Stevens-Johnson Syndrome

From EyeWiki
Original article contributed by: Arden H. Wander, MD, John Kroger
All contributors: Arden H. Wander, MD and Maria A. Woodward, MD
Assigned editor:
Review: Assigned status Not reviewed by Vatinee Bunya, MD on February 17, 2017.



Stevens-Johnson Syndrome
Classification and external resources
OMIM 608579
DiseasesDB 4450
MeSH D013262


Introduction

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.[1]

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.[1] Of note, chronic ocular changes secondary to SJS-TEN develop in 21-29% of pediatric cases and 27-59% of adult survivors.[2] 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.[1]

Pathophysiology

The exact pathophysiology of Stevens-Johnson Syndrome is unknown. In the majority of cases of SJS, up to 75% are attributed to delayed drug hypersensitivity reactions to a medication or medication metabolite.[3] 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. [4][5][6]

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.[3] The mechanism for M. pneumoniae induced SJS remains unclear. Potential explanations include molecular mimicry and the hematogenous spread of M. pneumoniae to the epidermis. [7]

In the case of molecular mimicry, it is hypothesized the body forms antibodies against M. pneumoniae surface antigens. These surface antigens are similar in structure to self-antigens, and 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.[5]

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.[7]

Disease Classification

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.[1]

SJS - TEN Spectrum Degree of Total Body Surface Area Involvement
Stevens-Johnson Syndrome <10%
Stevens-Johnson/Toxic Epidermal Necrolysis 10-30%
Toxic Epidermal Necrolysis >30%

1. Nirken MH, High WA, Roujeau J-C. StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. August 2015. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis. Accessed October 17, 2016.

Diagnosis

Stevens-Johnson Syndrome is a clinical diagnosis. Given the grave implications of misdiagnosis, physicians should have 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 and face, and recent history of new medication exposure or recent 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.[1]

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.[8] Granulysin is able to 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.[4]

Physicians should go beyond the diagnosis of SJS and attempt to identify the inciting agent. In cases which medication hypersensitivity is suspected, the inciting 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.[1] 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.[7]

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, and arthralgia.[9] The rash associated with SJS typically presents as ill-defined macules on the trunk and face. These macules subsequently coalesce, and the skin becomes tender to the touch. The skin becomes exquisitely tender and pain is well out of proportion to the relatively benign appearance of the skin at the early stages. 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.[1]

Most cases of SJS are attributed to a delayed hypersensitivity reaction to medications. In a review of patients with SJS, 74% of cases reported a history of recent initiation of a new medication or an increase in medication dosage.[3] 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 recommended the the patient’s entire home medication regiment be discontinued and serology testing be performed to assess for acute M. pneumoniae infection.[1]

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. 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.[1]

The most common ocular finding at initial presentation is bilateral conjunctival hyperemia with purulent discharge.1 This was noted to be present in 78% of acute SJS cases[2], and may present prior, during, or following the development of skin eruptions.[3] 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.[10] 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.[1] 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 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.

Visual acuity is rarely impacted in the acute setting of SJS, with 90% of cases maintaining 20/40 vision or better at one-year follow-up. Specific factors in the acute phase that were predictive of poor visual outcomes were corneal neovascularization and opacification.[1] These corneal changes are typically observed in the late stage or chronic form of SJS, and occur secondary to chronic inflammation of the ocular surface resulting in subsequent loss of the Limbal stem cells.

Timeline of Ocular Symptoms within a Population of Pediatric Patients with SJS

Time Ocular Manifestations Percentage of Patient Population Effected
Day 1 Conjunctivitis 78%
Subconjunctival hemorrhage 33%
Conjunctival membranes 28%
Day 3 Conjunctival ulceration
Superficial punctate epithelial erosions 50%
Epithelial defects 25%
Lid Margin Ulceration
Week 4 Symblepharon 28%
Ankyloblepharon 11%
Week 5-6 Trichiasis 8%
Anterior blepharitis 6%
Punctal auto-occlusion 8%
Week 7 Subconjunctival scarring
Month 3-4 Lid margin keratinization 22%
Meibomian gland disease 25%
Corneal opacification 11%
Month 5-11 Dry eye 28%
Districhiasis 11%
Limbal stem cell failure 8%
Corneal vascularization 8%

[2] Catt CJ, Hamilton GM, Fish J, Mireskandari K, Ali A. Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children. Am J Ophthalmol. 2016;166:68-75.

Medication-Induced SJS

The up to 75% of SJS cases are attributed to a delayed medication hypersensitivity reaction.3 The most common inciting medications are listed in the table below.

