Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

SJS/TEN

Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe immunologic skin reactions characterized by necrosis, skin detachment, and involvement of the mucous membrane of the eyes, mouth, and/or genitals. One of the first symptoms of both SJS and TEN are fever and flu-like symptoms which include body aches and cough. Following suit in 1 to 3 days is the formation of a red to purple rash, and blistering and peeling of the skin that usually begins in the face, and then spreads to other areas of the body. Other symptoms include conjunctivitis, difficulty swallowing and breathing, genital pain, and difficulty urinating. The difference between SJS and TEN is that SJS is less severe, with skin detachment involving less than 10% of the body surface; In TEN, skin detachment involves more than 30% of the body surface. Regardless of severity, both are life-threatening emergencies and are usually caused by certain medications, which include anticonvulsants, allopurinol, sulfonamides, antibiotics, NSAIDs, and contrast media. Moreover, these dermatologic reactions can also be triggered by infections like pneumonia, herpes virus, and hepatitis A. Individuals who have HIV, a compromised immune system, a family history of SJS/TEN, or variation of the HLA-B gene are at an increased risk of developing SJS/TEN.

Necrosis from SJS/TEN is caused by immune activation where induction of cytotoxic T lymphocytes, CD4+ cells, and innate immune cells lead to the secretion of granulysin and other cytokines. The drug-associated antigen or metabolite interacts and binds to the major histocompatibility complex (MHC) type 1 or cellular peptide to form an immunogenic compound. CD8+ cells present in blister fluid induces keratinocyte apoptosis. CD40 ligand cells induce the release of TNF-alpha, nitrous oxide, IL-8, and cell adhesion antibodies. TNF-alpha induces apoptosis. As a result, the secretion of these molecules puncture the cell membrane, causing widespread apoptosis. It is a Type IV cell mediated reaction. Another mechanism involved in the cause of SJS/TEN is that the drug metabolites become immunogenic and stimulate the immune system, known as the pro-hapten concept. About 5-20% of SJS/TEN are idiopathic, meaning, it is caused spontaneously with an unknown cause; however, 50-95% of cases are caused due to immune predisposition and exogenous factors, for instance, particular medications listed below:

Anticonvulsants: lamotrigine, carbamazepine, phenytoin, phenobarbitone

Allopurinol: >100 mg per day

Sulfonamides: cotrimoxazole, sulfasalazine

Antibiotics: penicillins, cephalosporins, quinolones, minocycline

Acetaminophen

Nevirapine (non-nucleoside reverse-transcriptase inhibitor)

NSAIDs: oxicam type mainly

Contrast media

Genetic factors play a role. Individuals of with the HLA-A*31:01 or HLA-B*15:02 are at risk for developing SJS/TEN upon ingestion of carbamazepine. On the other hand, those with the HLA-B*58:01 genes are more likely to develop SJS/TEN upon the ingestion of allopurinol.

SJS mortality ranges from 5 to 18% and usually lasts about 4-6 weeks. There is moderate mucocutaneous and systemic involvement that leads to blistering and atypical target lesions involving 10% of the body surface area. Clinical manifestations are epidermal detachment, hemorrhagic skin, joint pain, onset of pneumonia, and serious ocular involvement. In TEN, clinical manifestations include erythema and massive bullae formation that ruptures and peels. The mortality is 30%, often within 8 days after bullae formation. Likewise, 70% heal with potential for scarring.

In SJS/TEN, prevention is key. For instance, it is important to perform HLA-B testing in susceptible races. For instance, in Han Chinese, Thai, Malaysian, and South Indians, they have a higher likelihood of carrying the HLA-B*1502 gene. If these individuals take anticonvulsants containing aromatic compounds, they may develop SJS/TEN. Europeans that carry the HLA-B*5701 who take abacavir are also at risk, or if they carry HLA-A*3101 and take carbamazepine. Individuals with the human leukocyte antigen (HLA) allotypes are at an increased risk of SJS/TEN when exposed to aromatic anticonvulsants and allopurinol. Due to genetic factors, it is important to inform family members of the affected patient since they are at risk of developing the disease if taken particular medications as well. Managing SJS/TEN is performed in a hospital setting, and involves immediate cessation of suspected causative drug(s). Supportive care involves nutritional and fluid replacement (crystalloid) by intravenous and nasogastric routes, maintaining body temperature (since temperature regulation is impaired given dermatologic necrosis), pain relief, skin care and infection control, topical silver nitrate or chlorhexidine (avoid silver sulfadiazine), and application of dressings like gauze with petrolatum or non-adherent nanocrystalline-containing gauze. It is important to avoid using adhesive tape. Further, using mouthwashes or topical oral anesthetics may be advised if mucosal membranes are involved. Regular assessment for infection of the skin, mucous membranes, and catheter sites is necessary. According to case reports and small patient series, it has been reported that there is benefit from delivery of an active adjuvant treatment during the first 24-48 hours of illness. For instance, administration of cyclosporin 3-5 mg/kg/day, cyclophosphamide, or intravenous immunoglobulin (IVIG) 2-3 g/kg, and plasmapheresis have had variable responses.

