Stevens-Johnson syndrome (SJS) is an acute mucocutaneous disease characterized by sudden high fever, conjunctivitis, skin rash, followed by erosions and blisters on the skin and mucous membranes throughout the body. Toxic epidermal necrolysis (TEN) is a disease type that includes the severe form of SJS. Many cases have a history of drug administration before onset, and it is also a serious adverse drug reaction. This disease was named after American pediatricians Albert Mason Stevens and Frank Chambliss Johnson, who reported two cases of children with fever, conjunctivitis, and erosions of the skin and oral mucosa in 1922. Later, in 1956, Alan Lyell reported toxic epidermal necrolysis (TEN), and both were organized as severe drug eruptions on the same spectrum.
Classification
Area of skin lesions
SJS
Less than 10% of body surface area
SJS/TEN overlap
10–30% of body surface area
TEN
More than 30% of body surface area
The ocular findings of SJS and TEN are similar, making it difficult to distinguish between them based on eye findings alone. Therefore, in ophthalmology, SJS and TEN are often collectively referred to as SJS in a broad sense. The pathogenesis and ocular sequelae are also treated as a nearly common spectrum.
The incidence is extremely rare, with a few cases per million people per year, but it can occur at any age including children, without gender difference. In the United States, an incidence of 12.35 cases per million per year has been reported 8). Mortality rates are high: 4.8% for SJS and 14.8% for TEN 3), with some reports indicating up to 30% for TEN 1).
The frequency of ocular complications in SJS/TEN is about 70%, occurring in 53–88% of adults 8). Severe ocular complications involving both pseudomembrane and corneal/conjunctival epithelial defects are seen in approximately 40% of all SJS/TEN cases 10). Because of the high mortality rate, systemic management is the main focus during the acute phase, but the most common sequelae are ocular disorders, including visual impairment due to severe corneal opacity and dry eye that persist throughout life 11). In cases that progress to corneal epithelial stem cell deficiency, the corneal epithelial cells that should be supplied centripetally from the limbus become insufficient, and tissue with conjunctival-derived blood vessels invades the corneal surface. Since this irreversible change is the core of visual impairment, the quality of acute-phase treatment within a few days of onset is the most important factor determining prognosis 13).
SJS/TEN is often recognized first in pediatrics, dermatology, or emergency departments, but in cases where ocular symptoms precede skin lesions, patients may first visit an ophthalmologist. In the presentation with systemic fever and rash, differentiation from acute bilateral conjunctivitis is always a concern. Therefore, even general ophthalmologists need to facilitate early diagnosis and multidisciplinary treatment through collaboration with other specialties. At the initial visit, systemic symptoms and mucocutaneous findings should be evaluated, and if bilateral conjunctivitis with fever is present, active collaboration with dermatology and emergency departments is necessary. In suspected cases, early hospitalization and aggressive ophthalmologic intervention during the acute phase directly improve visual prognosis.
QWhat is the difference between SJS and TEN?
A
SJS and TEN are diseases on the same spectrum, classified by the area of skin involvement. Less than 10% of body surface area is SJS, 10–30% is SJS/TEN overlap, and more than 30% is TEN. Ocular findings are similar and difficult to distinguish, so in ophthalmology they are collectively referred to as SJS in a broad sense. Mortality rates are 4.8% for SJS and 14.8% for TEN 3). The incidence of severe ocular complications is about 40% of all SJS/TEN cases 10).
Ocular surface photograph of Stevens-Johnson syndrome
Wibowo E, Maharani RV, Sutikno NA. Symblepharon as Ocular Manifestation Post Stevens-Johnson Syndrome: A Rare Case. Romanian Journal of Ophthalmology. 2024 Oct-Dec; 68(466):$2. Figure 1. PMCID: PMC11809831. License: CC BY.
Both eyes are narrowed and cannot open fully; the right anterior segment is covered with scars and granulation tissue, and the left eye shows narrowing and scars after eyelid transplantation. This illustrates severe ocular surface changes in the chronic phase in terms of main symptoms and clinical findings.
Bilateral conjunctival injection, foreign body sensation, and ocular pain: A rash mainly on the trunk occurs simultaneously with or within a few days of the ocular symptoms.
Decreased visual acuity: Caused by corneal and conjunctival epithelial defects in the acute phase and corneal opacity in the chronic phase.
Dryness and photophobia: Persist due to dry eye in the chronic phase.