Drug Class Members of Drug Class Medication Uses
Xanthine Oxidase Inhibitor Allopurinol Reduce uric acid levels
Aromatic Anti-convulsants Phenytoin, Carbamazepine, Oxcarbazepine, Phenobarbital Prophylactic prevention of seizures
Antibacterial Sulfonamides Sulfamethoxazole, Sulfaisodimidine, Sulfadiazine, Sulfonamide15 Antibiotics
Sodium Channel Blocking Antiepileptic Lamotrigine Prophylactic prevention of seizures
Non-Nucleoside Reverse Transcriptase Inhibitor Nevirapine HIV anti-viral agent
Oxicam NSAIDs Meloxicam, piroxicam, Anti-inflammatory agent

[1]Nirken MH, High WA, Roujeau J-C. StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. August 2015. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis. Accessed October 17, 2016.

[11]Chantachaeng W, Chularojanamontri L, Kulthanan K, Jongjarearnprasert K, Dhana N. Cutaneous adverse reactions to sulfonamide antibiotics. Asian Pac J Allergy Immunol. 2011;29(3):284-9.

[12]Sriram A, Sreya K, Lakshmi PN. Steven Johnson syndrome and toxic epidermal necrolysis: A review. International Journal of Pharmacological Research. 2014;4(4):158-165. doi:10.7439.

Ophthalmic Medications

Though not commonly associated with inducing SJS, below is a list of ophthalmic medications which were attributed for inciting SJS.

Ophthalmic Medications implicated for inducing SJS

Oral Agents

  • Sulfonamides
  • Doxycycline
  • NSAIDs


Topical Agents

  • Scopolamine
  • Tropicamide
  • Sulfonamide


[13]Harper S. Stevens Johnson Syndrome.

Infectious Agents

Infectious agents are responsible for inciting up to 25% of SJS. Mycoplasma pneumoniae is responsible for the vast majority of these cases, accounting for 88% of all non-medication induced cases of SJS.[3] A comprehensive list of infectious agents attributed for inciting SJS is listed below. Included in this list is Herpes simplex virus (HSV). While there is a strong association between HSV and erythema multiforme (EM), HSV is the causative agent for a minority of SJS cases.[14][15]

Infectious causes for SJS

  • Mycoplasma pneumoniae
  • Cytomegalovirus
  • Herpes Simplex
  • Streptococcus
  • Yersinia
  • Adenovirus
  • Measles
  • Varicella Zoster


[13]Harper S. Stevens Johnson Syndrome.

[16]Iyer G, Srinivasan B, Agarwal S, Pillai VS, Ahuja A. Treatment Modalities and Clinical Outcomes in Ocular Sequelae of Stevens-Johnson Syndrome Over 25 Years--A Paradigm Shift. Cornea. 2016;35(1):46-50.

Risk Factors

HIV

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.[1] Medication Exposure Rapid introduction of high dosages of medications associated with SJS further increases a patient’s risk of developing SJS.[1]

HLA Subtypes

It has been discovered that specific HLA subtypes carry an increased risk for development of SJS 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.[1][12]

HLA Subtype Medication class at greatest risk of inciting SJS
A*0206 SJS with ocular disease
A2 NSAIDs
A29 Sulfonamides
B12 Sulfonamides, NSAIDs
B15:02 Aromatic anticonvulsants
B58:01 Allopurinol
DR7 Sulfonamides
DQB1*0601 SJS with ocular disease

[1]Nirken MH, High WA, Roujeau J-C. StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. August 2015. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis. Accessed October 17, 2016.

[12]Sriram A, Sreya K, Lakshmi PN. Steven Johnson syndrome and toxic epidermal necrolysis: A review. International Journal of Pharmacological Research. 2014;4(4):158-165. doi:10.7439.

Treatment of Ocular Manifestations in the Acute phase of SJS

A recent publication by Dr. Darren G. Gregory created a grading system to assess and guide treatment of ocular lesions during the acute phase of SJS. This grading system categorizes the severity of SJS as mild, moderate, severe, and extremely severe based on the degree of lid margin, cornea, and conjunctival involvement. Cases demonstrating less than one-third lid margin involvement, conjunctival defects less than 1 cm at greatest diameter, and no corneal epithelial defects were classified as mild or moderate. Such cases were treated with topical Moxifloxacin 0.5% QID, Cyclosporin 0.05% BID, and Dexamethasone 1% BID. In addition to medical management, these patients also underwent periodic sweeping of the fornices to break up any developing synechiae and to remove all inflammatory debris present on the ocular surface. Cases demonstrating greater than one-third lid margin involvement, conjunctival defects greater than 1 cm, and corneal epithelial defects were classified as severe or extremely severe. In these instances, an amniotic membrane was surgically placed over the entire bulbar and palpebral conjunctiva in addition to the instillation of the topical agents as listed above.[17]