References

Oakley, Amanda M. “Stevens-Johnson Syndrome - StatPearls - NCBI Bookshelf.” Steven-Johnson Syndrome, 10 Apr. 2023, www.ncbi.nlm.nih.gov/books/NBK459323/.

“Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - about the Disease.” Genetic and

Rare Diseases Information Center, rarediseases.info.nih.gov/diseases/7700/stevens-johnson-syndrometoxic-epidermal-necrolysis. Accessed 8 June 2023.

Zimmerman, Danielle, and Nam Hoang Dang. “Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): Immunologic Reactions.” Edited by Joseph L. Nates and Kristen J. Price, Oncologic Critical Care, 9 July 2019, www.ncbi.nlm.nih.gov/pmc/articles/PMC7122590/.

Written by Aleksandra Agranovich

Steven Johnsons Syndrome (SJS)

Steven Johnson syndrome is a very rare but serious skin disease that usually occurs due to a drug-related side effect. SJS can be characterized by the detachment of the epidermis and mucous membrane. Patients who have this condition often experience flu-like symptoms, a painful rash and blisters. Toxic Epidermal Necrolysis (TEN) is also a skin disease that is very much similar to SJS. Both of these conditions, if untreated, can lead to complications of the liver, kidneys, and respiratory tract (Hasegawa, 2020). The pathogenicity of SJS/TEN can be explained by extensive epidermal cell death. In addition, this disease also tends to activate many different types of cytokines within the immune system which may lead to inflammation.

The drugs that most commonly cause this disease include carbamazepine and allopurinol. Carbamazepine is an anticonvulsant that can be used to treat seizures, epilepsy, and neuropathic pain. Allopurinol, on the other hand, is a medication that is indicated to decrease high levels of uric acid in patients who have gout. The recommended treatment for SJS/TENS most often includes supportive care. However, according to guidelines, systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists may be considered as well.

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug related reaction. DRESS occurs as a result of drug-induced hypersensitivity and can be seen with fever, lymphadenopathy, hematologic abnormalities, and organ failure (Husain, 2013).

The most common offending agents include anticonvulsants such as carbamazepine or phenytoin and sulfonamide antibiotics. Unlike SJS/TEN, DRESS syndrome usually takes 2-6 weeks to occur. The most important way to prevent and treat DRESS syndrome is to discontinue the medication that is being given.

Resources

Hasegawa A, Abe R. Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis. F1000Res. 2020;9:F1000 Faculty Rev-612. Published 2020 Jun 16. doi:10.12688/f1000research.24748.1

Husain, Zain et al. “DRESS syndrome: Part I. Clinical perspectives.” Journal of the American Academy of Dermatology vol. 68,5 (2013): 693.e1-14; quiz 706-8. doi:10.1016/j.jaad.2013.01.033

Liotti, Lucia et al. “Clinical features, outcomes and treatment in children with drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis.” Acta bio-medica : Atenei Parmensis vol. 90,3-S 52-60. 29 Jan. 2019, doi:10.23750/abm.v90i3-S.8165

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but serious skin diseases that are characterized by widespread epidermal necrosis and sloughing of skin. These T-cell mediated, type IV hypersensitivity reactions are associated with significant morbidity and mortality. These two diseases have the same pathophysiology and symptoms with the difference in diagnosis being based on the body surface area (BSA) affected. Patients with <10% BSA affected are diagnosed with SJS while patients with >30% BSA affected receive a diagnosis of TEN. There is an overlap between the diseases between 10-30% BSA affected. Often times, SJS/TEN are caused by an adverse reaction to a medication. Symptoms usually present within 8 weeks of beginning therapy with a new medication but most cases appear between 4 days and 4 weeks. Initially, patients with SJS/TEN present with fever, malaise, sore throat, and cough. Photophobia, conjunctival itching or burning, and pain when swallowing may be early signs of mucosal involvement. After 1-3 days of this prodromal period, the skin involvement appears as erythematous macules or atypical target lesions on the trunk. These macules and lesions are painful and will start to blister and peel. When mucous membranes are involved it presents as redness, blisters and erosions on the lips and inside the mouth. Eye involvement presents as redness, irritation and pain (Ergen 2017). This acute phase lasts around 8-12 days. Re-epithelialization begins after several days and takes 2-4 weeks (Frantz 2021).