Malaise and sore throat: Many patients experience these as cold-like prodromal symptoms preceding the onset.
Clinical Findings (Findings Confirmed by Physician Examination)
Bilateral conjunctival injection: Severe injection that occurs almost simultaneously with mucosal and skin rashes.
Pseudomembrane formation: A characteristic finding in the acute phase, adhering to the conjunctival surface in a wing-like fashion.
Corneal and conjunctival epithelial defects: May be extensive. Persistent epithelial defects can lead to corneal infection, melting, or perforation.
Eyelid redness and swelling: In severe cases, the eyelids cannot be opened. Loss of eyelashes may also be observed.
Corneal pseudomembrane: May appear a few days after hospitalization4).
Acute ocular findings are directly linked to severity classification: The acute ocular severity classification by Sotozono et al. divides cases into Grades 0 to 3 based on the presence of pseudomembrane, epithelial defect, and corneal epithelial defect11).
If a patient visits an ophthalmologist before noticing the rash, it may be misdiagnosed as viral conjunctivitis. It is essential to check for fever and systemic rash.
Chronic phase (scarring phase)
Severe dry eye: Almost all cases have tear secretion deficiency due to obstruction of the lacrimal gland ducts. Meibomian gland dysfunction is also frequently present.
Trichiasis: Persists for many years and worsens the ocular surface condition. Often requires epilation 3–4 times per month in line with the hair cycle.
Symblepharon: The fornix disappears and the palpebral conjunctiva adheres to the bulbar conjunctiva.
Conjunctival invasion of the cornea: When corneal epithelial stem cells are lost, conjunctival tissue covers the corneal surface, leading to visual impairment.
Epithelial keratinization: In severe cases, the ocular surface becomes keratinized like skin.
Loss of palisades of Vogt: This is a clinical sign of loss of corneal epithelial stem cells at the limbus.
The severity of ocular complications does not necessarily correlate with the extent of skin lesions. Cases have been reported where the eye not receiving eye drops developed more severe damage than the contralateral eye, indicating that SJS/TEN is fundamentally a systemic immune disease1).
For predicting the development of ocular complications, the presence of pseudomembrane formation, corneal epithelial defects, and conjunctival hyperemia in the acute phase are important factors. A Japanese multicenter study reported that cases with pseudomembrane formation or corneal epithelial defects in the acute phase had a high rate of severe chronic ocular sequelae11). Therefore, during the acute phase, detailed ocular findings should be recorded daily or every few days, and grading should be followed over time.
SJS/TEN is often triggered by drug administration. In children, Mycoplasma infection is often a preceding factor. Many patients experience cold-like symptoms such as malaise and sore throat before onset, and some viral infection is thought to be a trigger, but the detailed mechanism is unknown. The latency period from drug initiation to onset is relatively short, often 4 days to 1 month, with the most frequent onset within 2–3 weeks after starting the suspected drug. However, cases after long-term administration also occur, so the duration of administration alone cannot rule out a causal relationship.
Category of cause
Representative drugs/factors
Antibacterials
Sulfa drugs (e.g., ST combination) are the most common
Antiepileptic drugs
Carbamazepine, phenytoin, lamotrigine
Analgesics and antipyretics
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Uric acid-lowering drugs
Allopurinol
Antineoplastic drugs
Immune checkpoint inhibitors (ICIs)
Infections
Mycoplasma infection (especially in children), herpes simplex virus
Many cases have been reported, especially with antiepileptic drugs. Cases have been reported of onset 35 days after combined use of carbamazepine and phenytoin 3), and of TEN after switching to lamotrigine 7). The contribution of NSAIDs to onset is thought to involve inhibition of prostaglandin production.
In recent years, SJS/TEN caused by immune checkpoint inhibitors (ICIs) has also been reported. In a post-marketing survey of tislelizumab, 3 cases of TEN were identified among 3,795 adverse events 5). The median time to onset of ICI-induced SJS/TEN is 32 days, and a report of 305 cases followed up found 69 deaths 4).
Eye drops can also induce SJS/TEN. A case of systemic SJS/TEN overlap (99% body surface area) has been reported after use of brinzolamide eye drops, a sulfonamide carbonic anhydrase inhibitor1). Systemic absorption through the conjunctiva and nasal mucosa is thought to trigger a systemic immune response in genetically susceptible individuals.
