Stevens-Johnson syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Stevens-Johnson syndrome is a life-threatening condition affecting the skin, in which due to cell death the epidermis separates from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes. Although the majority of cases are idiopathic, the main class of known causes is medications, followed by infections and (rarely) cancers.

It is named for Dr. Albert Mason Stevens and Dr. Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in 1922.^[1][2]

There is agreement in the medical literature that Stevens-Johnson syndrome can be considered a milder form of toxic epidermal necrolysis (TEN). Stevens-Johnson Syndrome involves less than 10 percent of body surface area while TEN involve more than 30 percent body surface area. However, there is debate whether it falls on a spectrum of disease that includes erythema multiforme and erythema multiforme major (also known as erythema multiforme majus).^{[3][4][5][6][7]}

SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum. The exact pathogenesis of SJS/TEN is not completely understood. However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis^[8]. Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells. On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , Perforin/Granzyme B , and Granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease.

Stevens-Johnson Syndrome is caused by drug reactions in the majority of the cases although it is also seen in certain viral and bacterial infections, and certain malignancies. Most commonly implicated drugs include sulfa drugs, Allopurinol, anti-epileptics (phenobarbital, carbamazepine, lamotrigine), antibiotics (for example Penicillin), and NSAIDs. Infections that are associated with SJS may include HIV, HSV, Mumps, Mycoplasma, Mycobacteria, Hepatitis and Streptococcal Infection.

Common risk factors in the development of SJS include Immunodeficiency, HIV infection, active malignancy (particularly Hematological cancers), genetic Predisposition ( HLA-B 1502 and HLA-B 5801 variants in particular) on exposure to anti-epileptic medications or Allopurinol. Other risk factors may include past or family history of SJS/TEN, radiation therapy and rapid use of medications.

SJS is a rare condition, with a reported incidence of around 2-7 per 1000,000 people per year and a mean mortality rate of 4.8 percent. It is seen in patients of all age groups but particularly in children and young adults. Females are more commonly affected than males

SJS proper (with less than 10% of body surface area involved) has the mortality rate of around 5%. The risk of death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account. Other outcomes include organ damage and blindness.

Stevens-Johnson syndrome (SJS) usually begins with a fever, sore throat, and fatigue, which is misdiagnosed and usually treated with antibiotics. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient’s ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.^[9]

Common physical examination findings of SJS include rash or redness that is seen as red or reddish purple macules that enlarge to form bullae, vesicles and may rupture later to leave denuded skin underneath. Nikolsky sign may be positive which shows sloughing of the skin by gentle lateral pressure on the erythematous skin. In addition to skin, mucosal involvement is found mostly in oral mucosa in addition to the nasopharynx and ocular involvement-can be seen as edema, erythema, blistering, sloughing, necrosis and ulceration. In addition to these changes: fever, hypotension, and tachycardia can be seen in patients with SJS

SJS is mainly diagnosed through the clinical skin findings. However, a skin biopsy is helpful in making the definitive diagnosis. Other tests are done to either rule out the superimposed bacterial infection, measure disease severity or detect the causative agent or organism. Tests include CBC, BMP, Blood cultures, ESR, CRP, IL-6, ELISA for virus detection among others^[10].

There are no x-ray findings associated with SJS. However, an x-ray may be helpful in the diagnosis of pulmonary complications of Stevens-Johnson Syndrome, in which CXR may show interstitial lung infiltrates^[11]

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis should be managed in a burn unit, Specialized dermatology or Intensive Care unit. Patient’s fluid status, hemodynamic stability, wound surface area and pain should be assessed and managed immediately upon admission. Treatment is initially similar to that of patients with thermal burns, and continued care can only be supportive (e.g. IV fluids) and symptomatic (e.g. analgesic mouth rinse for mouth ulcer); there is no specific drug treatment. Treatment with corticosteroids is controversial since it might aggravate the condition or increase risk of secondary infections. Other agents have been used, including cyclophosphamide and cyclosporine, among with cyclosporin has exhibited some therapeutic success. Intravenous immunoglobulin (IVIG) treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics. An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids leading to corneal vascularization and impaired vision, as well as a host of other ocular problems. Also, an extensive physical therapy program ensues after the patient is discharged from the hospital.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

It is named for Dr. Albert Mason Stevens and Dr. Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in 1922.^[1][2]

• SJS was first discovered by Dr. Albert Mason Stevens and Dr. Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in 1922 in two patients, boys aged 7 and 8 years

The following are a few famous cases of disease name:

