Stevens-Johnson syndrome (SJS) is a dermatologic emergency, characterized by the presence of epidermal and mucosal bullous lesions involving less than 10% of the total body surface area (TBSA). SJS is a rare disease process with an estimated incidence of 2 to 7 cases per million per year. In its earliest stages, SJS typically presents with a flu-like prodromal phase. This may precede or occur concurrently with the development of a macular rash involving the trunk and face. As the disease progresses, the macular rash coalesces, the involved areas develop bullae, and the epidermal layer eventually sloughs off.
SJS and toxic epidermal necrolysis are considered to be on the spectrum of the same disease process. SJS is the more mild variant with <10% of TBSA involvement. TEN-SJS is an intermediate classification with 10-30% TBSA involvement. TEN is the most severe form, with >30% TBSA involvement. During the acute phase of SJS-TEN, 80% of patients will have ocular involvement. Of note, chronic ocular changes secondary to SJS-TEN develop in 21-29% of pediatric cases and 27-59% of adult survivors. It is recommended that an ophthalmologist be consulted early in the course of suspected cases of SJS to initiate interventions that will lessen the likelihood of developing chronic ocular complications of SJS/TEN.
The exact pathophysiology of Stevens-Johnson Syndrome is unknown. Up to 75% of SJS cases are attributed to delayed drug hypersensitivity reactions to a medication or medication metabolite. In these instances, the responsible drug or drug metabolite is processed by keratinocytes and presented via the major histocompatibility class I complex to CD8 cytotoxic T cells. This leads to the proliferation of cytotoxic T cell primed against the offending agent and initiates the signaling cascade that recruits additional cytotoxic T cells and natural killer cells to the epidermis. Once recruited to the epidermis, cytotoxic T cells and natural killer cells release granulysin, a cationic cytolytic protein. Granulysin disrupts the cellular membrane of target cells, allowing the influx of ions into the target cell. This causes mitochondrial damage and activates apoptosis mediators that results in keratinocyte apoptosis. 
The remaining 25% of SJS cases not attributable to medication hypersensitivity are believed to be caused by an infectious source. The vast majority of these cases are due to Mycoplasma pneumoniae infection. The mechanism for M. pneumoniae induced SJS remains unclear. Potential explanations include molecular mimicry and the hematogenous spread of M. pneumoniae to the epidermis. 
In the case of molecular mimicry, it is hypothesized the body forms antibodies against M. pneumoniae surface antigens. These bacterial surface antigens are similar in structure to self-antigens. The antibodies generated against M. pneumoniae cross react with keratinocytes directly or with soluble serum proteins. Antibodies that cross-react with keratinocytes produce cellular injury through the antibody-antigen interaction and subsequent recruitment of inflammatory mediators. It is speculated that antibodies directed against serum proteins produce circulating immune complexes that deposit within the vasculature. This leads to the development of vasculitis with keratinocyte injury occurring secondary to ischemic changes incurred by the vasculitis.
The alternate hypothesis for keratinocyte injury secondary to M. pneumoniae infection may be related to the hematogenous spread of M. pneumoniae from the lungs to the skin. The presence of M. pneumoniae within the epidermis generates a localized immune response. It is hypothesized that this focal immune response leads to the production of cytokines that generate epidermal bullous lesions. Support for this theory stems from the isolation of M. pneumoniae from within SJS bullous lesions.
SJS, SJS/TEN, and TEN represent a spectrum of the same disease process. The classification between each of these entities is based on the degree of total body surface area involvement.
|SJS - TEN Spectrum||Degree of Total Body Surface Area Involvement|
|Stevens-Johnson/Toxic Epidermal Necrolysis||10-30%|
|Toxic Epidermal Necrolysis||>30%|
Table 1. Classification of SJS and TEN
Stevens-Johnson Syndrome is a clinical diagnosis. Given the grave implications of misdiagnosis, there should be a high index of clinical suspicion for SJS when a patient presents with the constellation of high fever (>102.2), malaise, arthralgia, a macular rash involving the trunk, neck and face, and recent history of new medication exposure or recently increased dosage of an existing medication. The diagnosis of SJS can be confirmed by performing a skin biopsy of an effected area. Histologic analysis of SJS skin lesions reveal partial to full thickness keratinocyte necrosis with minor perivascular lymphohistiocytic infiltrate.