The pathophysiology behind SJS/TEN is not completely understood. There are several drugs that are known to cause these skin reactions. Those drugs include: lamotrigine, phenytoin, carbamazepine, valproic acid, phenobarbital, TMP-SMX, aminopenicillins, tetracyclines, cephalosporins, NSAIDs, allopurinol, nevirapine, nivolumab, and pembrolizumab (Frantz 2021). SJS/TEN may also be caused by infection with mycoplasma pneumonia being the most common infectious cause. There are several hypotheses for their development. The first is the hapten/pro-hapten concept that small-molecule drugs will covalently bind to proteins in serum, forming a complex that is recognized by certain HLA molecules and presented to T-cells to cause an immune response. The second is that chemically inert drugs cannot undergo covalent binding with serum proteins so they bind HLA molecules directly leading to T-cell activation. The third is that drugs bind inside HLA binding pockets in a way that alters presentation of self-proteins to T-cells, so that they are no longer recognized as self, leading to an immune response (Frantz 2021). It is still unknown which hypothesis is true but we know that the end result is T-cell activation leading to an immune response.

The first step in the management of SJS/TENs is identifying the disease and discontinuing the causative agent. After this first important step, management mostly involves supportive care. Patients should be kept in a warm environment due to their skin’s loss of thermoregulatory function. Fluids and electrolytes are needed as well as enteral nutrition due to the mucosal involvement causing difficulty with oral ingestion. Infection control and wound care are also very important parts of recovery as infection is a common complication with these diseases. There is no guideline recommended pharmacologic treatment however, corticosteroids and IV immunoglobulin are two common treatments that may be implemented (Frantz 2021).

Resources:

Ergen EN, Hughey LC. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. JAMA Dermatol. 2017;153(12):1344. doi:10.1001/jamadermatol.2017.3957

Frantz R, Huang S, Are A, Motaparthi K. Stevens–Johnson Syndrome and toxic epidermal necrolysis: A review of diagnosis and management. Medicina. 2021;57(9):895. doi:10.3390/medicina57090895

Stevens-Johnson Syndrome, also known as SJS, is a rare albeit a very serious and unpredictable disorder that affects the skin, mucous membrane, genitals and eyes. It is denoted as an adverse reaction primarily to certain medications and can occasionally be caused by an infection. Key examples of medication that are causative agents include allopurinol, nevirapine, the “oxicam” class of non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam, sulfa antibiotics including sulfamethoxazole (commonly available as the combination antibiotic Bactrim; sulfamethoxazole-trimethoprim), lamotrigine, sertraline, and sulfasalazine, and several different antipsychotics including carbamazepine, phenobarbital, and phenytoin. What I found to be one of the scariest parts of this syndrome is that SJS can occur up to two weeks after a person has discontinued the use of a medication. This is why certain of these causative agents like lamotrigine are required to have very careful tapering up or tapering off. There are also certain risk factors that predisposes a patient to SJS which include an HIV infection, cancer, and a weakened immune system such as an organ transplant and other autoimmune diseases.

The most common symptoms of SJS is skin pain in conjunction with flu-like symptoms which may include but are not limited to a general feeling of malaise, a high temperature of equal to or greater than 100.4 degrees Fahrenheit, a headache, and a cough. These symptoms are all presented in the initial stages of the clinical presentation of SJS and a couple of days later are subsequently followed by a rash that resembles the appearance of a target as they resemble spots that are lighter around the border and darker towards the center. Albeit the rash isn’t itchy, it typically spreads over a number of days or even hours. This is followed by large blisters on the skin that burst and result in painful sores. Other distinctive symptoms are facial and lip swelling in addition to blistered and ulcerated mucous membranes inside a person’s mouth, throat, eyes, and genital tract.

Treating Stevens-Johnson Syndrome requires immediate medical attention. The first step in treating SJS is complete cessation of any medications that may be the causative agents of SJS; since this may be difficult to determine, complete cessation of all non-essential medications is strongly recommended. Treatment for relief of SJS symptoms while under hospitalization include strong painkillers in order to alleviate the pain of affected areas of the skin, moist and cool compressions held against affected areas of the skin, replacement fluids to supply fluids and nutrition that’s inserted into the human body through a nasogastric tube (a tube that is placed through the nose and into the stomach), and a short course of oral steroids in order to better control inflammation of the skin. In addition to this, antibiotics can be administered in case sepsis (which is extremely dangerous) is detected in the blood and eye drops/eye ointments for particular eye-related SJS symptoms. Severe cases of SJS may be needed to treat in either the burn unit or the intensive care unit (ICU).

References-

Stevens-Johnson Syndrome. National Health Service (NHS) UK. https://www.nhs.uk/conditions/stevens-johnson-syndrome/

Stevens-Johnson Syndrome. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/stevens-johnson-syndrome/symptoms-causes/syc-20355936

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are rare and severe mucocutaneous blistering diseases associated with high mortality. SJS and TEN are not separate conditions, rather are part of a disease spectrum with SJS as less severe and TEN as more severe. SJS is when skin detachment includes less than 10% of the body's surface and TEN is when skin detachment includes more than 30% of the body’s surface. Patients with 10-30% skin detachment may experience SJS/TEN overlap. But whether the patient experiences SJS, TEN or both SJS/TEN all these forms are life threatening medical emergencies that require immediate treatment.

