulatory therapies like intravenous immunoglobulin (IVIG), corticosteroids, or cyclosporine are used controversially, with evidence supporting cyclosporine for reducing progression. Multidisciplinary care involving dermatologists, ophthalmologists, and others is essential to address complications like ocular scarring or respiratory involvement. Prognosis varies by severity, with mortality rates of about 5–10% for SJS, rising to 25–35% for TEN, primarily due to secondary infections or organ failure; survivors may face long-term sequelae such as chronic eye problems, skin dyspigmentation, or nail abnormalities. Prevention focuses on avoiding known triggers in at-risk individuals, including genetic screening for high-risk alleles before prescribing implicated drugs.

Clinical Presentation

Signs and Symptoms

Stevens–Johnson syndrome (SJS) often commences with a prodromal phase lasting 1 to 14 days, featuring nonspecific flu-like symptoms such as fever, , , , malaise, fatigue, and . This initial period may also include stinging eyes, , and upper involvement, with patients appearing generally unwell. The typically precedes the onset of cutaneous manifestations by 1 to 3 days, though it can extend up to a week in some cases. Following the prodrome, a characteristic rash emerges, beginning as tender, erythematous or purpuric macules, often irregularly shaped and starting on the face and upper trunk before spreading to the limbs. These lesions progress rapidly over hours to days, evolving into atypical target-like structures with dusky or grey centers, flaccid bullae, and sheets of epidermal , accompanied by positive where gentle pressure causes epidermal detachment. The skin involvement leads to painful erosions and , with the extent varying from limited patches in milder cases to more widespread ; full progression from rash onset to peak detachment typically occurs within 1 to 3 weeks. Mucous membrane involvement is a hallmark feature, affecting at least two sites in up to 90% of cases and nearly universally in the oral cavity, with painful erosions, ulcers, and hemorrhagic crusts on the , tongue, and buccal mucosa causing severe and . Ocular manifestations include conjunctival hyperemia, , chemosis, and pseudomembrane formation, potentially leading to corneal ulcers and vision impairment if extensive. Genital and anogenital erosions occur in up to 77% of female patients and cause and discomfort, while respiratory tract involvement may present as with erosions extending to the and bronchi. Systemic symptoms accompany the mucocutaneous changes, including persistent high fever, profound , , , and anorexia, reflecting the acute inflammatory response. Multi-organ involvement can manifest as gastrointestinal distress with , , or ; respiratory complications such as ; renal issues including ; and hematologic abnormalities like or . The overall severity correlates with the percentage of affected by detachment, influencing the intensity of symptoms and potential complications.

Classification

Stevens–Johnson syndrome (SJS) is classified based on the extent of epidermal detachment as a percentage of (BSA), forming a spectrum with (TEN). SJS is defined by detachment involving less than 10% of BSA, while the SJS/TEN overlap syndrome involves 10–30% detachment, and TEN is characterized by more than 30% detachment. Prognostic assessment in SJS and related conditions utilizes the SCORTEN score, a validated severity-of-illness index originally developed for TEN but applicable across the spectrum. The score comprises seven independent risk factors, each assigned one point: age greater than or equal to 40 years, heart rate greater than or equal to 120 beats per minute, presence of cancer or hematologic , detached BSA greater than or equal to 10%, serum level greater than 10 mmol/L, serum level less than 20 mmol/L, and serum glucose level greater than 14 mmol/L (equivalent to 252 mg/dL). Mortality risk escalates exponentially with increasing SCORTEN values; for instance, a score of 0–1 predicts approximately 3.2% mortality, while a score of 5 or higher approaches 90%. SJS must be differentiated from , a distinct entity often triggered by infections rather than drugs. Clinically, SJS features atypical, flat target lesions or purpuric macules predominantly on the trunk, accompanied by widespread mucosal erosions and significant epidermal detachment, whereas EM presents with raised, typical target lesions in an acral distribution (extremities) and limited mucosal involvement. Histologically, SJS shows considerable overlap with TEN, including full-thickness epidermal , subepidermal bullae, and a lichenoid lymphocytic infiltrate, with no reliable microscopic criteria to distinguish the two. Classification thus relies primarily on clinical evaluation of detachment thresholds rather than findings alone.

Medications

Medications are implicated in approximately 80% of Stevens–Johnson syndrome (SJS) cases. This association underscores the role of pharmacological agents as primary triggers, often through immune-mediated reactions. The mechanisms typically involve T-cell activation against drug-derived antigens, leading to widespread , though the exact pathways vary by agent. Among the high-risk drugs, stands out, particularly in certain populations where the risk of SJS is substantially increased in carriers of the HLA-B*58:01 allele, with odds ratios exceeding 50. Anticonvulsants, especially aromatic ones like and , are frequently associated, with odds ratios exceeding 100 in population studies. antibiotics, such as cotrimoxazole, account for a significant proportion of cases, often through sulfonamide-specific metabolites that elicit cytotoxic T-cell responses. Nonsteroidal drugs (NSAIDs), notably oxicams like , carry elevated risks due to their reactive metabolites. Fluoroquinolone antibiotics, including and levofloxacin, are also implicated, contributing to about 4% of antibiotic-related SJS globally. The latency period for drug-induced SJS is typically 1-8 weeks following initiation of the offending medication, with symptoms often emerging within 4-28 days. Re-exposure to the same drug can shorten this interval dramatically, sometimes to days, due to primed immune memory. SJS reactions to these medications are generally dose-independent, reflecting an idiosyncratic rather than accumulation. However, first-time exposure to aromatic anticonvulsants like heightens the risk, as the initial sensitization phase amplifies subsequent immune activation. Pharmacogenetic factors play a critical role, particularly the HLA-B*15:02 allele, which confers a substantially increased risk of carbamazepine-induced SJS in Asian populations, with odds ratios up to 348 in . This association has prompted screening recommendations prior to initiating in at-risk groups, such as those of , Thai, or Indian ancestry, to mitigate severe outcomes.