Recent studies have demonstrated that granulysin can be used as a marker for the diagnosis of SJS. Serum granulysin levels are elevated prior to the development of bullous skin lesions, providing a means to confirm the diagnosis of SJS earlier in the disease process. Granulysin can be detected within bullous fluid. The concentration of granulysin within bullous fluid correlates with the severity of the acute phase of SJS and can be used to determine the patient’s prognosis.
In cases where medication hypersensitivity is suspected, attempts should be made to identify the inciting agent. The suspected medication should be discontinued immediately. If the patient has no recent medication exposure, one should have a high suspicion for M. pneumoniae induced SJS and perform serology testing to confirm the diagnosis. It is important to differentiate between drug hypersensitivity and M. pneumoniae associated cases of SJS. Cases of M. pneumoniae SJS are typically more responsive to systemic corticosteroid therapy with a milder cutaneous course, but more severe ocular complications relative to medication induced SJS.
|Drug Class||Members of Drug Class||Medication Uses|
|Xanthine Oxidase Inhibitor||Allopurinol||Reduce uric acid levels|
|Anti-convulsants||Phenytoin, Carbamazepine, Oxcarbazepine, Phenobarbital||Treatment of seizures|
|Antibacterial Sulfonamides||Sulfamethoxazole, Sulfaisodimidine, Sulfadiazine, Sulfonamide||Antibiotics|
|Sodium Channel Blocking Antiepileptic||Lamotrigine||Treatment of seizures|
|Non-Nucleoside Reverse Transcriptase Inhibitor||Nevirapine||HIV anti-viral agent|
|Oxicam NSAIDs||Meloxicam, Piroxicam||Anti-inflammatory agent|
Table 2. Medications commonly implicated in inducing SJS.
Ophthalmic Medications Associated with SJS
Though not commonly associated with inducing SJS, below is a list of oral and topical ophthalmic medications which have been attributed for inciting SJS.
Infectious agents are responsible for inciting up to 25% of SJS. As mentioned above, Mycoplasma pneumoniae is responsible for the vast majority of these cases and accounts for 88% of all non-medication induced cases of SJS. While there is a strong association between Herpes Simplex Virus (HSV) and erythema multiforme (EM), HSV is the causative agent for a minority of SJS cases.
Infectious causes for SJS
- Mycoplasma pneumoniae
- Herpes Simplex
- Varicella Zoster
The incidence of SJS was found to be 100 times higher in individuals infected with HIV relative to the general population. The increased risk in this population is attributed to polypharmacy, immune dysregulation, and the presence of multiple concurrent infections. Medication Exposure Rapid introduction of high dosages of medications associated with SJS further increases a patient’s risk of developing SJS.
It has been discovered that specific HLA subtypes carry an increased risk for development of SJS in various populations after exposure to certain classes of medications. It has also been noted that specific HLA subtypes A*0206 and DQB1*0601 carry increased risk for ocular complications secondary to SJS.
|HLA Subtype||Medication class at greatest risk of inciting SJS|
|A*0206||SJS with ocular disease|
|DQB1*0601||SJS with ocular disease|
Table 3. HLA subtypes associated with SJS.
Acute Phase SJS
The majority of patients with SJS experience a prodromal phase, which may precede or follow the development of the cutaneous findings. The prodromal phase is characterized by a high fever (>102.2), malaise, myalgia, arthralgia, and keratoconjunctivitis. The rash associated with SJS typically presents as ill-defined tender macules on the trunk and face. These macules subsequently coalesce and the skin becomes exquisitely tender. As the disease process progresses, the involved areas of skin transition from confluent macules to vesicles and bullae. These areas of skin will eventually become necrotic and slough off.