• Manute Bol (Oct. 16, 1962 – June 19, 2010) was a Sudanese-born basketball player and political activist
• Padma Lakshmi – Actress, Model, cookbook author
• Gene Sauers – American professional golfer ^[3]
• Karen Elaine Morton (Oct. 3,1958 – Feb.11, 2014) – Playboy Playmate of the Month July 1978, died from organ failure due to complications from Stevens-Johnson Syndrome^[4].
• Samantha Reckis -The child was given the popular pain reliever after showing signs of fever around thanksgiving in 2003 and later developed TEN which is more severe form of SJS – Family was awarded $63 million in Motrin case in their lawsuit against Johnson & Johnson^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

There is agreement in the medical literature that Stevens-Johnson syndrome can be considered a milder form of toxic epidermal necrolysis (TEN). Stevens-Johnson Syndrome involves less than 10 percent of body surface area while TEN involve more than 30 percent body surface area. However, there is debate whether it falls on a spectrum of disease that includes erythema multiforme and erythema multiforme major (also known as erythema multiforme majus).^{[1][2][3][4][5]}

Skin lesions can be classified into 5 Different Categories as defined below^[6]:

• Bullous Eythema Multiforme: Detachment below 10% of the body surface area (BSA) plus localized typical targets or raised atypical targets
• Stevens-Johnson Syndrome: Detachment below 10% of the body surface area plus widespread erythematous or purpuric macules or flat atypical targets
• Stevens-Johnson and Toxic Epidermal Necrolysis Overlap: Detachment between 10% and 30% of the body surface area plus widespread purpuric macules or flat atypical targets
• Toxic Epidermal Necrolysis with Spots: Detachment above 30% of the body surface area plus widespread purpuric macules or flat atypical targets
• Toxic Epidermal Necrolysis without Spots: Detachment above 10% of the body surface area with large epidermal sheets and without any purpuric macule or target

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum. The exact pathogenesis of SJS/TEN is not completely understood. However, It is believed that SJS/TEN is immune-mediated and the result of an MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis^[1]. Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug-specific cytotoxic T cells. On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand, perforin/granzyme B, and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease.

• The exact pathogenesis of SJS/TEN is not completely understood

• However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis^[1]
• Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells
• On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , perforin/granzyme B , and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease as explained below.
  • T lymphocytes found in bisters were CD8+, HLA-DR+, CLA+ (cutaneous lymphocyte antigen), CD56+ and were shown to be strongly immunoreactive for granzyme B suggesting perforin/granzyme mediated cytotoxicity^[2]
  • There is also beleived to be some involvement of the soluble FasL (sFasL) in keratinocyte apoptosis in SJS and TEN. sFasL is secreted by peripheral bood mononuclear cells (PBMC’s) and interacts with the Fas that is expressed on keratinocyte leading to apoptosis. Higher serum levels of sFasL may be seen in patients with suspicion of SJS/TEN^[3]
  • Recent studies suggest that the Granulysin, which is a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte apoptosis in SJS/TEN^[4] and is identified by gene expression profiling as the highly cytotoxic molecule and confirmed by PCR and immunohistochemistry. Granulysin concentrations in blister fluid were found to be 2x to 4x more than the Perforin/Granzyme B/sFasL thus making it the most important cytotoxic molecule in SJS/TEN pathogenesis^[5]
  • Other cytokines that may be associated with trafficking, activation and proliferation of cytotoxic T cells and other immune cells include IFN-Y(gamma), TNF-aplha, IL-2, IL-5, IL-6, IL-10, IL-13. IL-15 was one of the cytokines that was seen in the highest amount and also correlated with disease severity and mortality. Studies also suggest that IL-15 is important in mentaining long-lasting cytotoxic T lymphocyte responses as well as generating and mentaining Nk cells. It is also responsible for enhancing MHC-I antigen presentation thus has an important contribution in SJS/TEN pathogenesis^[6]

• Some people have genetic predisposition which increases their risk of developing SJS in response to certain trigger medications. The most common genetic variation contributing to the predisposition is seen in the HLA-B gene. Examples include
  • People with HLA-B 1502 gene have 10 percent risk of developing SJS on exposure to anti-epileptic drugs like Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine^[7]
  • People with HLA-B 5801 have high risk of developing SJS on exposure to Allupurinol^[8]
  • Certain studies have identified HLA-B 3101 as a genetic risk factor for carbamazepine induced skin reactions including SJS^[9]
  • HLA-B 1511, HLA-B 2402 are also considered to increase SJS risk in certain populations
• Genetic Polymorphism in CYP2C gene variants may lead to an increased risk of SJS/TEN on exposure to certain anti-seizure medications in some populations^[10]

Some conditions that are associated with an increased risk of SJS/TEN include HIV, immunodeficiency, active cancers (mostly hematological) and some genetic factors.

