Stevens–Johnson syndrome

Stevens–Johnson syndrome
Classification and external resources
Man with Stevens–Johnson syndrome
ICD-10	L51.1
ICD-9	695.13
OMIM	608579
DiseasesDB	4450
MedlinePlus	000851
eMedicine	emerg/555 derm/405
MeSH	D013262

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two forms of a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex that affects the skin and the mucous membranes. The most well known causes are certain medications, but it can also be due to infections, or more rarely, cancers.

Classification

Stevens–Johnson syndrome (SJS) is a milder form of toxic epidermal necrolysis (TEN).^[1] These conditions were first recognised in 1922.^[2]

Both diseases can be mistaken for erythema multiforme.^[3] Erythema multiforme is sometimes caused by a reaction to a medication, but is more often a type IV hypersensitivity reaction to an infection (caused most often by Herpes simplex) and is relatively benign.^{[citation needed]} Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications.^{[citation needed]} Their consequences are potentially more dangerous than those of erythema multiforme.^{[citation needed]}

Signs and symptoms

Mucosal desquamation in a person with Stevens–Johnson syndrome

Conjunctivitis (inflammation of eye and eyelid) in SJS

Stevens–Johnson syndrome (SJS) usually begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore 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.^[4]

Pathology

Micrograph showing full thickness epidermal necrosis with a basket weave-like stratum corneum and separation of the dermis and epidermis. Skin biopsy. H&E stain.

SJS, like toxic epidermal necrolysis and erythema multiforme, is characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum. An idiosyncratic, delayed hypersensitivity reaction has been implicated in the pathophysiology of Stevens–Johnson syndrome. Certain population groups appear more susceptible to develop Stevens–Johnson syndrome than the general population. Slow acetylators, patients who are immunocompromised (especially those infected with HIV ), and patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk.

Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites. For example, patients with sulfonamide-induced toxic epidermal necrolysis have been shown to have a slow acetylator genotype that results in increased production of sulfonamide hydroxylamine via the P-450 pathway. These drug metabolites may have direct toxic effects or may act as haptens that interact with host tissues, rendering them antigenic.

Antigen presentation and production of tumor necrosis factor (TNF)–alpha by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocyte proliferation and enhances the cytotoxicity of the other immune effector cells. A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic lymphocytes. The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin.

In 1997, Inachi et al. demonstrated perforin-mediated apoptosis in patients with Stevens–Johnson syndrome. Perforin, a pore-making monomeric granule released from natural killer cells and cytotoxic T lymphocytes, kills target cells by forming polymers and tubular structures not unlike the membrane attack complex of the complement system.

Apoptosis of keratinocytes can also take place as a result of ligation of their surface death receptors with the appropriate molecules. Those can trigger the activation of the caspase system, leading to DNA disorganization and cell death.

Apoptosis of keratinocytes can be mediated via direct interaction between the cell-death receptor Fas and its ligand. Both can be present on the surfaces of the keratinocytes. Alternatively, activated T-cells can release soluble Fas ligand and interferon-gamma, which induces Fas expression by keratinocytes. Researchers have found increased levels of soluble Fas ligand in the sera of patients with SJS/TEN before skin detachment or onset of mucosal lesions.

The death of keratinocytes causes separation of the epidermis from the dermis. Once apoptosis ensues, the dying cells provoke recruitment of more chemokines. This can perpetuate the inflammatory process, which leads to extensive epidermal necrolysis.

Higher doses and rapid introduction of allopurinol and lamotrigine may also increase the risk of developing SJS/TEN. Risk is lessened by starting these at the low doses and titrating gradually.

There is evidence that systemic lupus is a risk factor as well.

Causes

Stevens–Johnson syndrome (SJS) is thought to arise from a disorder of the immune system.^[4] The immune reaction can be triggered by infections, drugs, or medications.^[5] In some groups, drug reaction may be aggravated by genetic factors.^[6]

Infections

SJS can be caused by infections. It usually follows common infections such as herpes simplex virus, influenza, mumps, cat-scratch fever, histoplasmosis, Epstein-Barr virus, mycoplasma pneumoniae, or similar. Infectious causes Viral diseases that have been reported to cause Stevens–Johnson syndrome include the following:

• Herpes simplex virus (possibly; remains a debated issue)
• AIDS
• Coxsackievirus
• Viral infections
• Influenza
• Hepatitis
• Mumps

In children, Epstein-Barr virus and enteroviruses have been identified. More than half of the patients with Stevens–Johnson syndrome report a recent upper respiratory tract infection.