The acute phase of SJS typically lasts between 8-12 days, and is followed by re-epithelialization of the denuded areas of skin. This re-epithelialization process occurs over the span of 2-4 weeks. In the interim between the loss of the skin barrier and re-epithelialization, patients are at high risk for developing bacterial infections.
Bilateral conjunctival hyperemia with purulent discharge is the most common ocular finding at initial presentation and is seen in 78% of acute SJS cases (Table 4).  Conjunctivitis may present prior, during or following the development of skin eruptions. As the disease course progresses, inflammatory changes to the ocular surface may lead to the development of bulbar and conjunctival ulcerations with subsequent pseudomembrane formation, epithelial sloughing, anterior uveitis, panophthalmitis, corneal ulceration, and corneal perforation. There is a high correspondence between sites of bulbar and tarsal conjunctival ulceration in the acute phase and development of symblepharon, subconjunctival scarring, and posterior lid margin keratinization in the late phase of SJS. For this reason, it is highly recommended that individuals with SJS with ocular involvement receive thorough exams, including eversion the upper and lower lids to check for sites of bulbar and palpebral conjunctival ulceration. Doing so will allow early recognition and intervention that will lessen the likelihood of these late phase manifestations of SJS and spare the cornea insults secondary to these adnexal changes.
|Time||Ocular Manifestations||Percentage of Patients Affected|
|Day 3||Conjunctival ulceration|
|Superficial punctate epithelial erosions||50%|
|Lid Margin Ulceration|
|Week 7||Subconjunctival scarring|
|Month 3-4||Lid margin keratinization||22%|
|Meibomian gland disease||25%|
|Month 5-11||Dry eye||28%|
|Limbal stem cell failure||8%|
Table 4. Timeline of ocular signs and symptoms in pediatric patients with SJS.
Management of the Acute Phase of SJS
If a potential triggering medication is identified, it should be discontinued immediately to improve prognosis. Rapid discontinuation of inciting medications is associated with a 30% reduction in mortality for each day the drug was discontinued before the progression of the macular rash to bullae. If no medications can be identified, it is sometimes recommended that the patient’s entire home medication regiment be discontinued and serology testing be performed to assess for acute M. pneumoniae infection.
The initial goal of treatment should be to provide essential life support during the acute phase of the disease, Efforts should be taken to maintain as sterile of an environment as possible to lessen the patient’s likelihood of developing an infection and sepsis. During this time, special attention should also be paid to the patient’s hydration status and electrolyte levels. The compromised skin barrier increases the rate of evaporative fluid loss, predisposing individuals to dehydration and hypovolemic shock. Use of systemic steroids during acute stage is controversial due to concerns of increased risks of infection, masking signs of septisemia, delay in re-epithelialization and potentially higher mortality rates.  
Eye Care During the Acute Phase
Patients in the acute phase SJS should have daily ocular exams to monitor for disease progression and development of any infection. Normal saline should be used to rinse away epithelial debris. All SJS patients should receive frequent preservative-free artificial tears and ointments to provide adequate lubrication and reduce epithelial injury. Patients with any corneal or conjunctival epithelial defects should be started on prophylactic topical antibiotics, preferably a fourth generation fluoroquinolone. It is suggested that pseudomembranes and adhesions are lysed daily to decrease risk of symblepharon formation. 
Patients with less than one-third lid margin involvement, conjunctival defects less than 1 cm at greatest diameter, and no corneal epithelial defects are classified as having mild or moderate ocular involvement. Such cases are typically treated with topical moxifloxacin 0.5% four times a day, cyclosporine 0.05% twice daily, and topical steroids (prednisolone acetate 1% four to eight times a day or dexamethasone 0.1% twice daily). Cases demonstrating greater than one-third lid margin involvement, conjunctival defects greater than 1 cm, and corneal epithelial defects are classified as severe or extremely severe. In such patients an amniotic membrane (AM) grafting should be performed in addition to the above mentioned treatment modalities. Ambniotic membrane is placed over the entire ocular surface including bulbar and palpebral conjunctiva and fornices, positioned with a symblephron ring and secured surgically to the lid margins. ProKera (Biotissue), a commercially available amniotic membrane fused to a ring can be used in patients not agreeing to AM transplant or who are too unstable for a surgical procedure. AM grafting should be performed as soon as possible once significant epithelial defects are noted and irreversible scarring occurs after 7 to 10 days. Patients with severe disease may require more then one AM transplant.  Some advocate that there is benefit of AM transplant for all cases of SJS regardless of the degree of ocular involvement.