In this study, at three months’ follow-up, none of the patients with mild or moderate ocular SJS demonstrated visual deficits, dry eye symptoms, or scarring. 18% of the severe cases developed mild tarsal conjunctival scarring by this time point. None of the severe patients demonstrated visual deficits or dry eye symptoms. Of the cases classified as being extremely severe, 60% required multiple amniotic membrane transplants. 10% of these patients had a mild visual deficit, 30% had scarring of the lid margin and tarsal conjunctiva, and 30% endorsed dry eye symptoms and photophobia.[17]

This treatment scheme advocated by Dr. Gregory contrasts that of an earlier study performed by Sharma et al. In this study, patients were delegated into treatment arms of medical treatment or amniotic membrane transplant in addition to medical treatment. No emphasis was placed on the severity of the patient’s ocular SJS in determining which treatment arm the patient was assigned. The results of this study demonstrated better best corrected visual acuity, tear film breakup time, Schirmer test results, and decreased chronic ocular surface changes in the amniotic membrane transplant arm. This study showed overall benefit for all cases of SJS with ocular manifestations receiving AMT, regardless of the degree of ocular involvement.[18] This contrasts Dr. Gregory’s selective treatment of only severe and extremely severe cases of SJS with amniotic membrane therapy. Further assessment will be needed to determine if there is a higher frequency of chronic ocular sequelae of SJS in the medically treated arm in Dr. Gregory’s study relative to the mild cases of SJS treated with AMT in Dr. Sharma’s study.

Prognosis

Mortality

Patient mortality rates correlate with the degree of total body surface area involved. The mortality rate of adult patients ranges from 10% for individuals with SJS to 30% for individuals with the more severe TEN.[19] The mortality rate is lower in children, with rates ranging from 0-17% for SJS.2 For more specific estimation of mortality, the SCORTEN score can be used on admission to assess the percentage likelihood of patient survival.[19]

Visual Outcomes

Markers in the acute phase of SJS that are predictive of a poor long-term visual outcome are corneal neovascularization and opacification. The vast majority of individuals do not have appreciable visual acuity deficits following the acute stage of SJS.[2]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.[20]

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.[2][21] These ocular surface changes are insidious in nature and do not correlate with the severity of the acute phase. These changes make take years to manifest before becoming clinically apparent, and have the potential to negatively affect vision. As such, each ocular symptom a SJS survivor develops could herald the onset of chronic ocular SJS and should receive a thorough evaluation.[22][21][23]

Epidemiology of Late SJS Ocular Changes

The overall incidence of these late ocular surface changes is 21-29% in pediatric cases and 27-59% in adult SJS survivors.[2]

Pathophysiology of Late SJS Ocular Changes

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.[22][16] 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. [22][10][16]

Histologic analysis of the ocular surface of SJS survivors reveals both innate and cellular immune system dysfunction. There are elevated levels of neutrophils, mast cells, and T lymphocytes in the ocular surface of SJS survivors relative to those of the normal population. This inflammatory infiltrate was present despite the lack of any overt signs of ocular surface inflammation. It is postulated that long-term exposure to the inflammatory cytokines, fibrogenic cytokines, and extracellular matrix proteases released by this cellular infiltrate lead to the late ocular surface changes seen with SJS.[22]

The alternate explanation for the pathophysiology of late ocular surface changes points 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.[10][16]

Regardless of the cause, the presence of longstanding inflammation of the ocular surface leads to the loss of essential ocular surface structures. The most commonly affected structures are the palisades of Vogt and Meibomian glands.[24] 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 inability to regenerate the corneal epithelium following injury. This leads to the clouding and conjunctivalization of the native cornea, and correlates to a poor prognosis for allogenic corneal transplants.[25] The Meibomian glands produce the tear film. This tear film 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 production, leading to the development of superficial punctate keratopathy, and further predisposes the corneal surface to micro trauma.[24]

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.[24]

Potential interventions for posterior lid margin keratinization include topical all-trans retinoic acid, autologous mucosal membrane grafting, and protective 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.[26] Autologous mucous membrane grafting is a more invasive process, requiring the surgical excision of the keratinized lid margin and replacing 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. This lessens the degree of superficial punctate and prevents mechanical injury to the cornea experiences from posterior eyelid margin, trichiasis, districhiasis, and other adnexal changes.[24][10]