SJS/TEN is usually caused by idiosyncratic drug reactions due to certain medications, infections, pre-existing health conditions, and family history. High-risk drugs that trigger SJS/TEN include allopurinol and antibiotics such as penicillins, cephalosporins, sulfonamides and quinolones. Other high risk drugs include antiepileptics such as lamotrigine, carbamazepine, and phenobarbital. Non-steroidal anti inflammatory drugs such as abacavir, nevirapine and oxicam derivatives are also known triggers of SJS/TEN. Symptoms of SJS/TEN that result from adverse drug reactions are often observed within a month to two months, and may even last up to two weeks after discontinuing the offending agent. Infections that trigger SJS/TEN involve both bacterial and viral infections such as herpes, pneumonia, hepatitis A, tuberculosis, influenza, measles and mumps. Health conditions that increase a person’s risk for SJS/TEN include patients who are HIV positive, HLA-B gene mutations, weakened immune system (ex. cancer), and family history of SJS/TEN.

The earlier the diagnosis and management of SJS/TEN, the better the recovery for the patient affected. Symptoms of SJS/TEN may appear within a one to four day influenza-like stage that includes fever, chills, headache and sore throat. Before any cutaneous lesions appear, signs of mucosal irritation (conjunctivitis, dysphagia, and dysuria) will occur. The skin blisters and peels leading to detachment of the skin which leaves the patient in immense pain. The areas of the body affected by SJS/TEN may typically start on the face and chest and eventually spread over the rest of the body. Skin rashes start as macules/patches that blister and erode. Skin lesions are irregular in shape, purpuric with necrotic centers. Individual skin lesions may coalesce to form large painful erythematous patches on the body. These skin lesions may display a positive Nikolsky sign in which the skin peels upon pressure applied.

Involvement of mucous membrane in multiple areas is a hallmark of SJS/TEN, and can range from a mild to severe form. The affected mucous membrane areas are located in oral (mouth), nasopharyngeal (throat), digestive tract, respiratory, genitourinary (genitals), and rectal routes.

Early signs of mucous membrane involvement are itching/burning on the eyes, light sensitivity, and painful swallowing. The greater the total body surface area involvement (TBSA) the more severe the disease. Patients who are taking high-risk drugs and develop SJS/TEN could develop red plaques or papules, blisters, erosions, and mucosal involvement which will persist for 2 months during usage.

In treating SJS/TEN is crucial to immediately discontinue the offending agent and all other unnecessary medications. The patient must be admitted into the hospital in an intensive care unit, burn unit or specialized dermatology unit to seek appropriate care, improving chances of recovery. Patients need to be stabilized hemodynamically through intensive skin/eye/mucous membrane treatment such as wound care & pain control, temperature management, infection prophylaxis, fluids and electrolytes and calorie replacement. Affected eyes must be treated immediately to prevent permanent eye damage and vision loss. Eye treatment includes saline rinses, lubrication through eye ointments and eye drops, topical corticosteroids, antibiotics and amniotic membrane transplantation (AMT). Aside from supportive care, various treatments have been tried by doctors that include intravenous immune globulin (IVIG), systemic corticosteroids, cyclosporine and anti-tumor necrosis factor (TNF) monoclonal antibodies however no agent other than cyclosporine have shown conclusive benefits.

1. Smith C. Erythema Multiforme, Stevens–Johnson Syndrome, Toxic Epidermal Necrolysis, Staphylococcal Scalded Skin Syndrome. In: Soutor C, Hordinsky MK. eds. Clinical Dermatology. McGraw-Hill; Accessed June 15, 2021. https://accessmedicine-mhmedical-com.jerome.stjohns.edu/content.aspx?bookid=2184&sectionid=165460970

2. Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis. U.S. Department of Health & Human Services; National Institutes of Health. https://rarediseases.info.nih.gov/diseases/7700/stevens-johnson-syndrometoxic-epidermal-necrolysis. Accessed 2021 June 15.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most life-threatening dermatologic skin reactions, typically caused by medications. These two adverse cutaneous reactions appear as erythematous or violaceous patches of skin with various types of skin lesions, such as bullae, blisters, and ulcers, and epidermal detachment. SJS is classified as less than 10% of the body surface area with epidermal detachment while TEN is classified as over 30% and there is SJS/TEN overlap in between (10-30%). The SJS/TEN overlap typically involves the oral mucosa and other mucocutaneous areas. Other non-specific symptoms may include pain, fever, stinging eyes, malaise, sore throat, etc. SJS and TEN are commonly associated with drugs such as allopurinol, carbamazepine, phenytoin, lamotrigine, oxcarbazepine, phenobarbital, sulfonamide antibiotics, etc. Some of these drugs require patients to undergo pharmacogenomic testing before initiation of the drug to screen for certain genetic factors that may put the patient at high risk for SJS/TEN. For example, carbamazepine typically requires screening for the HLA-B*1502 allele prior to treatment initiation and patients who test positive for the allele should avoid using carbamazepine unless there are no other drug options and the benefits outweigh the risks. Even after being approved to use the drug, patients must be counseled to monitor for any skin reactions or other adverse reactions, especially during the first two months after drug initiation since a negative allele detection does not completely rule out the possibility of SJS/TEN. Management of SJS/TEN involves immediate discontinuation of the offending drug and supportive care. Supportive care usually consists of fluid and electrolyte replenishment and careful wound care. Treatment of SJS/TEN should be tailored to the individual patient because there is no drug to cure these conditions. Even after initial resolution, patients tend to live with long-term consequences such as scarring, irregular pigmentation, and other chronic skin conditions.

References:

1. Schneider JA, Cohen PR. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6):1235-1244. doi:10.1007/s12325-017-0530-y

2. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:39. Published 2010 Dec 16. doi:10.1186/1750-1172-5-39

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are often confused since they are so clinically similar. They are a delayed-type hypersensitivity reaction and differ in their distribution on the body. SJS affects <10% of body surface area while TEN affects 30% or more. The range of 10 to 30% of body distribution is known as the SJS/TEN overlap. Notably, both disorders affect 1 to 5 people in a million, making it extremely rare. Source 1 notes that severity and incidence may be increased in the case of bone marrow transplant recipients. The most common drugs that put patients in risk of SJS or TEN includes sulfa drugs, antibiotics like aminopenicillins, fluoroquinolones, and cephalosporins, antiseizures like phenytoin, carbamazepine, phenobarbital, valproate, NSAIDs, and antiretroviral drugs. If not drug related, other causes include infection, vaccination, or graft vs host disease. Merck notes that it is rare that a cause cannot be identified and this is valuable in that the more documentation of causes collected, the more efficiently future cases can be diagnosed due to statistics. Current perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis from Lerch, Marianne, et.al states “the acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.”

1. https://www.merckmanuals.com/professional/dermatologic-disorders/hypersensitivity-and-inflammatory-skin-disorders/stevens-johnson-syndrome-sjs-and-toxic-epidermal-necrolysis-ten

2. https://pubmed.ncbi.nlm.nih.gov/29188475/

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe and life-threatening skin reactions that have various causes such as viral or bacterial infections, drugs, or genetics (HLA-B*15:02 with carbamazepine in Asian population). With mortality rate being high, it is important for patients to receive immediate medical attention. Both skin conditions are commonly referred to as erythematous rashes that can be bullae or atypical lesions that will develop on the face and trunk of the body. These lesions will eventually spread out to other regions on the body with the epidermal layer separating from the dermis which is described as extremely painful. SJS/TEN is thought to be brought on by the activation of T-cells. The T-cells will be stimulated by drugs binding to the T-cell receptor through the antigen-presenting cells. The stimulation further transverses into the destruction of the epidermis caused by cytotoxic CD8+ T-cell apoptosis. SJS covers about 10% of the total body surface area while TEN is a more extreme case that covers more than 30% of the total body surface area. A patient suffering from SJS/TEN will first appear with systemic symptoms such as a fever and upper respiratory tract conditions followed by the painful rash. Other areas that can be affected could be the mucous membranes of the eyes, genitalia, and the mouth leading to dryness and erosion. There have been reports of SJS/TEN affecting major organ systems involving the liver, kidneys, and the lungs which is the reason why healthcare professionals must leap into action to provide specialized care for patients to reduce mortality risk. SJS/TEN has a large association with drugs. The most common type of drugs to cause SJS/TEN are antibiotics, allopurinol, NSAIDs, and anticonvulsants. Along with drug assessment, physicians may incorporate genetic testing for certain patients if they possess risk factors that put them at a higher risk of developing SJS/TEN.