SJS/TEN after COVID-19 vaccination has also been reported 2). Vaccine-induced SJS/TEN tends to develop within 1–8 days, which is shorter than drug-induced SJS/TEN (2–3 weeks) 2).
HLA genotypes are strongly associated with SJS/TEN susceptibility. Testing for HLA-B58:01 before allopurinol administration and HLA-B15:02 before carbamazepine administration is recommended 8). Furthermore, HLA-A*02:06 has been reported to show a strong association in Japanese SJS/TEN patients with severe ocular complications 12). Analysis of these HLA polymorphisms plays an important role in identifying causative drugs and pre-medication screening.
QWhich drugs can cause SJS/TEN?
A
The most common causative drugs are sulfa drugs (antibiotics) and antiepileptic drugs (carbamazepine, phenytoin, lamotrigine), followed by NSAIDs and allopurinol. In recent years, reports due to ICIs (immune checkpoint inhibitors) have also increased 5)6). Eye drops (brinzolamide) can also induce systemic SJS/TEN 1). Onset after COVID-19 vaccination has also been reported 2). Specific HLA polymorphisms such as HLA-B58:01, HLA-B15:02, and HLA-A*02:06 determine susceptibility 8)12).
SJS diagnostic criteria (3 mandatory items)10): (1) Severe mucosal lesions at the mucocutaneous junction (hemorrhagic or congestive), (2) Erosions or blisters covering less than 10% of body surface area, (3) Fever ≥38°C. SJS is diagnosed when all three major items are met. Accessory findings include atypical target-like erythema multiforme, bilateral nonspecific conjunctivitis (corneal epithelial damage and/or pseudomembrane formation), and epidermal necrotic changes on histopathology.
TEN diagnostic criteria (3 mandatory items)10): Blisters, epidermal detachment, or erosions covering more than 10% of body surface area, exclusion of staphylococcal scalded skin syndrome (SSSS), and fever ≥38°C.
Even cases diagnosed as SJS may progress to TEN during the peak phase, so reassessment is necessary after initial evaluation 10).
Grading of Ocular Complications
Grade 0: No ocular lesions. Prophylactic artificial tears are recommended 11).
Grade 1: Conjunctival hyperemia only, no corneal lesions. Antibiotic eye drops 3 times daily and steroid eye drops 6 times daily are recommended 8).
Grade 2: Corneal involvement without pseudomembrane. In addition to the above, amniotic membrane transplantation (Prokera or amniotic membrane transplant; AMT) is recommended8).
Grade 3: Corneal involvement with pseudomembrane. Aggressive treatment including AMT is recommended8).
Systemic severity assessment by SCORTEN: SCORTEN (SCORe of Toxic Epidermal Necrosis) is a widely used scoring system for predicting prognosis in SJS/TEN. It evaluates seven items: age ≥40 years, presence of malignancy, heart rate ≥120/min, epidermal detachment ≥10%, elevated serum urea nitrogen, elevated blood glucose, and low serum bicarbonate. Higher scores indicate increased mortality and help objectively determine the need for intensive care and systemic management. Ophthalmologists contribute to treatment decisions by collaborating with dermatology and emergency departments and sharing SCORTEN.
Slit-lamp examination: Assess pseudomembrane, conjunctival injection, corneal and conjunctival epithelial defects, and symblepharon.
Fluorescein staining: Visualize the extent of corneal and conjunctival epithelial defects.
Conjunctival sac culture: In chronic cases with exacerbation of infection, check for MRSA or MRSE carriage.
Impression cytology: Confirm conjunctival epithelial invasion into the cornea and the presence of goblet cells.
Anterior segment OCT and in vivo confocal microscopy: Useful for evaluating POV and corneal epithelium, and for diagnosing limbal stem cell deficiency8).
HLA genotyping: Used to identify causative drugs and for pre-medication screening8)12).
Viral conjunctivitis: May be misdiagnosed when patients present with only ocular symptoms in the acute phase. Pay attention to systemic fever and rash.
Ocular cicatricial pemphigoid: Similar to chronic cicatrizing keratoconjunctivitis. It is an autoimmune disease with a gradual course; impression cytology and immunohistochemistry are useful for differentiation.
Staphylococcal scalded skin syndrome (SSSS): Must be excluded according to TEN diagnostic criteria. SSSS mainly occurs in children, with epidermal detachment at the granular layer level (superficial), and is histopathologically distinct from TEN, which causes necrosis down to the dermis.
Limbal stem cell deficiency after chemical or thermal injury: Differentiated by history8).
