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Stevens Johnson Syndrome
Cornea
1. Overview, Nomenclature & Clinical Analogy
Exam pearl
- Clinical Analogy: Think of Stevens-Johnson Syndrome as a 'chemical fire' starting on the mucosal surfaces of the body. The conjunctiva is a mucous membrane - when the 'fire' reaches the eye, it triggers an acute inflammatory cascade that burns bridges between epithelium and stroma, replacing them with scar tissue. What you are left with - symblepharon, limbal stem cell deficiency, dry eye - is the architectural rubble of that fire. The ophthalmologist's role is both a firefighter in the acute phase and a reconstruction architect in the chronic phase.
Nomenclature & Spectrum
| Condition | Body-surface-area (BSA) Detachment | Mucous Membrane | Mortality | Key Feature |
|---|---|---|---|---|
| Erythema Multiforme Minor | • Not a Bastuji-Garin category • Original category: bullous erythema multiforme | Minimal | <1% | • Target lesions • Acral |
| Erythema Multiforme Major | • Not a Bastuji-Garin category • Original category: bullous erythema multiforme | ≥1 site | ~3% | • Erythema multiforme + mucosal involvement • Herpes simplex virus (HSV)-triggered |
| Stevens-Johnson Syndrome | <10% | • One or more sites • ≥2 sites commonly | 5–15% | • Drug-induced • Purpuric macules • Flat atypical targets |
| Stevens–Johnson syndrome–toxic epidermal necrolysis (SJS–TEN) Overlap | 10–30% | Mucosal involvement may occur | 20–30% | • Widespread purpuric macules • Flat atypical targets |
| Toxic Epidermal Necrolysis (TEN) | >30% | Almost universal | 25–50% | • Sheet-like epidermal loss |
| Condition | Body-surface-area (BSA) Detachment | Mucous Membrane | Mortality | Key Feature |
|---|---|---|---|---|
| Erythema Multiforme Minor | • Not a Bastuji-Garin category • Original category: bullous erythema multiforme | Minimal | <1% | • Target lesions • Acral |
| Erythema Multiforme Major | • Not a Bastuji-Garin category • Original category: bullous erythema multiforme | ≥1 site | ~3% | • Erythema multiforme + mucosal involvement • Herpes simplex virus (HSV)-triggered |
| Stevens-Johnson Syndrome | <10% | • One or more sites • ≥2 sites commonly | 5–15% | • Drug-induced • Purpuric macules • Flat atypical targets |
| Stevens–Johnson syndrome–toxic epidermal necrolysis (SJS–TEN) Overlap | 10–30% | Mucosal involvement may occur | 20–30% | • Widespread purpuric macules • Flat atypical targets |
| Toxic Epidermal Necrolysis (TEN) | >30% | Almost universal | 25–50% | • Sheet-like epidermal loss |
Exam pearl
- Exam Pearl (Bastuji-Garin Classification, 1993): Stevens-Johnson syndrome (SJS) versus toxic epidermal necrolysis (TEN) is classified by the extent of epidermal detachment and cutaneous-lesion pattern, NOT by the severity of ocular involvement.
- Eyes can be severely affected even in Stevens-Johnson syndrome (<10% body surface area).
- Never dismiss ocular evaluation in “mild” Stevens-Johnson syndrome.