In cases of Meibomian gland dysfunction with poor tear production, potential treatment options include artificial tears, punctal occlusion, salivary gland transplantation, and scleral lens placement. 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 is a more invasive procedure that involves the harvesting of minor salivary glands and transplanting them in the superior and inferior conjunctival fornices. Case studies have demonstrated 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, and serves as the final alternative to corneal keratoplasty in cases with corneal opacification.[24][27]

In cases where there is severe corneal opacification, conjunctivalization, or keratinization refractory to all other treatment measures, it may be necessary to place a keratoprosthesis to regain vision in the effected eye. This is viewed as a last resort to restore vision.11 Keratoplasty is generally contraindicated in SJS survivors due to the high fail rate of the donor cornea. This high failure rate is attributed to high levels of inflammation following surgery and poor epithelialization of the donor corneal surface due to limbal stem cell insufficiency.[9]

There are three techniques for keratoprosthesis, the Boston type I, Boston type II keratoprosthesis, and the modified osteo-odonto-keratoprosthesis. The Boston type I procedure is reserved for cases where there is no adnexal change and good tear film overlying the ocular surface. In cases where there are alterations to the adnexa and tear film layer, the Boston type II and modified osteo-odonto-keratoprosthesis are indicated.[24]

Differential Diagnosis

1. Drug Reaction

Drug reactions represent a type I hypersensitivity reaction to a medication. Drug reactions are much more common than SJS, with drug reactions 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 flare 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.[28]

2. Erythema Multiforme

Erythema multiforme (EM) was 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, but 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.[10][29][30]

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.[31][32]

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.[33]

Future Treatment Options

Limbal Epithelial Stem Cell Transplant

In cases of SJS with late ocular surface changes, chronic inflammation leads to the loss of the Palisades of Vogt and limbal epithelial stem cells. This process is typically bilateral, making it impossible to perform autologous limbal stem cell transplantation due to concerns of compromising the stem cell population of the less effected cornea.[34] The loss of Limbal stem cells also makes it impossible for epithelialization of the donor corneal surface following cornea transplant.[9] This drastically increases the likelihood of corneal transplant failure. 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.[35] 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.[4] 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.

Recurrence

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.21 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]

Additional Recommendations

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.[36]