Blepharitis/Meibomian gland inflammation: Considered in the differential diagnosis for chronic eyelid margin changes, but distinguished by the presence or absence of scarring.
Systemic treatment: Steroid pulse therapy (methylprednisolone 500–1,000 mg/day for 3 days, 1–2 courses) is initiated early after onset10). In severe cases, IVIG therapy (0.4–1.0 g/kg/day for 3–5 days) or plasma exchange may be added. Early high-dose administration, as tolerated by the patient’s general condition, is important to suppress the progression of ocular surface inflammation. Options such as cyclosporine (3–5 mg/kg/day), etanercept, infliximab, and other TNF-α inhibitors may be added, with reported efficacy particularly in steroid-resistant or persistent cases. Systemic management in a burn unit or intensive care unit with temperature control, fluid management, nutritional support, and infection prevention is essential, and multidisciplinary team-based comprehensive treatment is provided.
Topical ocular treatment: Betamethasone eye drops or ointment is applied frequently, 6–10 times daily, to prevent symblepharon formation. Antibiotic eye drops are used concomitantly for infection prophylaxis. Whether corneal epithelial stem cells can be preserved is the most important factor determining long-term visual prognosis11)13).
Early amniotic membrane transplantation (AMT): Recommended for Grade 2 or higher8). Reports indicate that 9 out of 10 extremely severe cases achieved BCVA 20/208). Additional antibiotic prophylaxis is needed as infectious keratitis occurs in 35% of cases8). Ophthalmic evaluation within 24–48 hours of onset and early AMT intervention improve visual prognosis13). Amniotic membrane transplantation can be performed by suturing to cover the bulbar conjunctiva, fornix, and palpebral conjunctiva completely, or by using a sutureless ring device such as Prokera. Prokera can be placed in the treatment room, avoiding invasive surgery in the acute phase, and its use is expanding in clinical practice. Amniotic membrane has anti-inflammatory, anti-angiogenic, and anti-scarring properties, and promotes ocular surface wound healing by sustained release of growth factors and anti-inflammatory cytokines.
Chronic Phase Treatment
Dry eye management: Frequent instillation of preservative-free artificial tears, hyaluronic acid eye drops, rebamipide eye drops (promotes mucin production and anti-inflammatory effects), diquafosol eye drops (promotes water and mucin secretion), and punctal plugs are used. Dry eye in the chronic phase of SJS is not simply a decrease in tear volume; it is a complex severe dry eye involving lipid layer abnormalities due to meibomian gland dysfunction, mucin deficiency due to goblet cell loss, and conjunctival epithelial keratinization. Therefore, management with a single agent is difficult, and a multi-drug strategy to supplement each component of the tear film is necessary. Since preservatives worsen keratoconjunctival epithelial damage, preservative-free formulations should be selected for all eye drops whenever possible.
Trichiasis management: Regular epilation every 3–4 times per month according to the hair cycle. For fine, depigmented lashes, titanium forceps or suture forceps are effective. In recurrent cases, eyelid surgery for lash root resection or electrolysis (hair root destruction) is added. Trichiasis after SJS differs from ordinary age-related entropion; it is caused by mild marginal entropion at the posterior lid margin extending to the scar tissue of the lash roots, altering the direction of lash growth. Therefore, not only simple epilation but also active treatment of the underlying scarring of the lid margin is necessary. If long-standing trichiasis is left untreated, it can cause pseudopterygium, corneal astigmatism, and corneal opacity, so early intervention is desirable.
Inflammation management: Low-concentration steroid eye drops suppress chronic inflammation and slow the progression of cicatricial changes. Pay attention to MRSA/MRSE carriage and select appropriate antibiotics based on culture. In SJS/TEN patients with severe ocular sequelae, the carriage rate of MRSA/MRSE in the conjunctival sac is high, which can trigger recurrence of ocular surface inflammation and infectious keratitis. Therefore, regular conjunctival sac cultures and consideration of MRSA-effective antibiotics such as vancomycin or linezolid when necessary are considered. With chronic steroid eye drops, monitor intraocular pressure and secondary glaucoma, and perform regular tonometry.
Scleral lenses and visual rehabilitation: Limbus-supported hard contact lenses and scleral lenses are effective for improving visual function in severe dry eye and irregular ocular surface.