• On gross examination in SJS/TEN, blisters/erosions/bullae and vesicles are seen along with Confluent redness and skin sloughing. Nikolsky Sign may be positive which is the detachment of superficial epidermis on gentle pressure or rubbing of skin

On microscopic histopathological analysis,full-thickness extensive keratinocyte necrosis that develop into subepidermal bullae is seen in established SJS/TEN^[11]. Satellite cell necrosis may also be seen^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Stevens-Johnson Syndrome is caused by drug reactions in the majority of the cases although it is also seen in certain viral and bacterial infections, and certain malignancies. Most commonly implicated drugs include sulfa drugs, Allopurinol, Anti-epileptics (phenobarbital, carbamazepine, lamotrigine), antibiotics (for example Penicillin), and NSAIDs. Infections that are associated with SJS may include HIV, HSV, Mumps, Mycoplasma, Mycobacteria, Hepatitis and streptococcal Infection.

There are different triggers for Stevens-Johnson Syndrome Include drug-induced, infections, some systemic and Autoimmune disease among others.

One of the main triggers to cause SJS is the drug induced reaction

• Usually happens in first 2 months of treatment with drugs (often within 4-28 days)
• Typically occur after the first prolonged exposure to drug
• Unlikely to be caused by drugs that are being taken for a long time by the patient
• The most commons drugs that can cause SJS include^[1]:
  • Anti-Infective Sulfonamides
  • Allupurinol^[2]
  • Anti-Epileptics include
    • Phenobarbital
    • Carbamazepine,
    • Lamotrigine
    • Barbiturates
  • Antibiotics include
    • Pencilllin
    • Sufa drugs
    • Ciprofloxacin has also been reported to be associated with SJS^[3]
  • Other Less commonly associated drugs may include
    • Acetaminophen
    • Albendazole
    • Amifostine
    • Amoxicillin
    • Boceprevir
    • clofarabine
    • Cefadroxil
    • Cefotaxime sodium
    • Certolizumab pegol
    • Ceftazidime
    • Clobazam
    • Etravirine
    • Levobunolol hydrochloride
    • Diclofenac
    • diclofenac (patch)
    • Fluconazole^[4]
    • Indinavir
    • Isotretinoin
    • Lincomycin Hydrochloride
    • Valdecoxib
    • Penicillin
    • Interferon gamma
    • Barbiturates
    • Saquinavir mesylate
    • Sulfas
    • Phenytoin
    • Piperacillin
    • Piperacillin/tazobactam
    • Modafinil
    • Oxaprozin
    • Lamotrigine
    • Nevirapine
    • Ibuprofen,^[5] (ethosuximide, Carbamazepine)^[6][7]
    • Infliximab, Imatinib
    • Rabeprazole
    • Raltegravir
    • Ritonavir

SJS can be caused by infections, usually following viral infections:

• Herpes simplex virus
• Influenza
• HIV
• Mumps
• Hepatitis A
• Cat-scratch fever
• Histoplasmosis
• Epstein-Barr virus

Some bacterial infections may be associated with SJS, including following^[8]:

• Group A- Beta Hemolytic streptococci
• Mycoplasma Pneumoniae^[9]
• Diptheria
• Brucellosis
• Typhoid fever
• Mycobacteria

• Malignancy (carcinomas and lymphomas)
• Idiopathic factors (up to 50% of the time). SJS has also been consistently reported as an uncommon side effect of herbal supplements containing ginseng.
• SJS may also be caused by cocaine usage.^[10]
• Drug side effects:
  • Atovaquone and proguanil hydrochloride
  • Cefaclor
  • Ceftibuten
  • Cefotetan disodium
  • Cytomegalovirus immune globulin
  • Dactinomycin
  • Doripenem
  • Ethosuximide
  • Felbamate
  • Imipenem-Cilastatin
  • Ibritumomab tiuxetan
  • Lacosamide
  • Meropenem
  • Muromonab-CD3
  • Sorafenib
  • Spironolactone
  • Rifampin
  • Trovafloxacin mesylate
  • Trospium
  • vandetanib

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Stevens-Johnson syndrome must be differentiated from other diseases that cause fever, ulcers in the mucous membranes and skin, sore throat, and fatigue, including chickenpox, herpes zoster, erythema multiforme, among others.

Different rash-like conditions can be confused with Stevens-Johnson syndrome and are thus included in its differential diagnosis. The various conditions that should be differentiated from Stevens-Johnson syndrome include:^{[1][2][3][4][5][6][7]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

SJS is a rare condition, with a reported incidence of around 2-7 per 1000,000 people per year and a mean mortality rate of 4.8 percent. It is seen in patients of all age groups but particularly in children and young adults. Females are more commonly affected than males

• The incidence of SJS is approximately 2-7 per 1000,000 individuals per year.^[1]
• The incidences of SJS, SJS-TEN, and TEN were found to be a mean 5.3, 0.8, and 0.4 cases per million children per year in the US^[2]
• The mean estimated incidences of SJS, SJS/TEN, and TEN were found to be 9.2, 1.6, and 1.9 per million adults per year in the US^[3]

• Between years 2009-2012, the Mean adjusted mortality was 4.8% for SJS, 19.4% for SJS/TEN, and 14.8% for TEN^[4]

• Patients of all age groups may develop SJS.