Infections

Infections account for approximately 20% of Stevens-Johnson syndrome (SJS) cases overall, with a higher proportion (up to 30%) in children under 15 years where they predominate as triggers. Among pediatric cases, is the most frequent infectious agent, implicated in up to 50% of infection-associated SJS in some series. Other common pathogens include (HSV) and (), while bacterial infections such as species are occasional contributors. These triggers are particularly relevant in immunocompromised individuals, where viral infections like may exacerbate susceptibility. The mechanism involves infection-induced immune dysregulation, where pathogens like M. pneumoniae provoke a T-cell-mediated response, leading to apoptosis and epithelial damage via pathways such as Fas-FasL interaction and granulysin release. This process often occurs independently of drug exposure, distinguishing it from pharmacological triggers, though molecular mimicry and cytokine dysregulation (e.g., elevated IL-17) contribute to the aberrant immune activation. In children, M. pneumoniae typically precedes SJS by 1-2 weeks, triggering a cascade of cytotoxic T-lymphocyte activity against mucosal and epithelia. Diagnostic clues include preceding respiratory or gastrointestinal symptoms, such as , fever, or in 80% of M. pneumoniae-associated cases, often confirmed by positive , PCR testing, or culture for the implicated pathogen. For HSV, mucosal erosions with viral PCR positivity provide key evidence, while CMV detection via or PCR is critical in immunocompromised patients. A representative example is M. pneumoniae-associated SJS, which frequently presents with minimal cutaneous involvement (e.g., sparse erythematous macules) but severe affecting the oral, ocular, and genital regions, as seen in pediatric outbreaks where respiratory infection precedes the eruption by days to weeks. In such cases, the condition may overlap with reactive infectious mucocutaneous eruption (RIME), emphasizing prominent mucosal disease over widespread skin detachment.

Emerging Triggers

Recent advancements in have identified immune checkpoint inhibitors, such as and nivolumab, as emerging triggers for Stevens–Johnson syndrome (SJS) and (TEN), particularly in cancer patients. These immunotherapies, used to enhance T-cell responses against tumors, have been linked to severe cutaneous adverse events in approximately 0.1-1% of treated individuals, often with a rapid onset within days to weeks following infusion. A of randomized controlled trials confirmed an elevated risk of SJS/TEN with these agents, with symptoms including widespread mucocutaneous erosions and epidermal detachment, necessitating prompt discontinuation and supportive care. As of 2025, data indicate incidence rates of about 6.89 per 10,000 patients treated with ICIs. Targeted anticancer therapies, including BRAF inhibitors (e.g., ) and EGFR inhibitors (e.g., , ), are increasingly associated with SJS/TEN in settings, reflecting the growing use of precision medicine. These agents disrupt specific signaling pathways in cancer cells but can provoke immune-mediated reactions, with case series reporting multiple instances of severe blistering and shortly after initiation. Real-world data highlight a rising incidence of these events, driven by expanded indications for such therapies in diverse malignancies like and non-small cell . Other novel factors include rare associations with vaccinations, such as mRNA vaccines, documented in isolated case reports involving mucosal involvement and skin detachment typically emerging 1-2 weeks post-vaccination. Combinations of with concurrent medications, like anticonvulsants, have also been implicated in localized or multifocal SJS eruptions confined to irradiated fields, underscoring synergistic risks in multimodal . Additionally, illicit substances such as (ecstasy) have been reported to trigger SJS/TEN through direct toxic effects on , with presentations including fever and targetoid lesions. As of 2025, from databases indicates a progressive increase in SJS/TEN cases linked to anticancer therapies since 2020, potentially 2- to 3-fold higher in targeted and immunotherapeutic regimens compared to earlier periods, attributed to broader adoption of these treatments. This trend is compounded by challenges in underreporting, as overlapping toxicities often mask distinct SJS/TEN features, leading to delayed recognition and higher morbidity in patients. Enhanced is essential to quantify these risks accurately.

Pathophysiology

Immune Response Mechanisms

Stevens–Johnson syndrome (SJS) is characterized as a reaction, a delayed T-cell-mediated triggered by drugs or s presented by via (MHC) class I molecules, leading to activation of + cytotoxic T cells. These + T cells infiltrate the and recognize drug-modified peptides, initiating a cytotoxic cascade that targets and causes widespread . Natural killer (NK) cells also contribute to this process by amplifying the T-cell response through similar recognition mechanisms. A primary mediator of keratinocyte apoptosis in SJS is granulysin, a cytotoxic protein expressed and released by activated CD8+ T cells and NK cells from cytotoxic granules. Granulysin levels in blister fluid and serum of SJS patients are significantly elevated and correlate directly with disease severity and extent of epidermal necrosis, making it a key effector molecule in the pathogenesis. This release induces direct damage to keratinocytes, independent of other apoptotic pathways, and contributes to the characteristic epidermal detachment observed in SJS. The Fas-Fas ligand (Fas-FasL) pathway further drives keratinocyte death, with upregulation of FasL on cytotoxic T cells and soluble FasL in patient serum binding to Fas receptors on , activating cascades and causing at the dermo-epidermal junction. This interaction promotes detachment of the epidermis from the , exacerbating tissue damage in lesional skin. A amplifies the immune response in SJS, involving proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which upregulate FasL expression and granulysin production while promoting overall . Additionally, perforin and , released by + T cells, form pores in target cell membranes and activate intracellular pathways, further contributing to keratinocyte destruction and tissue injury. Recent studies as of 2024 have identified additional pathways, including necroptosis mediated by receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins, as well as innate immune activation via the , which amplify death and inflammation in SJS/TEN. The predominance of mucosal involvement in SJS, affecting sites such as the oral, ocular, and genital mucosa in nearly all cases, is a hallmark feature.