Scleral lenses for visual improvement: For severe dry eye with irregular corneal surface, scleral lenses or limbus-supported large-diameter contact lenses such as BostonSight PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem) are useful. By retaining a buffer solution between the lens and the cornea, they optically correct fine corneal irregularities and maintain a continuous moist environment, suppressing the progression of epithelial damage. Many patients with bilateral SJS experience not only refractive correction but also reduction of pain, photophobia, and foreign body sensation.
For severe visual impairment due to conjunctival tissue invasion into the cornea, limbal stem cell transplantation (LSCT) or cultured mucosal epithelial transplantation is performed. There are three types of limbal stem cell transplantation depending on the surgical technique. A systematic review of autologous limbal stem cell transplantation reported anatomical/functional success rates of 81%/74.4% for conjunctival-limbal autograft (CLAu), 78%/68.6% for simple limbal epithelial transplantation (SLET), and 61.4%/53% for cultivated limbal epithelial transplantation (CLET)9). CLAu and SLET showed significantly better outcomes than CLET (p=0.0048)9).
Cultured mucosal epithelial transplantation includes a method using autologous oral mucosal epithelial sheets, and autologous oral mucosal epithelial transplantation is approved as advanced medical care in Japan13). In cases such as bilateral SJS where autologous limbal tissue is not available, a small amount of the patient’s own oral mucosa is harvested, expanded into an epithelial sheet in culture medium, and then transplanted onto the corneal surface using amniotic membrane or fibrin glue as a carrier. During the preparation of cultured epithelial sheets, a medium supplemented with retinol and EGF is used to eliminate xenogeneic substances. Combination with mitomycin C to suppress fibroblast activity may also be employed. After transplantation, combined use of steroid eye drops and immunosuppressive agents is continued to prevent recurrence of ocular surface inflammation.
Penetrating keratoplasty (PKP) is considered for corneal scarring, but in the absence of limbal stem cells, epithelialization failure is likely, and the prognosis of PKP alone is limited8). Therefore, in severe LSCD, a two-stage surgery is often selected: first, limbal stem cell transplantation or cultured mucosal epithelial transplantation is performed to stabilize the ocular surface, followed by lamellar keratoplasty or penetrating keratoplasty for corneal opacity13).
The Boston keratoprosthesis (KPro) is used as an option for severe cases where vision recovery is difficult with other treatments 8). In particular, for bilateral SJS cases without autograft sources, type II (mucous membrane-covered) using titanium optical and tissue components has been reported as a means to overcome chronic conjunctivalization and eyelid adhesions. However, long-term complications such as glaucoma, retinal detachment, infection, and device exposure are not uncommon, requiring strict lifelong management. In a case of brinzolamide-induced SJS/TEN, PKP was performed for symblepharon and corneal scarring, improving visual acuity to 0.05 1).
Since ocular surface inflammation can recur after ophthalmic surgeries such as cataract surgery, even in mild cases, sufficient anti-inflammatory treatment with oral steroids is necessary postoperatively. Preoperatively, conjunctival sac culture should confirm carriage of MRSA or MRSE, and prophylactic antibiotic eye drops should be administered as needed. For cataract surgery, it is recommended to minimize the wound size, protect the ocular surface with viscoelastic substances, and complete the surgery in as short a time as possible.
QWhat is the most important aspect of treatment in the acute phase?
A
Sufficient anti-inflammatory treatment of the ocular surface in the acute phase is most important. In addition to systemic steroid pulse therapy (methylprednisolone 500–1,000 mg/day for 3 days) 10), frequent administration of topical betamethasone eye drops is necessary. If corneal epithelial stem cells can be preserved in the acute phase, corneal transparency is likely to be maintained. For Grade 2 or higher, adding early amniotic membrane transplantation can be expected to achieve good visual prognosis even in severe cases 8).
The pathophysiology of SJS/TEN is explained by an excessive cellular immune response to drug metabolites against a background of genetic predisposition, followed by widespread epithelial cell apoptosis and secondary inflammation and tissue damage. Although the targeting of epidermal and mucosal epithelial cells is common throughout the body, on the ocular surface, the combination of limbal stem cell location, blood flow, and tear film components makes inflammation more likely to persist and directly leads to loss of tissue regenerative capacity.