Chronic Phase SJS
Following the acute phase of SJS, patients remain at risk for developing additional ocular sequelae. This includes symblepharon formation, forniceal shortening, Meibomian gland injury, entropion, trichiasis, punctal occlusion, limbal stem cell deficiency, corneal conjunctivalization, corneal neovascularization, as well as keratinization of the eyelid margins and ocular surface. These ocular surface changes are insidious in nature and might not correlate with the severity of the acute phase. These changes make take years to manifest before becoming clinically apparent and may lead to decreased vision. A SJS survivor who develops a new ocular symptom should be taken seriously as it could herald the onset of chronic ocular SJS. The overall incidence of chronic ocular surface changes is 21-29% in pediatric cases and 27-59% in adult SJS survivors.
Current hypotheses for the pathogenesis of the late ocular surface changes observed in SJS survivors include persistent inflammation of the ocular surface following the acute injury and longstanding surface irritation secondary to repeated ocular surface trauma from adnexal changes incurred in the acute phase. Support for persistent inflammation following the acute phase comes from histologic analysis of the ocular surface of SJS survivors and the successful use of immunomodulatory agents in several case series to prevent the progression of ocular surface changes. 
Late ocular surface changes often point to unrecognized or untreated adnexal changes that cause repeated micro trauma to the ocular surface. This repeated trauma produces longstanding inflammation and leads to the development of persistent epithelial defects, destruction of ocular surface tissue structures, and predisposes the ocular surface to infection. Potential contributing adnexal changes include posterior lid margin keratinization, lagophthalmos, entropion, ectropion, trichiasis, and districhiasis. Of these, the most commonly implicated adnexal change is posterior lid margin keratization.
Presence of longstanding inflammation of the ocular surface leads to the loss of essential ocular surface structures, including palisades of Vogt and Meibomian glands. The palisades of Vogt are contained within the limbus and house the stem cell precursors responsible for replenishing the epithelial cell layer of the cornea. Injury to the palisades and subsequent loss of the limbal stem cells leads to the impaired regeneration the corneal epithelium. This leads to the clouding and conjunctivalization of the cornea, and correlates to a poor prognosis for allogenic corneal transplants. The Meibomian glands produce components of the tear film which hydrates the ocular surface and provides lubrication for the passage of the eyelids across the eye’s surface. In the setting of Meibomian gland dysfunction, there is poor tear film production, leading to the development of superficial punctate keratopathy, and further predisposes the corneal surface to micro trauma.
Treatment of Ocular Manifestations in the Chronic Phase of SJS
As noted above, posterior lid margin keratinization is strongly associated with pathological changes to the cornea that lead to reduced visual acuity. Eyelid margin ulceration in the acute phase is a precursor lesion for development of eyelid margin keratinization. As such, it is highly recommended that patients receive daily, if not more frequent, ophthalmic examinations with fluorescein staining and eversion of the superior and inferior palpebrae to rule out posterior lid involvement. Early identification of eyelid margin involvement allows for preventative measures to lessen the likelihood of eyelid margin keratinization and subsequent development of late corneal changes which could impair vision.
Management options for the posterior lid margin keratinization include topical all-trans retinoic acid, autologous mucosal membrane grafting, and protective scleral contact lenses. Both topical all-trans retinoic acid and autologous mucosal membrane grafting reduce the degree of lid margin keratinization. All-trans retinoic acid provides a non-invasive means to treat keratinization by altering epithelial cell differentiation. Autologous mucous membrane grafting requires surgical excision of the keratinized lid margin and replacement it with mucosal membrane grafted from the oral cavity. 