Genetic and Pharmacological Factors

Stevens–Johnson syndrome (SJS) exhibits strong genetic predispositions, particularly through associations with specific human leukocyte antigen (HLA) alleles that influence drug-induced immune responses. The HLA-B15:02 allele is strongly linked to carbamazepine-induced SJS/toxic epidermal necrolysis (TEN), with an odds ratio exceeding 100 in Han Chinese populations, where the allele frequency is notably high at 8-10%. This association arises because HLA-B15:02 presents drug-derived peptides to T cells, triggering cytotoxic responses in susceptible individuals. Similarly, the HLA-B*58:01 allele confers a substantial risk for allopurinol-induced SJS/TEN, with odds ratios up to 729-fold in certain ethnic groups such as Han Chinese and Thai patients, where the allele is present in 10-15% of the population compared to less than 1% in Europeans. These HLA variants highlight how genetic markers can predict hypersensitivity by facilitating aberrant T-cell activation against drug-altered self-peptides. Beyond HLA loci, (TCR) involvement plays a critical role in the restricted underlying SJS . Studies have identified a biased TCR repertoire, including specific Vβ chain expansions, in lesional skin and blood of patients reacting to drugs like , where these receptors recognize drug-hapten complexes presented by HLA molecules. For instance, public TCR clonotypes, shared across patients, demonstrate drug-specific , amplifying the inflammatory cascade in genetically primed individuals. This restricted TCR usage underscores the pharmacologically driven, antigen-specific nature of SJS, distinct from polyclonal responses in milder drug eruptions. Pharmacological factors intersect with genetics through polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes, particularly cytochrome P450 (CYP450) enzymes, which modulate the formation of reactive metabolites. Variants in CYP2C9, such as the 3 allele, impair detoxification of drugs like phenytoin, leading to accumulation of immunogenic haptens that provoke SJS in susceptible carriers; this polymorphism reduces enzyme activity by up to 80% and is associated with higher plasma drug levels and adverse outcomes. These metabolic inefficiencies exacerbate risk when combined with HLA predispositions, as slower clearance prolongs exposure to neoantigens. The U.S. Food and Drug Administration (FDA) recommends pre-treatment pharmacogenomic screening for HLA-B15:02 in high-risk Asian populations before initiating carbamazepine, and similarly for HLA-B*58:01 with allopurinol, to mitigate SJS/TEN incidence through alternative therapies. Ethnic variations in SJS incidence are largely attributable to differing frequencies of these risk loci. Asian populations, including , Thai, and Indian groups, experience higher rates of drug-induced SJS (up to 4-6 cases per million annually) due to elevated prevalence of HLA-B15:02 (5-15%) and HLA-B58:01 (6-12%), compared to 1-2 cases per million in Europeans with frequencies below 1%. This disparity emphasizes the need for ethnicity-tailored , as the same drugs pose amplified risks in genetically enriched cohorts.

Diagnosis

Clinical Assessment

Clinical assessment of Stevens–Johnson syndrome (SJS) begins with a thorough history to identify potential triggers and risk factors. Patients should be queried about recent medication exposures, particularly new drugs initiated within 1 to 8 weeks prior to symptom onset, as these are the most common culprits, including anticonvulsants, , sulfonamides, and antibiotics. A history of recent infections, such as Mycoplasma pneumoniae or viral illnesses, should also be elicited, as they can precipitate SJS in a subset of cases. Additionally, inquiring about family history of adverse drug reactions or genetic predispositions, such as HLA-B*1502 alleles, is essential to assess hereditary risks. The physical examination focuses on evaluating the extent of and mucosal involvement to gauge severity and systemic effects. (BSA) affected by epidermal detachment is assessed, with SJS typically involving less than 10% BSA, often presenting as erythematous macules, target-like lesions, or bullae that progress to erosions. A positive Nikolsky sign—epidermal detachment induced by gentle lateral pressure on perilesional —supports the . Mucosal sites are examined for erosions or ulcerations, which occur in over 90% of cases and commonly affect at least two sites, including the oral cavity (lips and buccal mucosa), eyes (), and genitals. are monitored closely for indicators of systemic involvement, such as ( greater than 120 beats per minute), which may signal , , or hemodynamic instability. Differential diagnosis is crucial to distinguish SJS from mimicking conditions, relying on clinical morphology and history. major is differentiated by its more localized, acral distribution of typical target lesions and less severe mucosal involvement, often linked to rather than drugs. presents with widespread superficial epidermal peeling, primarily in children, without significant mucosal erosions or prodromal symptoms, and is caused by staphylococcal exotoxins. Drug reaction with eosinophilia and systemic symptoms (DRESS) is excluded by its features of diffuse rash, facial edema, , and organ involvement (e.g., ) without epidermal . Initial laboratory tests support the clinical evaluation and help inform prognosis via the SCORTEN score. A (CBC) is obtained to detect , , lymphopenia, or , which may indicate or secondary . assess for elevated transaminases signaling hepatic involvement, while renal function tests (including and ) and electrolytes (notably ) evaluate for or metabolic derangements. Upon suspicion of SJS, immediate discontinuation of any potentially causative drugs is imperative to halt disease progression and improve outcomes, as delays can exacerbate mortality risk.