SJS/TEN is classified as a type IV (delayed-type) hypersensitivity reaction. Drug metabolites presented on MHC class I molecules play a central role, with CD8+ cytotoxic T lymphocytes (CTLs) being key 5). Activated CD8+ T cells secrete TNF-α and IFN-γ, inducing keratinocytes to produce nitric oxide (NO). This NO promotes keratinocyte death via the Fas/Fas ligand pathway 5). Widespread apoptosis of keratinocytes leads to full-thickness epidermal necrosis and detachment, observed histopathologically as complete necrosis of the epidermal basal layer. Confirming a positive Nikolsky sign and epidermal basal layer necrosis on skin biopsy is useful for differentiating from conditions such as SSSS.
Granulysin has been identified as a major mediator of keratinocyte death in SJS/TEN 5). NK cells also mediate keratinocyte death through binding of the CD94/NKG2C receptor to HLA-E molecules on keratinocytes 5). TNF-α upregulates the expression of cell death-related molecules in the epidermis, ultimately leading to widespread epidermal detachment 5).
Furthermore, there is a theory that vasculitis due to immune complex deposition in the subepithelial vessel walls of the skin and mucous membranes is involved, and microcirculatory disturbances are considered a contributing factor to erosion formation and delayed wound healing. Inhibition of prostaglandin production, a common mechanism of NSAIDs, is also presumed to be involved in the development of SJS/TEN 13).
In the eye, epithelial detachment and loss of hemidesmosomes can occur before immune cell infiltration 8). Basal vacuolization is observed in early keratinocytes despite the absence of immune cells, suggesting cytokine dysregulation prior to immune infiltration 8). This indicates that ocular surface inflammation may precede or occur simultaneously with the systemic drug reaction, providing a rationale for frequent topical steroid administration in the acute phase as a disease-modifying intervention rather than mere symptomatic treatment.
In the late phase, CD8+ cytotoxic T lymphocytes infiltrate and target keratinocytes 8). In the chronic phase, neutrophils persist in conjunctival tissue, potentially driving immune dysregulation and leading to limbal stem cell damage 8). Persistent chronic inflammation progresses conjunctival fibrosis and scarring, leading to goblet cell loss, obstruction of accessory lacrimal glands, and meibomian gland dysfunction, irreversibly disrupting the tear film. To break this chronic cycle, long-term suppression with low-concentration steroid eye drops is necessary even for mild inflammation.
Anatomy and loss mechanism of corneal epithelial stem cells
Corneal epithelial stem cells reside in the basal layer of the limbal epithelium, accounting for less than 1% of all basal cells. These stem cells proliferate and differentiate while migrating centripetally toward the central cornea, maintaining the turnover of the entire corneal epithelium. An anatomical feature of the limbal epithelium is the radial fold structure called the palisades of Vogt (POV), which contains abundant blood vessels, nerves, and a specialized microenvironment that forms the stem cell niche. POV are normally easier to observe in the superior and inferior quadrants, but may not be clearly visible in healthy eyes of individuals aged 10 years or younger or 70 years or older. Therefore, diagnosis is made by combining findings such as conjunctival epithelial invasion and differences in epithelial staining, rather than relying solely on the absence of POV.
When extensive corneoconjunctival epithelial defects occur in the acute phase and limbal stem cells are lost, conjunctiva-derived epithelium covers the corneal surface, leading to opacification and neovascularization. This process is called limbal stem cell deficiency (LSCD) 8). SJS is one of the major causes of chronic LSCD, and in a single-center study of 738 eyes, 10.4% were attributed to SJS 8). In recent years, attempts have been made to objectively diagnose the severity and distribution of LSCD by combining identification of goblet cells via impression cytology, direct observation of POV basal cells using in vivo confocal microscopy, and layer-specific evaluation of epithelial thickness using anterior segment OCT8).
HLA-A02:06 is strongly associated with SJS/TEN with severe ocular complications in Japanese individuals 12). Susceptible HLA types have been identified for specific drugs, such as HLA-B58:01 (allopurinol), HLA-B15:02 (carbamazepine), and HLA-B57:01 (abacavir), and pre-administration screening is increasingly enabling prevention of onset 8). These HLA polymorphisms function as key molecules that regulate interactions between T cell receptors (TCRs) and drugs/drug metabolites. The hapten hypothesis and the p-i (pharmacologic interaction) hypothesis have been proposed, suggesting that the drug molecule itself or its reactive metabolite directly binds to the peptide-binding groove of the HLA molecule, altering the presentation of self-peptides and inducing an abnormal autoreactive T cell response. Elucidation of these molecular mechanisms will provide a foundation for future prevention strategies and safe drug selection.