Additional Resources


References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 Nirken MH, High WA, Roujeau J-C. StevensJohnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. August 2015. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis. Accessed October 17, 2016.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Catt CJ, Hamilton GM, Fish J, Mireskandari K, Ali A. Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children. Am J Ophthalmol. 2016;166:68-75.
  3. 3.0 3.1 3.2 3.3 3.4 Wetter DA, Camilleri MJ. Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic. Mayo Clin Proc. 2010;85(2):131-8.
  4. 4.0 4.1 4.2 Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343-50.
  5. 5.0 5.1 Wei HM, Lin LC, Wang CF, Lee YJ, Chen YT, Liao YD. Antimicrobial Properties of an Immunomodulator - 15 kDa Human Granulysin. PLoS ONE. 2016;11(6):e0156321.
  6. Saeed HN, Chodosh J. Immunologic Mediators in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Semin Ophthalmol. 2016;31(1-2):85-90.
  7. 7.0 7.1 7.2 Narita M. Classification of Extrapulmonary Manifestations Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis. Front Microbiol. 2016;7:23.
  8. Fujita Y, Yoshioka N, Abe R, et al. Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens-Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol. 2011;65(1):65-8.
  9. 9.0 9.1 9.2 Sotozono C, Ueta M, Koizumi N, et al. Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology. 2009;116(4):685-90.
  10. 10.0 10.1 10.2 10.3 10.4 Jain R, Sharma N, Basu S, et al. Stevens-Johnson syndrome: The role of an ophthalmologist. Surv Ophthalmol. 2016;61(4):369-99.
  11. Chantachaeng W, Chularojanamontri L, Kulthanan K, Jongjarearnprasert K, Dhana N. Cutaneous adverse reactions to sulfonamide antibiotics. Asian Pac J Allergy Immunol. 2011;29(3):284-9.
  12. 12.0 12.1 12.2 Sriram A, Sreya K, Lakshmi PN. Steven Johnson syndrome and toxic epidermal necrolysis: A review. International Journal of Pharmacological Research. 2014;4(4):158-165. doi:10.7439.
  13. 13.0 13.1 Harper S. Stevens Johnson Syndrome.
  14. Wetter DA. Treatment of Erythema Multiforme. UpToDate. October 2015. https://www.uptodate.com/contents/treatment-of-erythema-multiforme. Accessed October 17, 2016.
  15. Auquier-dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019-24.
  16. 16.0 16.1 16.2 16.3 Iyer G, Srinivasan B, Agarwal S, Pillai VS, Ahuja A. Treatment Modalities and Clinical Outcomes in Ocular Sequelae of Stevens-Johnson Syndrome Over 25 Years--A Paradigm Shift. Cornea. 2016;35(1):46-50.
  17. 17.0 17.1 Gregory DG. New Grading System and Treatment Guidelines for the Acute Ocular Manifestations of Stevens-Johnson Syndrome. Ophthalmology. 2016;123(8):1653-8.
  18. Sharma N, Thenarasun SA, Kaur M, et al. Adjuvant Role of Amniotic Membrane Transplantation in Acute Ocular Stevens-Johnson Syndrome: A Randomized Control Trial. Ophthalmology. 2016;123(3):484-91.
  19. 19.0 19.1 High WA, Nirken MH, Roueau J-C. Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. UpToDate. August 2016. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae. Accessed October 17, 2016.
  20. Kim DH, Yoon KC, Seo KY, et al. The role of systemic immunomodulatory treatment and prognostic factors on chronic ocular complications in Stevens-Johnson syndrome. Ophthalmology. 2015;122(2):254-64.
  21. 21.0 21.1 Hsu M, Jayaram A, Verner R, Lin A, Bouchard C. Indications and outcomes of amniotic membrane transplantation in the management of acute stevens-johnson syndrome and toxic epidermal necrolysis: a case-control study. Cornea. 2012;31(12):1394-402.
  22. 22.0 22.1 22.2 22.3 Chang VS, Chodosh J, Papaliodis GN. Chronic Ocular Complications of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: The Role of Systemic Immunomodulatory Therapy. Semin Ophthalmol. 2016;31(1-2):178-87.
  23. Yip LW, Thong BY, Lim J, et al. Ocular manifestations and complications of Stevens-Johnson syndrome and toxic epidermal necrolysis: an Asian series. Allergy. 2007;62(5):527-31
  24. 24.0 24.1 24.2 24.3 24.4 24.5 Kohanim S, Palioura S, Saeed HN. Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis e A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. The Ocular Surface. 2016;14(2):168-188.
  25. Lim P, Fuchsluger TA, Jurkunas UV. Limbal Stem Cell Deficiency and Corneal Neovascularization. Seminars in Ophthalmology. 2009;24:139-148.
  26. Soong HK, Martin NF, Wagoner MD, et al. Topical retinoid therapy for squamous metaplasia of various ocular surface disorders. A multicenter, placebo-controlled double-masked study. Ophthalmology. 1988;95(10):1442-6
  27. Sant' Anna AE, Hazarbassanov RM, de Freitas D, Gomes JÁ. Minor salivary glands and labial mucous membrane graft in the treatment of severe symblepharon and dry eye in patients with Stevens-Johnson syndrome. Br J Ophthalmol. 2012;96(2):234-9.
  28. Samel AD, Chu C-Y. Drug Eruptions. UpToDate. October 2016. https://www.uptodate.com/contents/drug-eruptions. Accessed October 17, 2016.
  29. French LE, Prins C. Erythema Multiforme, Stevens–Johnson syndrome and Toxic Epidermal Necrolysis. Dermatology. 20:319-333.
  30. Patz A. Ocular involvement in erythema multiforme. Arch Ophthal. 1950;43(2):244-56.
  31. Paradela S, Martinez-Gomez W, Fernandez-Jorge B. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus. SAGE Publications. March 2007.
  32. Merola JF, Moschella SL. Overview of Cutaneous Lupus Erythematosus. UpToDate. September 2016. https://www.uptodate.com/contents/overview-of-cutaneous-lupus-erythematosus. Accessed October 17, 2016
  33. Hall RP, Rao CL. Linear IgA Bullous Dermatosis. UpToDate. April 2016. https://www.uptodate.com/contents/linear-iga-bullous-dermatosis. Accessed October 17, 2016.
  34. Yuan S, Fan G. Stem cell-based therapy of corneal epithelial and endothelial diseases. Regen Med. 2015;10(4):495-504.
  35. Ortega Í, Deshpande P, Gill AA, Macneil S, Claeyssens F. Development of a microfabricated artificial limbus with micropockets for cell delivery to the cornea. Biofabrication. 2013;5(2):025008.
  36. Craven NM, Creamer D. Toxic epidermal necrolysis and Stevens–Johnson syndrome. Treatment of Skin Disease: Comprehensive Therapeutic Strategies.:766-769.