Histopathological Findings

Histopathological examination plays a crucial role in confirming the diagnosis of Stevens–Johnson syndrome (SJS) by revealing characteristic microscopic features of epidermal damage and immune-mediated injury. Key findings include full-thickness epidermal necrosis, where keratinocytes undergo widespread apoptosis progressing to confluent necrosis, often accompanied by satellite cell necrosis—small clusters of apoptotic cells adjacent to larger necrotic areas. At the dermo-epidermal junction, there is typically a sparse lymphocytic infiltrate, predominantly CD8+ T cells, with minimal dermal inflammation, distinguishing it from more inflammatory conditions. Unlike toxic epidermal necrolysis (TEN), which represents the severe end of the spectrum, SJS shows less extensive subepidermal blister formation, with detachment limited to focal areas rather than widespread. Immunohistochemical studies enhance diagnostic specificity by identifying cytotoxic mediators in lesional skin. Lesions are positive for granulysin, a key cytotoxic protein expressed by cytotoxic T cells and natural killer cells, which correlates with death. Similarly, perforin and are detected in the and blister fluid, indicating granule-mediated as a primary mechanism. These markers are absent or minimal in mimics like , aiding differentiation. To optimize diagnostic yield, an early punch (3-4 mm) from perilesional skin is recommended, ideally within the first few days of eruption, as this captures evolving apoptotic changes before secondary non-specific alterations occur. Biopsies from established lesions may show regenerative or , reducing specificity. Despite these features, has limitations; early biopsies can be non-diagnostic or non-specific, showing only subtle vacuolar interface changes that mimic other interface dermatitides such as lichenoid drug eruptions. Clinical correlation remains essential, as overlapping findings with or fixed drug eruptions preclude definitive diagnosis on histology alone. As of 2025, emerging employs single-cell sequencing on research biopsies to profile immune cell subsets and expression in SJS lesions, revealing tissue-specific T-cell activation patterns not visible in standard .

Management

Prevention Strategies

Prevention of Stevens–Johnson syndrome (SJS) primarily focuses on identifying and mitigating risk factors associated with its most common triggers, particularly medications and infections. Pharmacogenetic testing plays a crucial role in high-risk populations. For individuals of Asian ancestry, screening for the HLA-B15:02 allele is recommended before initiating therapy, as this variant is strongly associated with an increased risk of carbamazepine-induced SJS/ (TEN). Similarly, testing for the HLA-B58:01 allele is advised prior to starting in at-risk ethnic groups, including , Thai, and Korean populations, due to its link with allopurinol-related SJS/TEN. These screenings, supported by clinical guidelines, enable personalized prescribing and can significantly reduce incidence in susceptible individuals. To minimize drug-related risks, clinicians should prioritize alternatives to high-risk medications when feasible. Sulfonamide antibiotics, such as sulfamethoxazole, are among the most frequently implicated agents and should be avoided in favor of non-sulfonamide options for susceptible patients. For anticonvulsants like or , slow dose titration—starting at low doses and gradually increasing—helps reduce the likelihood of severe cutaneous reactions. In cases of or (HSV) infections, which can precipitate SJS in vulnerable individuals, prompt initiation of appropriate antimicrobial therapy, such as for or antivirals for HSV, is essential to prevent progression to severe mucocutaneous involvement. Patient education is a key preventive measure, particularly when initiating new . Individuals should be informed to monitor for and promptly report early , such as fever, , or , within the first few weeks of starting a , allowing for immediate discontinuation if needed. On a public health level, the U.S. (FDA) mandates black-box warnings on labels of high-risk drugs like and , highlighting SJS/TEN risks and the need for genetic screening in certain populations. Additionally, surveillance through systems like the FDA Adverse Event Reporting System (FAERS) and the RegiSCAR international registry facilitates ongoing monitoring of SJS cases, informing updated guidelines and risk mitigation strategies.

Acute Treatment Approaches

The primary immediate intervention for Stevens–Johnson syndrome (SJS) is the prompt withdrawal of any suspected causative , as continued exposure can exacerbate the condition and worsen outcomes. Patients with involvement exceeding 10% of (BSA) should be transferred urgently to a specialized burn unit or (ICU) for multidisciplinary management, mimicking the care provided for severe burns to address fluid loss, risk, and epithelial detachment. Supportive therapies form the cornerstone of acute care, focusing on maintaining and preventing secondary complications. Wound care involves gentle cleansing and the use of non-adherent dressings, such as silicone-based or petroleum gauze, to protect denuded and promote re-epithelialization while minimizing trauma. typically requires systemic opioids, administered judiciously to control severe discomfort from mucosal and cutaneous lesions without compromising respiratory function. Nutritional support is critical due to hypermetabolic demands and oral involvement; enteral feeding via nasogastric tube is preferred over parenteral routes to preserve gut integrity and reduce infection risk. Among specific immunomodulatory treatments, intravenous immunoglobulin (IVIG) is frequently administered at doses of 0.5–1 g/kg daily for 3 days to inhibit Fas-mediated apoptosis, though evidence on mortality reduction remains mixed. Cyclosporine, dosed at 3–5 mg/kg/day for up to 7–10 days with subsequent tapering, serves as a steroid-sparing alternative by suppressing T-cell activation and has shown promise in halting disease progression in retrospective studies. The use of systemic corticosteroids remains controversial due to heightened infection risk and lack of consistent benefit; they may be considered in select cases without contraindications, particularly in patients with limited BSA involvement, according to some guidelines. For severe ocular involvement, which occurs in up to 50% of cases and can lead to vision loss, amniotic transplantation is recommended early to reduce inflammation, promote corneal healing, and prevent formation; this involves placing cryopreserved amniotic over the ocular surface, often as a sutureless graft for rapid application. Emerging evidence from 2025 trials supports the use of biologics such as , a TNF-α inhibitor administered as a single 50 mg subcutaneous dose, to accelerate epidermal recovery and lower predicted mortality in corticosteroid-refractory cases, positioning it as a targeted option in specialized centers.