Epidemiology
- Incidence: Stevens–Johnson syndrome (SJS) = 1–6 / million/year; toxic epidermal necrolysis (TEN) = 0.4–1.2 / million/year
- Ocular involvement in acute Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): approximately 50–78%; more frequent in toxic epidermal necrolysis (TEN) than in Stevens–Johnson syndrome (SJS)
- Chronic ocular disease develops in approximately 30–50% of patients who survive acute Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
- Gender: slight female preponderance; all ages affected, drug-induced Stevens–Johnson syndrome (SJS) peaks in adults
- Higher genetic risk of carbamazepine-associated Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in several Southeast Asian populations is associated with the higher frequency of human leukocyte antigen-B15:02 (HLA-B15:02)
2. Etiology & Immunopathogenesis
Common Causative Drugs (High-Yield)
| Drug Category | Specific Agents | Risk / Notes |
|---|---|---|
| Anticonvulsants | • Carbamazepine • Phenytoin • Lamotrigine • Phenobarbital | • Well-established high-risk causative drugs • Human leukocyte antigen (HLA)-B*15:02 is associated with carbamazepine-related Stevens–Johnson syndrome/toxic epidermal necrolysis, particularly in relevant Asian ancestry |
| Sulfonamides | • Co-trimoxazole • Sulfasalazine | • Co-trimoxazole is a commonly implicated antibacterial sulfonamide • Sulfasalazine is a recognized, less frequent causative drug |
| Nonsteroidal anti-inflammatory drugs | • Oxicam class • Piroxicam • Meloxicam | • Oxicam derivatives, particularly piroxicam, have been associated with greater Stevens–Johnson syndrome/toxic epidermal necrolysis risk than several other nonsteroidal anti-inflammatory drug groups • Comparative risk for meloxicam is less certain |
| Allopurinol | • Allopurinol | • Major Stevens–Johnson syndrome culprit in some Asian populations • Human leukocyte antigen (HLA)-B*58:01 is associated with severe allopurinol hypersensitivity reactions, including Stevens–Johnson syndrome/toxic epidermal necrolysis |
| Antibiotics | • Aminopenicillins • Cephalosporins • Quinolones | • Recognized causes of Stevens–Johnson syndrome/toxic epidermal necrolysis • Lower relative risks than antibacterial sulfonamides in a large case-control study |
| Antiretrovirals | • Nevirapine • Abacavir | • Relevant clinical context: human immunodeficiency virus (HIV) patients • Human leukocyte antigen (HLA)-B*57:01 is strongly associated with abacavir hypersensitivity • Not a specific Stevens–Johnson syndrome marker without qualification |
| Checkpoint Inhibitors | • Nivolumab • Pembrolizumab | • Emerging, rare causes • Immunotherapy-related Stevens–Johnson syndrome/toxic epidermal necrolysis-like reactions |
| Drug Category | Specific Agents | Risk / Notes |
|---|---|---|
| Anticonvulsants | • Carbamazepine • Phenytoin • Lamotrigine • Phenobarbital | • Well-established high-risk causative drugs • Human leukocyte antigen (HLA)-B*15:02 is associated with carbamazepine-related Stevens–Johnson syndrome/toxic epidermal necrolysis, particularly in relevant Asian ancestry |
| Sulfonamides | • Co-trimoxazole • Sulfasalazine | • Co-trimoxazole is a commonly implicated antibacterial sulfonamide • Sulfasalazine is a recognized, less frequent causative drug |
| Nonsteroidal anti-inflammatory drugs | • Oxicam class • Piroxicam • Meloxicam | • Oxicam derivatives, particularly piroxicam, have been associated with greater Stevens–Johnson syndrome/toxic epidermal necrolysis risk than several other nonsteroidal anti-inflammatory drug groups • Comparative risk for meloxicam is less certain |
| Allopurinol | • Allopurinol | • Major Stevens–Johnson syndrome culprit in some Asian populations • Human leukocyte antigen (HLA)-B*58:01 is associated with severe allopurinol hypersensitivity reactions, including Stevens–Johnson syndrome/toxic epidermal necrolysis |
| Antibiotics | • Aminopenicillins • Cephalosporins • Quinolones | • Recognized causes of Stevens–Johnson syndrome/toxic epidermal necrolysis • Lower relative risks than antibacterial sulfonamides in a large case-control study |
| Antiretrovirals | • Nevirapine • Abacavir | • Relevant clinical context: human immunodeficiency virus (HIV) patients • Human leukocyte antigen (HLA)-B*57:01 is strongly associated with abacavir hypersensitivity • Not a specific Stevens–Johnson syndrome marker without qualification |
| Checkpoint Inhibitors | • Nivolumab • Pembrolizumab | • Emerging, rare causes • Immunotherapy-related Stevens–Johnson syndrome/toxic epidermal necrolysis-like reactions |
Immunopathogenesis - Step by Step
Exam pearl
- The Core Mechanism:
- Drug (hapten or reactive metabolite) → processed by antigen-presenting cells → presented via human leukocyte antigen (HLA) molecules
- → cytotoxic cluster of differentiation 8-positive (CD8+) T-lymphocyte activation
- → granzyme B and perforin release, with Fas ligand–Fas signaling implicated
- → keratinocyte apoptosis → epidermal–dermal cleavage.