In PD-1 inhibitor-induced SJS/TEN, PD-L1 expression, which is not normally detected in healthy skin, is significantly upregulated in lymphocytes and keratinocytes 5). This results in keratinocyte death mediated by activated CD8+ T cells 5).
QWhy does permanent damage remain in the cornea?
A
In the acute phase, when corneal epithelial stem cells (located in the basal cells of the limbal epithelium) are lost, regeneration of the corneal epithelium becomes impossible. The corneal surface is covered by conjunctival tissue with blood vessels and connective tissue, becoming opaque and irregular. In the chronic phase, the persistent presence of neutrophils drives immune dysregulation and maintains stem cell damage 8). Obstruction of the lacrimal gland ducts also contributes to tear secretion deficiency, and dry eye and corneal opacity persist throughout life.
With the expanded use of ICIs, reports of SJS/TEN are increasing. In a study of 13 cases of tislelizumab-induced SJS/TEN (China), 9 were male, with a mean age of 73.15 ± 7.13 years 5). Treatment regimens varied, including steroids alone, steroids + IVIG, and steroids + IVIG + cyclosporine, and 12 patients improved 5).
For a case of tislelizumab-induced SJS/TEN that did not improve with initial treatment with steroids and IVIG, a combination of a TNF-α inhibitor (recombinant human TNF receptor II-antibody fusion protein) and blood purification led to improvement 5). The application of TNF-α inhibitors in the treatment of SJS/TEN is attracting attention as a new therapeutic strategy.
Cultured Corneal Epithelial Sheets and Regenerative Medicine
Regenerative medicine for limbal stem cell deficiency has advanced significantly in recent years. By adding retinol and EGF to the culture medium, it has become possible to produce corneal epithelial sheets without feeder cells or serum, and transplant materials free of xenogeneic substances are being applied clinically 13). Autologous oral mucosal epithelial transplantation can be used as an autologous cell source even for bilateral LSCD, and is indicated for severe ocular surface diseases such as SJS 13). SLET is becoming widespread as a simpler and lower-cost procedure among LSCTs, and a review of existing studies has shown superior outcomes compared to CLET 9). Furthermore, a product in which oral mucosal epithelial cell sheets are attached to an amniotic membrane matrix has been launched as a regenerative medical product, and clinical application for bilateral LSCD is progressing. Clinical research on iPS cell-derived corneal epithelial cell sheets is also being conducted in Japan, and they are expected as a next-generation treatment for patients with bilateral disease who cannot obtain autologous cell sources.
It has been reported that sulfonamide eye drops can also cause systemic SJS/TEN. A systemic reaction covering 99% of the body surface area occurred 6 days after starting brinzolamide eye drops 1). It has been shown that absorption through the conjunctiva and nasal mucosa can trigger a systemic immune response in genetically susceptible individuals 1). This finding indicates that even eye drops used in ophthalmology can trigger severe systemic drug eruptions, and careful judgment is required when prescribing to patients with a history of drug allergy.
Cases of SJS/TEN complicated by fulminant type 1 diabetes have been reported 3). It is presumed that a systemic immune response destroys pancreatic β-cells, highlighting the importance of blood glucose monitoring during SJS/TEN management 3). Other systemic complications of SJS/TEN include acute interstitial pneumonia, acute kidney injury, liver dysfunction, and coagulation abnormalities, making continuous monitoring of multiple organs essential in systemic management.
Patients with SJS/TEN who have severe ocular sequelae require a combination of multiple treatments throughout their lives, including corneal transplantation, limbal stem cell transplantation, artificial cornea, and scleral lenses. In addition, ongoing treatment for dry eye, trichiasis, and chronic conjunctivitis, as well as regular visual field and intraocular pressure assessments, and management of secondary glaucoma and cataracts are necessary. Therefore, it is difficult for a single institution or department to manage these patients alone. A long-term follow-up system centered on corneal specialists and multidisciplinary collaboration with dermatology, collagen disease/internal medicine, oral surgery, and rehabilitation are essential. Low vision care and employment support are also important for maintaining patient quality of life, and early introduction of visual rehabilitation is recommended. Regarding medical expense subsidy systems, severe ocular sequelae associated with SJS/TEN may be partially covered under the framework of the designated intractable disease “severe erythema multiforme (acute phase)” and corneal diseases as sequelae, so it is advisable to provide information in collaboration with medical social workers.
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