Outcomes and Complications

Short-term Prognosis

The short-term prognosis of Stevens–Johnson syndrome (SJS) and its more severe variant, (TEN), is primarily determined by immediate mortality risks, which vary based on disease extent and patient factors. Mortality rates are approximately 5–10% for SJS, 30% for SJS/TEN overlap, and 30–50% for TEN, with higher rates associated with advanced age, underlying comorbidities such as or , and secondary infections. represents the leading during the acute phase, often exacerbated by extensive barrier loss leading to fluid and imbalances, while multi-organ failure, including respiratory and renal involvement, contributes significantly to fatalities. The SCORTEN (Score of ) model serves as a validated tool for predicting in-hospital mortality, incorporating seven prognostic factors: age ≥40 years, ≥120 bpm, serum urea level >10 mmol/L, serum glucose >14 mmol/L, serum bicarbonate <20 mmol/L, malignancy, and detached body surface area >10%. The mortality probability is calculated using the logistic formula: P(death)=elogit1+elogit,wherelogit=−4.448+1.237×SCORTEN scoreP(\text{death}) = \frac{e^{\text{logit}}}{1 + e^{\text{logit}}}, \quad \text{where} \quad \text{logit} = -4.448 + 1.237 \times \text{SCORTEN score} This yields approximate risks of 3.2% for scores 0–1, 12.1% for score 2, 35.7% for score 3, 58.3% for score 4, and 90% for scores ≥5, enabling clinicians to stratify risk and guide intensive care decisions. For survivors, recovery in the acute phase involves re-epithelialization of the skin, typically occurring over 2–3 weeks, though mucosal may lag. Hospitalization duration averages 2–4 weeks, depending on disease severity and complications, with supportive measures in specialized units such as burn centers or ICUs reducing mortality through optimized fluid management, infection control, and wound care. Early intervention, including prompt withdrawal of the offending drug within 24–48 hours of symptom onset, further improves short-term outcomes by limiting disease progression.

Long-term Effects

Survivors of Stevens–Johnson syndrome (SJS) often face significant ocular sequelae, particularly in cases involving acute eye involvement, which affects up to 80% of patients during the initial phase. Chronic complications include corneal scarring, severe , and vision loss, occurring in 30-50% of those with ocular involvement, potentially leading to permanent or blindness if untreated. , the adhesion of to the , is a common severe manifestation requiring surgical intervention such as amniotic transplantation or to restore ocular surface integrity and prevent further deterioration. Mucocutaneous long-term effects persist in a substantial proportion of survivors, with cutaneous sequelae reported in 23-100% of cases. These include scarring alopecia, resulting from follicular damage during the acute phase, leading to permanent in affected areas. Nail dystrophy, such as onychodystrophy or nail loss, affects nearly all patients and can cause chronic discomfort or functional impairment. Additionally, from scarred and mucous membranes is prevalent, while genital involvement in female survivors often manifests as due to vulvovaginal adhesions or , impacting sexual health and . The psychological burden on SJS survivors is profound, with post-traumatic stress disorder (PTSD) affecting up to 40% , alongside high rates of depression and anxiety stemming from the traumatic experience of severe illness and disfigurement. These mental health issues arise from prolonged hospitalization, body image disturbances, and fear of recurrence, with studies indicating that 17-51% of survivors exhibit PTSD symptoms based on validated scales. Recent 2025 research emphasizes the necessity for routine mental health screening in follow-up care to address these enduring psychosocial impacts and improve overall well-being. Systemic long-term complications, though less common than mucocutaneous or ocular issues, can involve internal organs in severe cases. A 2025 cohort study found that SJS/TEN survivors have an elevated risk of cardiovascular mortality, with hazard ratios of 1.69 for cerebrovascular accidents (95% CI, 1.46-1.96) and 1.55 for ischemic heart disease (95% CI, 1.32-1.82), particularly in the first few years post-diagnosis and among older patients or those requiring intensive care. Gastrointestinal strictures, particularly esophageal stenosis, may develop from mucosal sloughing, necessitating endoscopic dilation or surgical management to alleviate dysphagia and nutritional deficits. Pulmonary fibrosis or chronic lung disease occurs in a subset of patients with respiratory involvement during the acute phase, leading to persistent restrictive lung function and reduced exercise tolerance over years. Rehabilitation for SJS survivors requires a multidisciplinary approach, involving ongoing among ophthalmologists for ocular monitoring and interventions, dermatologists for and mucosal care, and psychologists for support. A November 2025 study underscores the need for improved post-discharge planning, including referrals, vision follow-up, , and coordinated care to address ongoing physical, emotional, and social challenges. This comprehensive follow-up, recommended for at least several years post-discharge, aims to mitigate complications through regular assessments, symptomatic treatments like lubricants for dry eyes or lubricants for , and psychosocial counseling to enhance . Early integration of such care has been shown to reduce the severity of chronic sequelae and support functional recovery.

