Stevens–Johnson syndrome
Stevens–Johnson syndrome is a type of severe skin reaction. Together with toxic epidermal necrolysis and [|Stevens–Johnson/toxic epidermal necrolysis] overlap, they are considered febrile mucocutaneous drug reactions and probably part of the same spectrum of disease, with SJS being less severe. Erythema multiforme is generally considered a separate condition. Early symptoms of SJS include fever and flu-like symptoms. A few days later, the skin begins to blister and peel, forming painful raw areas. Mucous membranes, such as the mouth, are also typically involved. Complications include dehydration, sepsis, pneumonia and multiple organ failure.
The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics and nevirapine. Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus, or the cause may remain unknown. Risk factors include HIV/AIDS and systemic lupus erythematosus.
The diagnosis of Stevens–Johnson syndrome is based on involvement of less than 10% of the skin. It is known as TEN when more than 30% of the skin is involved and considered an intermediate form when 10–30% is involved. SJS/TEN reactions are believed to follow a type IV hypersensitivity mechanism. It is also included with drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis and toxic epidermal necrolysis in a group of conditions known as severe cutaneous adverse reactions.
Treatment typically takes place in hospital such as in a burn unit or intensive care unit. Efforts may include stopping the cause, pain medication, antihistamines, antibiotics, intravenous immunoglobulins or corticosteroids. Together with TEN, SJS affects 1 to 2 people per million per year. Typical onset is under the age of 30. Skin usually regrows over two to three weeks; however, complete recovery can take months. Overall, the risk of death with SJS is 5 to 10%.
Signs and symptoms
SJS usually begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore treated with antibiotics. SJS, SJS/TEN, and TEN are often heralded by fever, sore throat, cough, and burning eyes for 1 to 3 days. Patients with these disorders frequently experience burning pain of their skin at the start of disease. 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 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.Causes
SJS is thought to arise from a disorder of the immune system. The immune reaction can be triggered by drugs or infections. Genetic factors are associated with a predisposition to SJS. The cause of SJS is unknown in one-quarter to one-half of cases. SJS, SJS/TEN, and TEN are considered a single disease with common causes and mechanisms.Individuals expressing certain human leukocyte antigen serotypes, genetical-based T cell receptors, or variations in their efficiency to absorb, distribute to tissues, metabolize, or excrete a drug are predisposed to develop SJS.
Medications
Although SJS can be caused by viral infections and malignancies, the main cause is medications. A leading cause appears to be the use of antibiotics, particularly sulfa drugs. Between 100 and 200 different drugs may be associated with SJS. No reliable test exists to establish a link between a particular drug and SJS for an individual case. Determining what drug is the cause is based on the time interval between first use of the drug and the beginning of the skin reaction. Drugs discontinued more than 1 month prior to onset of mucocutaneous physical findings are highly unlikely to cause SJS and TEN. SJS and TEN most often begin between 4 and 28 days after culprit drug administration. A published algorithm to assess drug causality gives structured assistance in identifying the responsible medication.SJS may be caused by the medications rivaroxaban, vancomycin, allopurinol, valproate, levofloxacin, diclofenac, etravirine, isotretinoin, fluconazole, valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil, lamotrigine, nevirapine, pyrimethamine, ibuprofen, ethosuximide, carbamazepine, bupropion, telaprevir, and nystatin. Genetic susceptibility plays a significant role in drug-induced Stevens-Johnson syndrome. Individuals who carry HLA-B15:02 or HLA-A31:01 are at substantially increased risk of carbamazepine-induced Stevens–Johnson syndrome.
Medications that have traditionally been known to lead to SJS, erythema multiforme, and toxic epidermal necrolysis include sulfonamide antibiotics, penicillin antibiotics, cefixime, barbiturates, lamotrigine, phenytoin and trimethoprim. Combining lamotrigine with sodium valproate increases the risk of SJS.
Nonsteroidal anti-inflammatory drugs are a rare cause of SJS in adults; the risk is higher for older patients, women, and those initiating treatment. Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. Similar to NSAIDs, paracetamol has also caused rare cases of SJS. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.
Infections
The second most common cause of SJS and TEN is infection, particularly in children. This includes upper respiratory infections, otitis media, pharyngitis, and Epstein–Barr virus, Mycoplasma pneumoniae and cytomegalovirus infections. The routine use of medicines such as antibiotics, antipyretics and analgesics to manage infections can make it difficult to identify if cases were caused by the infection or medicines taken.Viral diseases reported to cause SJS include: herpes simplex virus, AIDS, coxsackievirus, influenza, hepatitis, and mumps.
In pediatric cases, Epstein–Barr virus and enteroviruses have been associated with SJS.
Recent upper respiratory tract infections have been reported by more than half of patients with SJS.
Bacterial infections linked to SJS include group A beta-hemolytic streptococci, diphtheria, brucellosis, lymphogranuloma venereum, mycobacteria, Mycoplasma pneumoniae, rickettsial infections, tularemia, and typhoid.
Fungal infections with coccidioidomycosis, dermatophytosis and histoplasmosis are also considered possible causes. Malaria and trichomoniasis, protozoal infections, have also been reported as causes.
Pathophysiology
SJS is a type IV hypersensitivity reaction in which a drug or its metabolite stimulates cytotoxic T cells and T helper cells to initiate autoimmune reactions that attack self tissues. In particular, it is a type IV, subtype IVc, delayed hypersensitivity reaction dependent in part on the tissue-injuring actions of natural killer cells. This contrasts with the other types of SCARs disorders, i.e., the DRESS syndrome which is a Type IV, Subtype IVb, hypersensitivity drug reaction dependent in part on the tissue-injuring actions of eosinophils and acute generalized exanthematous pustulosis which is a Type IV, subtype IVd, hypersensitivity reaction dependent in part on the tissue-injuring actions of neutrophils.Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8+ T cells or CD4+ T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the antigen presentation pathways of the innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen component of their major histocompatibility complex ; and presents the MHC-associated peptides to T-cell receptors on CD8+ T cells or CD4+ T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. In all these cases, however, a non-self epitope must bind to a specific HLA serotype in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite. Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes: Studies have identified several HLA serotypes associated with development of SJS, SJS/TEN, or TEN in response to certain drugs. In general, these associations are restricted to the cited populations.
In some East Asian populations studied, carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502, an HLA-B serotype of the broader serotype HLA-B15. A study in Europe suggested the gene marker is only relevant for East Asians. This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered.
Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58. 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."
Other HLA associations with the development of SJS, SJS/TEN, or TEN and the intake of specific drugs as determined in certain populations are given in HLA associations with SCARs.