Key Immunological Players:
- Cluster of differentiation 8 (CD8)-positive cytotoxic T cells: Major effector cells in Stevens–Johnson syndrome/toxic epidermal necrolysis skin lesions; cluster of differentiation 8 (CD8)-positive T cells have also been identified in conjunctival and corneal tissues, but their status as the primary effector population in conjunctival epithelium is not established.
- Granulysin: Cytotoxic protein released by cytotoxic T lymphocytes and natural killer cells - a key mediator of disseminated keratinocyte death in Stevens–Johnson syndrome/toxic epidermal necrolysis (Chung et al., 2008).
- Fas ligand (FasL; cluster of differentiation 95 ligand [CD95L]): Fas/Fas ligand (FasL) signaling is implicated in keratinocyte apoptosis in Stevens–Johnson syndrome/toxic epidermal necrolysis; keratinocyte Fas ligand (FasL) expression and an autocrine loop remain controversial.
- Natural killer cells and natural killer T cells: Also contribute to cytotoxicity.
- Tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 6 (IL-6), interleukin 18 (IL-18): Detected or elevated in Stevens–Johnson syndrome/toxic epidermal necrolysis lesions, blister fluid, serum, or ocular samples; may contribute to inflammatory and cytotoxic pathways, but a specific role for all four in sustaining mucosal inflammation is not established.
- Regulatory T cells (Tregs): Suppressive function may be inadequate during acute Stevens–Johnson syndrome/toxic epidermal necrolysis, despite normal frequency; this supports impaired immunoregulation.
Ocular-Specific Pathogenesis:
- Conjunctival epithelial injury and inflammation → pseudomembrane/true membrane formation.
- Goblet cell destruction → impaired mucin component of the tear film.
- Limbal stem-cell destruction → limbal stem-cell deficiency → conjunctivalization of the cornea.
- Meibomian gland dropout → lipid layer deficiency → tear film instability.
- Chronic ocular-surface inflammation and scarring → subconjunctival fibrosis, symblepharon, and forniceal foreshortening.
- Scarring or obstruction of lacrimal duct openings → reduced aqueous tear contribution and severe dry eye.
Exam pearl
- Human leukocyte antigen (HLA) association - pharmacogenomics pearl:
- Human leukocyte antigen (HLA)-B*15:02 → carbamazepine-associated Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN); screen patients with ancestry in genetically at-risk populations before initiation.
- Human leukocyte antigen (HLA)-B*58:01 → allopurinol-associated Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (Han Chinese, Korean, Thai).
- Human leukocyte antigen (HLA)-B*57:01 → abacavir hypersensitivity.
- Human leukocyte antigen (HLA)-A*31:01 → carbamazepine-associated Stevens–Johnson syndrome (SJS) in Japanese/European ancestry.
- Food and Drug Administration (FDA) labeling recommended human leukocyte antigen (HLA)-B15:02 testing before carbamazepine initiation in patients with ancestry in genetically at-risk populations; avoid carbamazepine in human leukocyte antigen (HLA)-B15:02-positive patients unless benefits clearly outweigh risks.
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Keep reading Stevens Johnson Syndrome
12 more sections are included with the Clinical plan.
- Acute Ocular Manifestations
- Chronic Ocular Sequelae
- Investigations
- Management: Acute Phase
- Systemic Therapies
- Management: Chronic Phase & Surgical Rehabilitation