Epidemiology and History

Incidence and Risk Factors

Stevens–Johnson syndrome (SJS) is a rare severe cutaneous adverse reaction with a global incidence ranging from 1 to 7 cases per million person-years annually in the general population. This rate varies by region and study , with estimates from large cohort analyses showing averages around 3.4 to 5.8 cases per million. In high-risk groups, such as individuals with infection, the incidence is substantially elevated, reaching up to 1000 cases per million per year due to . Demographically, SJS displays a bimodal age distribution, with notable peaks among children under 10 years and adults over 60 years, reflecting vulnerabilities in both pediatric and elderly populations. There is a slight predominance, with female-to-male ratios typically between 1.5:1 and 2:1 across studies, though this varies by subtype and etiology. Major risk factors include HIV-related , which amplifies susceptibility to drug- and infection-triggered reactions; systemic , an autoimmune condition that heightens overall immune dysregulation; genetic predispositions like specific HLA alleles (e.g., HLA-B*1502 associated with reactions); and , where concurrent use of multiple medications increases the likelihood of adverse interactions. Geographic variations show higher incidence in Asian populations, attributed to pharmacogenetic factors such as the elevated prevalence of HLA alleles that predispose to drug-induced SJS/TEN. Seasonal peaks have been observed, often aligning with increased rates, such as outbreaks, with some studies reporting higher cases in summer months. As of 2025, emerging data indicate a rising incidence linked to use in , with progressive annual increases in SJS/TEN cases associated with inhibitors and other anticancer agents.

Historical Context and Notable Cases

Stevens–Johnson syndrome (SJS) was first described in 1922 by American pediatricians Albert Mason Stevens and Frank Chambliss Johnson, who reported cases in two young boys presenting with severe mucocutaneous eruptions, fever, , and , distinguishing it from based on its more extensive involvement and systemic features. Their seminal paper, published in the American Journal of Diseases of Children, marked the initial recognition of SJS as a distinct entity, though early literature often conflated it with Ritter's disease (now known as ), a bacterial toxin-mediated condition with superficial epidermal cleavage that mimicked the blistering but lacked the immune-mediated mucosal damage of SJS. By the 1950s, the condition was more formally delineated as Stevens–Johnson syndrome, coinciding with the introduction of the term "" (TEN) by Alan Lyell in 1956 to describe severe cases with extensive epidermal detachment, establishing SJS and TEN as part of a continuous spectrum based on the percentage of involved (SJS <10%, TEN >30%, overlap 10–30%). Key milestones in understanding SJS followed: in the , epidemiological studies solidified its strong association with medications, particularly sulfonamides, anticonvulsants like , and nonsteroidal anti-inflammatory drugs, with a landmark case-control analysis in 1995 identifying relative risks exceeding 100-fold for certain agents. The brought genetic insights, including the 2004 discovery of a robust link between the HLA-B*15:02 allele and carbamazepine-induced SJS in populations, prompting pharmacogenetic screening recommendations. In the , the SCORTEN prognostic score, developed in 2000 and validated through subsequent cohorts, enabled better risk stratification by incorporating factors like age, , and levels to predict mortality. Notable cases highlight SJS's clinical impact across demographics. Pediatric outbreaks linked to Mycoplasma pneumoniae infection have been documented, such as the 2013 cluster at a children's hospital involving eight confirmed cases among children aged 5–17 years, all with preceding respiratory symptoms and positive M. pneumoniae serology, underscoring infectious triggers in youth. In adults, high-profile instances include the 2010 death of NBA player from SJS complications following antibiotic treatment for in , where severe skin loss prevented oral intake for 11 days, leading to multiorgan failure. More recently, in the 2020s, anonymized reports of immunotherapy-related SJS/TEN have emerged in cancer patients, such as cases triggered by checkpoint inhibitors like , revealing immune activation as a novel precipitant in oncologic settings. Archival data from early 20th-century case series indicate mortality exceeding 50% due to limited supportive care, secondary infections, and , with outcomes improving dramatically to under 10% in modern settings through fluid , wound management, and infection control.

Research Directions

Current Advances

Recent advances in diagnostic tools for Stevens–Johnson syndrome (SJS) and (TEN) have focused on enhancing drug causality assessment beyond traditional algorithms like ALDEN, which is limited by assumptions that reduce precision in attributing specific culprits. A 2025 study highlighted the potential of tests, such as lymphocyte transformation testing (LTT) and cytokine stimulation assays, for improving causality determination, though these remain unvalidated for acute use. Additionally, integrated with IFN-γ assays has shown promise in identifying culprit drugs in drug reactions, including SJS/TEN, by analyzing T-cell responses with higher accuracy than conventional methods. Severity assessment has evolved with refinements to the SCORTEN score, incorporating novel inflammatory s to better predict mortality. The Re-SCORTEN, which adds the to ratio (RHR), improves prognostication in epidermal necrolysis patients by accounting for . A 2025 analysis confirmed that interleukin-6 (IL-6) levels correlate with disease severity and outcomes in SJS/TEN, serving as a potential to refine SCORTEN alongside traditional factors like age and involvement. Therapeutic trials have demonstrated encouraging results for biologic agents in managing SJS/TEN, particularly in reducing epidermal detachment and improving recovery. Etanercept, a tumor factor-α inhibitor, has exhibited efficacy in patients unresponsive to corticosteroids; a 2025 multicenter, open-label study of eight Japanese adults reported median re-epithelialization in 10 days and no deaths, with adverse events unrelated to the drug. Recent reviews and studies support etanercept's role in shortening hospitalization and halting progression, though larger randomized studies are needed. Targeting granulysin, a key cytotoxic mediator, remains an area of interest, with ongoing research into inhibitors showing preclinical promise for mitigating detachment, but clinical trials are still emerging. Guidelines for psychological care in SJS/TEN survivors have integrated routine PTSD screening, informed by 2025 systematic reviews revealing a high burden of sequelae. These reviews, analyzing observational studies, found PTSD prevalence ranging from 17% to 51% among survivors, often persisting beyond one year, and recommend tools like the Impact of Events Scale for early detection during follow-up. A 2025 meta-analysis emphasized systematic psychiatric evaluations for at least one year post-acute phase to address depression, anxiety, and quality-of-life impairments. Links between SJS/TEN and anticancer immunotherapies have prompted enhanced tracking through studies and cohorts, informing safer protocols. A 2025 cross-sectional analysis of inhibitor (ICI) use identified significant associations with SJS/TEN through analysis of over 13 million FAERS reports, with ICI exposure increasing risk (adjusted 9.14), highlighting the need for proactive monitoring in high-risk patients. Registries and retrospective cohorts from 2020-2025 have tracked ICI-induced cases, revealing that anti-TNF therapies can facilitate safe rechallenge while reducing recurrence, thus guiding multidisciplinary management in settings.