As opposed to the other methods, scleral lenses do not influence the degree of lid margin keratinization. Instead, scleral lens provide a protective barrier and hydrating tear film layer for the corneal surface thus minimizing the degree of mechanical injury to the cornea from the posterior eyelid margin, trichiasis, districhiasis, and other adnexal changes. PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem, Boston Foundation for Sight, Needham Heights, MA, USA) lens is an example of a custom-made scleral contact lens. The lens is typically filled with unpreserved saline before being placed in the eye and provides a unique microenvironment and sufficient oxygen supply for the cornea. Although it is expensive, PROSE lens has been found to be cost-effective in SJS patients. 
In cases of Meibomian gland dysfunction with poor tear production, treatment options include artificial tears, punctal occlusion, salivary gland transplantation. Artificial tears supplement natural tear production. Punctal occlusion prevents drainage of naturally produced tears, which increases the volume of the tear film on the ocular surface. Salivary gland transplantation involves harvesting of minor salivary glands and transplanting them in the superior and inferior conjunctival fornices. Case studies have demonstrated that salivary gland transplantation improves Schirmer test results, corneal transparency, visual acuity, and patient’s subjective experience of foreign body sensation. This procedure is reserved for severe cases of dry eye with little to no natural tear production.
There have been reports with mixed results of allogeneic limbal stem cell transplantation (LSCT) from a matched donor for SJS patients with limbal stem cell deficiency (LSCD). Delay in reepithelialization has been a major issue.  Since ocular SJS is typically a bilateral process, performing autologous limbal stem cell transplantation is risky due to concerns of compromising the stem cell population of the less effected cornea.
Penetrating keratoplasty has very poor outcomes and graft survival rates in SJS patients. The loss of limbal stem cells also makes epithelialization of the donor corneal surface very difficult following cornea transplant. Post-operative period if often complicated by non-healing epithelial defects, prolonged inflammation, corneal melt and transplant failure. 
In end-stage cases with severe corneal opacification, conjunctivalization, or keratinization refractory to all other treatment measures, keratoprosthesis might be a viable option to improve vision in the effected eye.  Keratoprosthesis (KPro) is replacement of damaged or opacified cornea with an artificial implant. Boston KPro is the most commonly used keratoprosthesis. The Boston type I KPro is reserved for patients with no adnexal change and good tear film overlying the ocular surface. The type II Boston keratoprosthesis is reserved for cases where there are alterations to the adnexa and tear film layer, such as SJS or Mucous Membrane Pemphygoid patients. This type of KPro requires a permanent tarsorraphy with only a small optic protruding through the lids. Modified osteo-odonto-keratoprosthesis uses an autologous uses an autologous tooth root and alveolar bone and is performed much less often than Boston KPro.
Patient mortality rates correlate with the degree of total body surface area involved. The mortality rate of adult patients ranges from 5% for individuals with SJS to 30% for individuals with the more severe TEN. The mortality rate is lower in children, with rates ranging from 0-17% for SJS.  For more specific estimation of mortality, the SCORTEN score can be used on admission to assess the percentage likelihood of patient survival.
Corneal neovascularization and opacification in the subacute phase of SJS are predictive of poor long-term visual outcomes. The vast majority of individuals do not have appreciable visual acuity deficits following the acute stage of SJS.Cases of reduced visual acuity typically occur in the late stage of disease. In these instances, decreased visual acuity was found to correlate with the number of chronic ocular surface complications.
The overall rate of recurrence for SJS-TEN is 7.2%. Causes for recurrence include re-exposure to the inciting medication, exposure to structurally similar medications, and re-exposure to the infectious agents that produced the initial episode of SJS.  Episodes of recurrence typically progress much faster than the initial episode of SJS-TEN, with development of cutaneous lesions occurring within 48 hours of re-exposure.