One of the ways to initially manage the condition is to discontinue the offending agent as soon as possible. This step is crucial to prevent worsening of the disease. After discontinuing the agent, patients are then given supportive care to improve drying effects with fluid and electrolyte replacement (0.7ml/kg/% affected area), nutritional supplementation (albumin solution), pain relief, and supplemental oxygen if it is needed. It is also important that patients receive proper skin care treatment to the epidermis to promote wound healing due the destroyed keratinocytes. If a patient is suspected to have bacterial or viral infection, they are given an antibiotic to help decrease the risk of sepsis. Patients may also be treated with adjunctive therapy. Although there is still lack of evidence on the efficacy of adjunctive treatment such as systemic steroids, TNF-a blockers, and IV immunoglobulins, they may play a role in the treatment of SJS/TEN. Some studies have shown that high-dose systemic corticosteroids used short-term may reduce the risk of mortality and improved wound healing. Reports on the use of IV immunoglobulins is still controversial due to the conflicting data. Furthermore, there is still a lack of evidence with TNF-a blockers. Also, different countries follow different treatment guidelines with some providing supportive care as first-line while others providing systemic adjunctive therapy as first-line. Nonetheless, all the guidelines agree to stop the offending agent immediately and use supportive care to increase survival rate.

References

Schneider, J. A., & Cohen, P. R. (2017). Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Advances in therapy, 34(6), 1235–1244. https://doi.org/10.1007/s12325-017-0530-y

Hasegawa, A., & Abe, R. (2020). Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis. F1000Research, 9, F1000 Faculty Rev-612. https://doi.org/10.12688/f1000research.24748.1

Stevens-Johnson Syndrome, or SJS, is a mucocutaneous reaction usually caused by medications, characterized by extensive necrosis and detachment of the skin. Mucous membranes like the eyes, mouth and genitals are often affected in SJS. This disease is classified as SJS when less than 10% of the body’s skin falls off, whereas with TENS, or toxic epidermal necrolysis, more than 30% of the skin falls off. TENS is much more severe and fatal, and SJS can progress into it (known as SJS/TENS overlap). The incidence of this serious condition is more prominent in immunocompromised populations, like those living with HIV/AIDS or cancer. It is also more common in women than in men, and it can present a fatality range ranging from 10-40% depending on the patient, severity and duration of the symptoms.

SJS/TENS is caused by drugs in the majority of cases in both adults and children. The typical onset of symptoms is 4 days to 4 weeks of that specific drug treatment, so drugs that are used for a long period of time (> 8 weeks) are unlikely to be the cause of SJS/TENS. In a large case control study on UpToDate, it was found that the main causative agents included Allopurinol, aromatic antiepileptic drugs and lamotrigine, antibacterial sulfonamides (including sulfasalazine), Nevirapine, and oxicam nonsteroidal anti-inflammatory drugs (NSAIDs). Anticancer therapies have also been found to cause SJS or SJS-like presentations. Infections (for example, Mycoplasma pneumoniae) are also known to cause SJS/TENS.

While the pathology is not completely understood, it is suggested that a cell-mediated cytotoxic reaction occurs against keratinocytes leading to massive apoptosis. Drugs also target specific mediators in the skin that cause toxic reactions. SJS/TENs will usually occur rapidly and this acute phase will last about 8 to 12 days. It will present in the patient as fever, severe mucous membrane involvement, and epidermal sloughing that may be generalized and result in large, raw, painful areas of denuded skin. this sloughing of the skin will occur a few days after vesicles and bullae form. This can progress to more life-threatening complications like fluid loss, electrolyte imbalance, hypovolemic shock, bacteremia and multiple organ failure.

Prompt withdrawal and discontinuation of the suspected causative agent is the first step in treating and managing SJS/TENS. Any ocular involvement requires immediate attention. Then begins supportive care, similar for a burn victim, like wound care, fluid and electrolyte management, nutritional support, temperature management, pain control, and monitoring or treatment of superinfections. These patients will be in an immense amount of pain and will likely require therapy (ex: opioids) and close attention regarding pain control. The use of any drug therapies to specifically treat SJS/TENS is controversial. For example, the use of systemic corticosteroids has been studied but not fully evaluated.

1. Whitney A High, MD. Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. Mar 2019.

2. Whitney A High, MD. Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. UpToDate. Jan 2021.

Stevens Johnson Syndrome is a rare and acute form of toxic epidermal necrolysis. This rare form of TEN often comes as a reaction to drug-associated CD8+ lymphocytes and the process involves an apoptosis pathway as well as granule-mediated exocytosis. The TNF alpha death pathway is also implicated in the development of SJS. There are numerous medication agents that are known to be culprits behind SJS include: lamotrigine, carbamazepine, phenytoin, phenobarbitone, Allopurinol, sulfonamides such as cotrimoxazole, sulfasalazine, penicillins, cephalosporins, quinolones, minocycline, Paracetamol/acetaminophen, Nevirapine (non-nucleoside reverse-transcriptase inhibitor), Nonsteroidal anti-inflammatory drugs (NSAIDs), and contrast media. For some patients, there may be a genetic predisposition to developing SJS. Unique human leukocyte antigen (HLA) allotypes within patients can cause them to become severely sensitive to medications such as abacavir and allopurinol.