Future Investigations

Ongoing research into Stevens–Johnson syndrome (SJS) emphasizes the need for high-quality prospective clinical trials to evaluate therapeutic interventions, as current evidence relies heavily on data and case series. The NATIENS trial, an international multicenter study, aims to identify the most effective management strategies for SJS and (TEN) by examining mechanisms of disease progression and treatment responses, potentially establishing level 1A evidence for supportive care beyond aggressive fluid resuscitation and wound management. Similarly, investigations into systemic immunomodulators such as corticosteroids, intravenous immunoglobulin (IVIG), and cyclosporine seek prospective data on their efficacy in halting disease progression and reducing mortality, with a focus on standardized protocols to address variability in current practices. Emerging therapies targeting specific immune pathways show promise for improving outcomes in SJS/TEN. Janus kinase inhibitors (JAKi), including , , and others, inhibit the activated by interferon-gamma, thereby reducing death and inflammation in preclinical models and off-label clinical use. A 2025 study demonstrated rapid re-epithelialization in seven high-risk TEN patients treated with JAKi, with survival rates exceeding expected mortality based on SCORTEN scores, prompting calls for randomized trials to compare JAKi , optimal dosing (oral versus intravenous), and combinations with inhibitors like . An ongoing phase II trial is specifically assessing tofacitinib's and in SJS/TEN patients, measuring endpoints such as time to re-epithelialization and complication rates. Pharmacogenomic research represents a critical frontier for SJS prevention and , building on established associations like HLA-B*1502 with carbamazepine-induced SJS in Asian populations. Future directions include expanding genome-wide association studies to identify novel susceptibility variants across diverse ethnic groups, integrating , profiling, and regulatory T-cell mobilization to predict risk before drug exposure. Implementation of pre-prescription genetic screening in high-risk scenarios, supported by international networks, could significantly reduce incidence, with ongoing studies exploring lymphocyte transformation tests for improved diagnostic accuracy. For long-term sequelae, particularly chronic ocular complications affecting up to 50% of survivors, investigations prioritize precision medicine approaches using targeted biologics tailored to individual inflammatory profiles. A 2025 study highlighted long-term physical ( and visual impairments), emotional (anxiety, depression), and social (isolation, support gaps) impacts on survivors, emphasizing needs for coordinated multidisciplinary care, referrals, and . Integration of for prognostic modeling, based on multimodal data like imaging and biomarkers, aims to predict severe outcomes and guide early interventions. Nationwide and international registries are advocated to facilitate large-scale data collection, enabling better understanding of disease trajectories and evaluation of novel therapies while addressing barriers such as high treatment costs and access disparities. Multidisciplinary collaborations, including , , and experts, are essential to standardize care and accelerate translation of research findings into clinical practice.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK459323/
  2. https://www.merckmanuals.com/professional/dermatologic-disorders/hypersensitivity-and-reactive-skin-disorders/stevens-johnson-syndrome-sjs-and-toxic-epidermal-necrolysis-ten
  3. https://my.clevelandclinic.org/health/diseases/17656-stevens-johnson-syndrome
  4. https://www.hopkinsmedicine.org/health/conditions-and-diseases/stevens-johnson-syndrome
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7121137/
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC8472007/
  7. https://dermnetnz.org/topics/stevens-johnson-syndrome-toxic-epidermal-necrolysis
  8. https://pubmed.ncbi.nlm.nih.gov/10951229/
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC9245022/
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC4173654/
  11. https://www.pathologyoutlines.com/topic/skinnontumorstevensjohnsonsyndrome.html
  12. https://www.nature.com/articles/s41598-023-40812-3
  13. https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-12-118
  14. https://www.nejm.org/doi/full/10.1056/NEJM199512143332404
  15. https://jamanetwork.com/journals/jamadermatology/fullarticle/2801093
  16. https://empendium.com/mcmtextbook/chapter/B31.II.856.6.
  17. https://ajph.aphapublications.org/doi/full/10.2105/AJPH.93.3.489
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC11283697/
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC2586963/
  20. https://jamanetwork.com/journals/jamadermatology/fullarticle/2818474
  21. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.949520/full
  22. https://academic.oup.com/bjd/article-abstract/184/1/176/6599836
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC3157806/
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC7122590/
  25. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.00023/full
  26. http://www.discoveryjournals.org/medicalscience/current_issue/v28/n154/e159ms3491.pdf
  27. https://journals.sagepub.com/doi/10.1177/000992289103000107
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC12439843/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC4516944/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC12339074/
  31. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00231-5/fulltext
  32. https://pubmed.ncbi.nlm.nih.gov/41250631/
  33. https://onlinelibrary.wiley.com/doi/10.1155/2018/5376476
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC7859912/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC12420621/
  36. https://jeccm.amegroups.org/article/view/8444/html
  37. https://ro-journal.biomedcentral.com/articles/10.1186/1748-717X-5-49