1. Drug Reaction
Drug reactions represent a type I hypersensitivity reaction to a medication. Drug reactions are much more common than SJS, occurring 1 in 1000 hospitalized patients. This hypersensitivity reaction is mediated by IgE and mast cells, as opposed to the T cell mediated type IV drug hypersensitivity of SJS. Drug reactions are associated with a wheal and pruritic rash that develops shortly after medication exposure and resolves within a few hours. It is important to note that secondary exposure to an inciting medication may lead to anaphylaxis and angioedema, which can compromise the airway.
2. Erythema Multiforme
Erythema multiforme (EM), once considered to be on a spectrum with SJS and TEN/EM, is currently viewed as an independent entity. It is classified into two forms, erythema multiforme minor and erythema multiforme major. The distinction between these two classifications is the presence of mucosal surface involvement. EM minor spares the mucosal surfaces while EM major is associated with mucosal lesions, which may include the ocular surface. The majority of cases last 1-2 weeks and heal without sequelae. The ocular lesions seen in EM major can be severe and lead to the same end ocular changes observed in SJS. Erythema multiforme major is commonly heralded by a prodromal phase with symptoms of fever, fatigue, and weakness. The rash associated with EM may become bullous and involve a significant portion of the total body surface area. Unlike SJS however, the vast majority of cases are secondary to infection with Herpes simplex, and the initial rash is targetoid and arranged in an acrofacial distribution.
3. Toxic Epidermal Necrolysis-like Acute Cutaneous Lupus
TEN-like acute cutaneous lupus is a rare cutaneous manifestation of lupus erythematosus. This syndrome is associated with sheet-like desquamation of sun exposed areas. Histopathology of the effected skin reveals basal cell vacuolization and full epidermal necrosis. Direct immunofluorescence reveals granular deposition of antibodies and complement. Autoantibody titers of anti-nuclear and anti-dsDNA antibodies are typically positive in effected individuals.
4. Drug-induced linear IgA Bullous Dermatosis
Drug-induced linear IgA bullous dermatosis may appear clinically indistinguishable from SJS. The majority of cases present within 1 month following initiation of a new medication. The presenting rash is variable with pediatric cases, and typically demonstrate annular blisters of the lower abdomen, thighs, and groin. This contrasts the rash pattern observed in adult cases, who develop annular lesions restricted to the face, truck, and extensor surfaces. This adult rash pattern mirrors rashes observed in cases of SJS. Histologic analysis of the bullous lesions in drug-induced linear IgA bullous dermatosis reveals subepidermal blistering with a neutrophil predominant infiltrate. Direct immunofluorescence reveals linear IgA deposits at the dermoepidermal junction. This differs from the paucicelluar lymphocytic infiltrate and absence of antibody deposits observed in SJS. Linear IgA may also manifest as mucus membrane pemphigoid which also may be only distinguished on pathology.
Future Treatment Options
Limbal Epithelial Stem Cell (LESC) Transplant
Current research is aiming to develop ex-vivo LESC culturing techniques to generate sufficient levels of LESC for autologous transplantation. Efforts are also being made to generate three dimensional scaffolds to generate a microenvironment to facilitate LESC outgrowth following transplantation. If successful, this will increase the yield of stem cells produced by cell culture while also reducing the total cell count needed for successful LESC colonization and re-epithelialization of the corneal surface.
Granulysin targeted therapy
Granulysin is the key mediator of keratinocyte apoptosis in SJS. The concentration of granulysin was shown to correlate with the severity of SJS, and depletion of granulysin with monoclonal antibodies was shown to increase keratinocyte viability in vitro. It is surprising that there are no ongoing trials to establish the efficacy of anti-granulysin antibody therapy as treatment for acute SJS-TEN at this time, but there is the potential this treatment modality will become the mainstay for SJS management.
In cases of known drug induced SJS, the patient should be warned to avoid the inciting medication and medications with similar drug structures to prevent recurrence. Given the association with specific HLA subtypes and SJS, the patient’s family members should be warned of their risk for developing SJS following exposure to the inciting medication.
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