• The incidence of SJS might be higher in Non White/Multiracial people as compared to White“Redirecting”.

• Women are more commonly affected by SJS than males“Redirecting”..

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Common risk factors in the development of SJS include immunodeficiency, HIV infection, active malignancy (particularly Hematological cancers), genetic Predisposition ( HLA-B 1502 and HLA-B 5801 variants in particular) on exposure to antiepileptic medications or Allopurinol. Other risk factors may include past or family history of SJS/TEN, radiation therapy and rapid use of medications.

Common risk factors in the development of Stevens-Johnson Syndrome include the following:

• Risk of Developing SJS is 100 times greater in HIV Infected people as compared to the general population^[1]

• Immunodeffeciency also increases the risk of developing SJS/TEN. Conditions may include Autoimmune diseases like SLE, Organ Transplant and HIV/AIDS^[2]

• Certain Malignancies increase the risk of SJS particularly Lymphomas and other Hematological cancers^[3]

• Some people have genetic predisposition which increases their risk of developing SJS in response to certain trigger medications. The most common genetic variation contributing to the predisposition is seen in the HLA-B gene. Examples include
  • People with HLA-B 1502 gene have 10 percent risk of developing SJS on exposure to anti-epileptic drugs like Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine^[4]
  • People with HLA-B 5801 have high risk of developing SJS on exposure to Allupurinol^[5]
  • Certain studies have identified HLA-B 3101 as a genetic risk factor for Carbamazepine induced skin reactions including SJS^[6]
  • HLA-B 1511, HLA-B 2402 are also considered to increase SJS risk in certain populations
• Genetic polymorphism in CYP2C gene variants may lead to an increased risk of SJS/TEN on exposure to certain anti-seizure medications in some populations^[7]

Other factors that may increase the risk of SJS inclde;

• Past history of SJS
• Family history of SJS
• High dose of medications
• Rapid Intake of medications
• Physical stimuli like radiation therapy^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

There is insufficient evidence to recommend routine screening for SJS

There is insufficient evidence to recommend routine screening for SJS

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

• The symptoms of SJS usually start within 2 months of starting a drug or other inciting trigger with symptoms such as red or reddish blue macules/papules on trunk and extremities and later increase in size and coalesce. Blisters/erosions/bullae and vesicles are seen later with confluent redness with skin sloughing. Most lesions heal rapidly within 1-3 weeks unless secondary bacterial infection of lesions occurs. Recovery can take longer, although it usually depends on the severity of symptoms and body surface area involved. Mortality rate is 1-5 percent in SJS and in TEN is 25-35 percent^[1]

• The symptoms of SJS usually start within 2 months of starting a drug or other inciting trigger with symptoms such as red or reddish blue macules/papules on trunk and extremities and later increase in size and coalesce.Blisters/erosions/bullae and vesicles are seen later with confluent redness with skin sloughing.
• Most lesions heal rapidly within 1-3 weeks unless secondary bacterial infection of lesions occurs.
• Recovery can take longer, although it usually depends on the severity of symptoms and body surface area involved

• Common complications of SJS/TEN include:
  • Bacterial Infections leading to sepsis – more common in age>40, WBC>10,00, BSA more than or equal to 30 percent^[2]
  • Opthalmologic – Ranging from pain, photophobia, conjuctivitis to keratitis and endopthalmitis. Appropriate treatment of acute ocular complications can prevent long term complications^[3]
  • Pulmonary – Pnemonia, Interstitial pneumonitis, ARDS (25 percent of patients have been reported to require mechanical ventilation)^[4]
  • Skin – Scarring or hypertrophic changes

• Prognosis and severity of SJS/TEN should be determined immediately after diagnosis to decide upon the appropriate medical management and setting.
• SCORTEN Severity of illness score may be used to determine the severity and prognosis

• Patients with SCORTEN score of 0-1 with limited skin involvement can be manged in non-specialized wards^[7]
• Patients with the SCORTEN score of 3 or more should be treated in an ICU.
• Depending on the extent of the skin sloughing/ Body surface are involved at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good
• Mortality rate is 1-5 percent in SJS and in TEN is 25-35 percent^[1]
• Mortality rate can be higher in elderly and those with extensive skin involvement

May include^[8][9][10]:

• Hypernatremia
• Neutropenia
• Thrombocytopenia
• Increased BUN

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