  38. https://pubmed.ncbi.nlm.nih.gov/32109316/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC3890653/
  40. https://www.asco.org/abstracts-presentations/ABSTRACT78382
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC11441865/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC5830968/
  43. https://pubmed.ncbi.nlm.nih.gov/19029983/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC3920257/
  45. https://pubmed.ncbi.nlm.nih.gov/39141587/
  46. https://pubmed.ncbi.nlm.nih.gov/21924464/
  47. https://www.nature.com/articles/jhg201547
  48. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations
  49. https://www.sciencedirect.com/science/article/pii/S1027811713000840
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC5106005/
  51. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis
  52. https://link.springer.com/article/10.1007/s40257-024-00889-6
  53. https://jamanetwork.com/journals/jamadermatology/fullarticle/395955
  54. https://www.nature.com/articles/s41467-024-52990-3
  55. https://www.ncbi.nlm.nih.gov/books/NBK321445/
  56. https://www.worldallergyorganizationjournal.org/article/S1939-4551%2819%2930666-0/fulltext
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC8146560/
  58. https://publications.aap.org/pediatrics/article/119/4/e1002/70169/Mycoplasma-pneumoniae-and-Atypical-Stevens-Johnson
  59. https://www.sciencedirect.com/science/article/pii/S2214250925001775
  60. https://www.mayoclinic.org/diseases-conditions/stevens-johnson-syndrome/symptoms-causes/syc-20355936
  61. https://www.pharmacytimes.com/view/10-black-box-warnings-every-pharmacist-should-know
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC10440110/
  63. http://www.regiscar.org/pdf/regiscarprotocol100312.pdf
  64. https://www.mayoclinic.org/diseases-conditions/stevens-johnson-syndrome/diagnosis-treatment/drc-20355942
  65. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae
  66. https://pmc.ncbi.nlm.nih.gov/articles/PMC2958184/
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC8915395/
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC12097413/
  69. https://pubmed.ncbi.nlm.nih.gov/40657848/
  70. https://emedicine.medscape.com/article/1197450-overview
  71. https://www.sciencedirect.com/science/article/pii/S0022202X1831964X
  72. https://eyewiki.org/Stevens-Johnson_Syndrome
  73. https://www.aao.org/eyenet/article/a-primer-on-stevens-johnson-syndrome
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC10115362/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC8100906/
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC9495335/
  77. https://pmc.ncbi.nlm.nih.gov/articles/PMC12024482/
  78. https://pubmed.ncbi.nlm.nih.gov/32810314/
  79. https://www.jaad.org/article/S0190-9622%2820%2930560-0/fulltext
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC7687230/
  81. https://pubmed.ncbi.nlm.nih.gov/40354513/
  82. https://jamanetwork.com/journals/jamadermatology/fullarticle/2830250
  83. https://www.sciencedirect.com/science/article/pii/0950352892900072
  84. https://www.researchgate.net/publication/13740108_Chronic_Lung_Disease_Following_Stevens-Johnson_Syndrome
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC6122425/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC7236394/
  87. https://jamanetwork.com/journals/jamadermatology/fullarticle/2841453
  88. https://pmc.ncbi.nlm.nih.gov/articles/PMC9945700/
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC5857362/
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC9900641/
  91. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165933
  92. https://onlinelibrary.wiley.com/doi/10.1111/1346-8138.17692?af=R
  93. https://www.jidonline.org/article/S0022-202X1730176-8/fulltext
  94. https://www.ncbi.nlm.nih.gov/books/NBK305397/
  95. https://sajhivmed.org.za/index.php/hivmed/article/view/944/1516
  96. https://www.mdpi.com/1424-8247/17/6/675
  97. https://pmc.ncbi.nlm.nih.gov/articles/PMC5674699/
  98. https://www.sciencedirect.com/science/article/pii/S0022202X17301768
  99. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.607532/full
  100. https://pmc.ncbi.nlm.nih.gov/articles/PMC3826606/
  101. https://pubmed.ncbi.nlm.nih.gov/19217690/
  102. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1646038/full
  103. https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=1000&context=historyofmedicine_presentations
  104. https://www.ncbi.nlm.nih.gov/books/NBK448135/
  105. https://www.sciencedirect.com/science/article/pii/S1027811713000864
  106. https://www.nature.com/articles/428486a
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC5893500/
  108. https://abcnews.go.com/Health/PainNews/manute-bol-lost-life-rare-stevens-johnson-syndrome/story?id=10975735
  109. https://pmc.ncbi.nlm.nih.gov/articles/PMC7093687/
  110. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-39
  111. https://pubmed.ncbi.nlm.nih.gov/40541663/
  112. https://www.sciencedirect.com/science/article/abs/pii/S0091674923011089
  113. https://jamanetwork.com/journals/jamadermatology/fullarticle/2787464
  114. https://pmc.ncbi.nlm.nih.gov/articles/PMC11816709/
  115. https://onlinelibrary.wiley.com/doi/10.1111/1346-8138.17860
  116. https://www.sciencedirect.com/science/article/pii/S1323893025000528
  117. https://onlinelibrary.wiley.com/doi/10.1111/ajd.14613
  118. https://www.researchgate.net/publication/394090290_Prevalence_and_predictors_of_posttraumatic_stress_disorder_in_Stevens_Johnson_syndrome_and_toxic_epidermal_necrolysis
  119. https://jamanetwork.com/journals/jamaoncology/fullarticle/2840512
  120. https://www.nature.com/articles/s41467-024-54180-7
  121. https://clinicaltrials.gov/study/NCT02987257
  122. https://pubmed.ncbi.nlm.nih.gov/32520664/
  123. https://www.nature.com/articles/s41392-024-02122-6
  124. https://clinicaltrials.gov/study/NCT06474078
  125. https://pmc.ncbi.nlm.nih.gov/articles/PMC10955758/
  126. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.588063/full
  127. https://pubmed.ncbi.nlm.nih.gov/40802913/
Add your contribution
Related Hubs
User Avatar
No comments yet.