Bacterial etiologies include the following:

• Group A beta-hemolytic streptococci
• Diphtheria
• Brucellosis
• Lymphogranuloma venereum
• Mycobacteria
• Mycoplasma pneumoniae
• Ricketsial infections
• Tularemia
• Typhoid

Possible fungal causes include coccidioidomycosis, dermatophytosis, and histoplasmosis. Malaria and trichomoniasis have been reported as protozoal causes.

Medication/drugs

Although Stevens–Johnson Syndrome can be caused by viral infections, malignancies, or severe allergic reactions to medication, the leading cause appears to be the use of antibiotics and sulfa drugs.^[7][8]

SJS can be caused by adverse effects of drugs allopurinol, valproate, levofloxacin, diclofenac, etravirine, isotretinoin, fluconazole,^[9] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,^[10] lamotrigine, nevirapine, pyrimethamine, ibuprofen,^[11] ethosuximide, carbamazepine, bupropion TELAPREVIR , and nystatin.^[12][13]

Medications that have traditionally been known to lead to SJS, erythema multiforme and toxic epidermal necrolysis include sulfonamides (antibiotics), penicillins (antibiotics), cefixime (antibiotic), barbiturates (sedatives), lamotrigine, and phenytoin (e.g., Dilantin) (anticonvulsants). Also Trimethoprime. Combining lamotrigine with sodium valproate increases the risk of SJS.^{[citation needed]}

Non-steroidal anti-inflammatory drugs are a rare cause of SJS in adults; the risk is higher for older patients, women and those initiating treatment.^[2] Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. Similar to Non-steroidal anti-inflammatory drugs, Paracetamol (Acetaminophen) has also caused rare cases^[14][15] of SJS. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.^[4]

Genetics

In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15.^[16][17][18] A study in Europe suggested that the gene marker is only relevant for East Asians.^[19][20]

Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (phenotype frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."^[21]

Treatment

SJS constitutes a dermatological emergency. All medications should be discontinued, particularly those known to cause SJS reactions. Patients with documented mycoplasma infections can be treated with oral macrolide or oral doxycycline.^[4]

Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g. intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.^[4]

Beyond this kind of supportive care, there is no accepted treatment for SJS. Treatment with corticosteroids is controversial. Early retrospective studies suggested that corticosteroids increased hospital stays and complication rates. There are no randomized trials of corticosteroids for SJS, and it can be managed successfully without them.^[4]

Other agents have been used, including cyclophosphamide and cyclosporine, but none has exhibited much 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, impaired vision and a host of other ocular problems.

Prognosis

SJS (with less than 10% of body surface area involved) has a mortality rate of around 5%. The mortality for toxic epidermal necrolysis (TEN) is 30–40 percent. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account.^[22] Other outcomes include organ damage/failure, cornea scratching, and blindness.^{[citation needed]}

Epidemiology

Stevens–Johnson syndrome is a rare condition, with a reported incidence of around 2.6^[4] to 6.1^[2] cases per million people per year. In the United States, there are about 300 new diagnoses per year. The condition is more common in adults than in children. Women are affected more often than men, with cases occurring at a two to one (2:1) ratio.^[2]

History

Stevens–Johnson Syndrome is named for Albert Mason Stevens and Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in the American Journal of Diseases of Children in 1922.^{[23][24][25][26]}

Notable cases

• Ab-Soul, American hip hop recording artist and member of Black Hippy.^[27]
• Padma Lakshmi, actress, model, television personality, and cookbook writer;^[28]
• Tessa Keller of MTV show Laguna Beach;^[29]
• Sabrina Brierton Johnson, whose family unsuccessfully sued the manufacturer of Children's Motrin, Johnson & Johnson, after a case of SJS blinded her.^[30]
• Manute Bol, former professional basketball player and member of NBA's Washington Bullets, Golden State Warriors, Philadelphia 76ers, and Miami Heat, who died from complications.^[31]
• Gene Sauers, three-time PGA Tour winner^[32]
• Calvin Lock, from Littleport, Cambridgeshire, almost died after he was given Nurofen, one of the most popular brands of children's medicine containing ibuprofen. Doctors diagnosed him as having SJS or Toxic Epidermal Necrolysis Syndrome.^[33][34]

See also

• Erythema multiforme major
• Alan Lyell
• List of cutaneous conditions

References

Stevan Johnson syndrome treatment s by medibird.com

Further reading

• Boyer, Woodrow Allen (May 2008). Understanding Stevens–Johnson Syndrome & Toxic Epidermal Necrolysis (New Expanded ed.). Raleigh, North Carolina: Lulu Press.