While the exact mechanism of SJS is speculated, it is theorized that the irritant (such as the medication) binds with the antigen or metabolite with the major histocompatibility complex (MHC) type 1 to form an immunogenic compound. The necrolysis process is T-cell mediated, leading to the recruitment of CD8+ cells, CD40 cells, TNF alpha, and interleukins. This reaction then ultimately leads to the breakdown of keratinocytes as well as epidermal necrosis. When a patient presents with SJS, the initial symptoms are nonspecific. This includes fever and malaise, which may not be easily identified as onset of SJS. Other nonspecific symptoms include myalgia, rhinitis, and sore eyes. However, by days three and fore, a rash may begin to form. As the rash progresses into a blistering rash, erosions appear on the face, trunk, limbs, and mucosal surfaces. Mucosal ulcerations that affect the lips, mouth and inner gastrointestinal tracts may also become present as SJS worsens.

If a patient is undergoing SJS then the first thing that is necessary is hospitalization. Patients are more than likely admitted to the intensive care unit or even the burn victim units due to the level of the epidermis that is involved. Once admitted to the hospital, one of the first measures that must be taken includes the discontinuation of current medications in order to eliminate the agent that is responsible for the manifestation of SJS. Due to the nature of the condition, fluid replacement and replenishment is a necessary step. This is something that is commonly done in burn victims, as well, due to the loss of much of the integumentary system. Wound care is another important aspect of treating SJS. Cool compresses to soothe blisters and regular cleaning of open wounds are necessary to ensure that the patient’s skin barrier remains infection-free. In addition, eye care may be required if SJS has progressed to the point where the mucosal barriers present are affected. Some medications may be initiated as well, including pain killers for symptomatic relief and antibiotics to prevent an infection.

https://www.mayoclinic.org/diseases-conditions/stevens-johnson-syndrome/diagnosis-treatment/drc-20355942

https://www.ncbi.nlm.nih.gov/books/NBK459323/

Stevens Johnson Syndrome (SJS) is a serious skin reaction usually initiated after certain drug treatment as the body’s immune response when a drug is not tolerated. It presents initially as a rash, with blisters on the extremities like the hands and the feet. It covers only 10% of the skin that can progress to something greater that involves 30% of the skin called TENS, which is much more serious in nature. Mortality associated with stevens Johnson syndrome is 5-18%, and usually lasts for a month to a month and a half (4-6 weeks). It can cause detachment of the epidermal portion of the skin. This can cause extreme joint pain and hemorrhagic skin. Steven Johnson syndrome can also cause serious secondary infections like pneumonia due to its effect on the lungs. It can have mucosal membrane involvement in the eyes, mouth, gastrointestinal tract and even the genital area depending on how much of the skin is involved in the reaction. Any medication can cause this reaction but a class that is known to cause stevens Johnson syndrome are anti-convulsant medications like carbamazepine, phenytoin and phenobarbital. In order to treat the reaction, it has to be treated based on how severe the reaction is. Treatment includes fluid hydration, temperature control since the patient will feel colder than usual due to the lack of skin barrier protecting the body, and proper analgesic therapy. HLA variant testing can be done prior to the use of certain drugs like Carbamazepine in order to test an individual’s likeliness of developing steven Johnson syndrome. Carbamazepine HLA testing tests for the HLA B*1502. Abacavir also requires testing prior to initiation of therapy for the HLA B*5701 allele. Lamotrigine also must be screened for the HLA B*1502 allele variant prior to starting therapy. Allopurinol also requires HLA-B*5801 screening, especially in the Asian population. The steven Johnson syndrome (SJS) is a rare and potentially fatal skin reaction that can cause copious amounts of skin to be shed. It is unpredictable in nature and involves CD8+ cytotoxic lymphocytes and TNF-alpha (tumor necrosis factor alpha) that are heavily involved in the body’s inflammatory response. It can also cause multiple organ failure including the liver, the kidney and the lungs. Treatment involves a multi-disciplinary approach with treatment from a dermatologist, respiratory specialist and regular care team. Pain management and supportive care is crucial to therapy management with steven Johnson syndrome. Corticosteroid treatment is also necessary for pain management and inflammation management. Routine examination of the skin and mucosal surfaces for infection and proper wound dressing is essential in order to heal the surface from the inside out. A pharmacist is also essential to conclude which drugs on a patient’s medication list can contribute to the steven Johnson syndrome (SJS) reaction and offer potential alternatives that can be used to replace the culprit therapy. It is necessary to do the appropriate monitoring and screening prior to any drug therapy. It is also necessary to look at the skin for any abnormalities when starting a new drug.

References:

https://www.ncbi.nlm.nih.gov/books/NBK459323/

Stevens-Johnson syndrome and Toxic Epidermal Necrolysis are rare, serious, and potentially fatal skin reactions in which there is mucosal loss with systemic symptoms. Medications are the common cause of these reactions. In SJS, there are blister and atypical target lesions in less than 10% of the body surface area. In TENS, blisters cover greater than 30% of the body surface area. SJS is about three times more common than TENS. The exact mechanism is unknown but some theories involve the cytotoxic CD8+ lymphocytes, binding of the drug to MHC-1 and T cell receptors, pro-hapten in which the metabolites become immunogenic, etc. Common drugs that cause SJS/TENS are allopurinol, long-acting sulfonamides, carbamazepines, fluoroquinolones, and hydantoin. There are genetic factors of human leukocytes antigen allotypes that can lead to an increased risk of SJS/TENS. An example would be Europeans with HLA-A*3101 has an increased risk if they take carbamazepine. Another example would be Han Chinese people who has HLA-B*5801 and take allopurinol. In the beginning of the reaction, there would be nonspecific symptoms like fever, cough, and myalgia. Then, in the next few days, a blistering rash and erosions will appear on mucosal surfaces. Organ failure can occur including the liver, kidney, and lungs. A multidisciplinary team is necessary to help manage the patient. This team includes specialists such as dermatologist, respiratory physician, intensivist, etc. A pharmacist is also essential to be included to determine the trigger for this condition. Supportive care is necessary to help manage the patient. This includes cessation of the suspected drug, fluid replacement, pain relief, nutritional assessment, etc. 

References

Oakley AM, Krishnamurthy K. Stevens Johnson Syndrome (Toxic Epidermal Necrolysis) [Updated 2020 Apr 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459323/

Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare, serious, and potentially fatal skin reaction in which massive amounts of skin are being shed. This is a rare and unpredictable reaction to medication that involves drug specific CD8+ cytotoxic lymphocytes, the Fas-Fas ligand, granule-mediated exocytosis, and tumor necrosis factor-alfa (TNF–alpha). Stevens-Johnson syndrome/toxic epidermal necrolysis can affect anyone with a genetic predisposition: any age, either sex and all races, although it is more common in older people and women. It is also much more likely to occur in people infected with human immunodeficiency virus (HIV). The biggest cause of Stevens-Johnson syndrome/toxic epidermal necrolysis is side effects of medications. In fact, medication side effects account for more than 80% of all Stevens-Johnson syndrome/toxic epidermal necrolysis cases. Some of the medications that cause this reaction include, but are not limited to, anticonvulsants, Allopurinol in doses more than 100mg per day, sulfonamides, antibiotics, and non steroidal anti-inflammatory drugs. Sepsis is the most common serious risk of Stevens-Johnson syndrome/toxic epidermal necrolysis due to bacteria now being able to bypass our defensive layer of skin. Organ failure may also occur including pulmonary, hepatic and renal systems. As a result of the severe complications that can arise from a patient suffering from Stevens-Johnson syndrome/toxic epidermal necrolysis, patients are advised to go to the hospital immediately where they will most likely be taken to a intensive care and/or burn unit and be examined by a specialist. The specialist will then usually recommend a daily skincare routine. This routine requires daily examination of skin and mucosal surfaces for infection, non-adherent dressings, and avoidance of trauma to the skin. Antibiotics may be required for secondary infection but are best avoided prophylactically. Corticosteroids are also prescribed in high dose for the first three to five days of admission.

References

Fakoya AOJ, Omenyi P, Anthony P, et al. Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis; Extensive Review of Reports of Drug-Induced Etiologies, and Possible Therapeutic Modalities. Open Access Maced J Med Sci. 2018;6(4):730-738.

Oakley, A. (2020, April 28). Stevens Johnson Syndrome (Toxic Epidermal Necrolysis). Retrieved August 14, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK459323/

Based on the type of drug that may be prescribed, there are certain HLA variant testing needed in order to be given prior to administration of the drug. Human leukocyte antigen testing detects inherited antibodies that can cause hypersensitivity reactions. Depending on which HLA variant that is being tested for, the patient will either get blood drawn from their vein and tested or a swab from the inside of their cheek. Though this process is fairly simple, it is critical to the safety of drugs that are at higher risk for Steven Johnson’s Syndrome (SJS). For example, HLA B*5701 is one of the most common HLA variants that need to be tested for when starting abacavir therapy. Abacavir is a very effective human immunodeficiency virus medication, however should not be used in any patients that are positive for the HLA B*5701 allele. Likewise carbamazepine, a common anticonvulsant, has high rates of hypersensitivity reactions and SJS. All patients should be screened prior to therapy for the HLA B*1502 to ensure that this medication will be safe for the patients. Lastly lamotrigine, another anticonvulsant/mood stabilizer, has the potential for SJS though hypersensitivity reactions as well. Yet again, all patients that are starting this medication must be screened for the B*1502 variant.

https://www.labcorp.com/help/patient-test-info/hla-testing

https://elifesciences.org/articles/34961

Stevens-Johnson Syndrome: