Stevens–Johnson syndrome (SJS) is a form of erythema multiforme which is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate 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
Classification
There is agreement in the medical literature that Stevens–Johnson syndrome (SJS) can be considered a milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922. Both diseases can be mistaken for erythema multiforme. 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. Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications. Their consequences are potentially more dangerous than those of erythema multiforme.Signs and symptoms
SJS usually begins with 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.Causes
SJS is thought to arise due to a disorder of the immune system.Infectious
It can be caused by infections (usually following infections such as herpes simplex virus, influenza, mumps, cat-scratch fever, histoplasmosis, Epstein-Barr virus, mycoplasma pneumoniae or similar).Medication/drugs
It can be due to adverse effects of drugs (allopurinol, diclofenac, etravirine, Isotretinoin, aka Accutane, fluconazole, valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, modafinil, lamotrigine, nevirapine, pyrimethamine, ibuprofen, ethosuximide, carbamazepine and gout medications)
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.
Medications that have traditionally been known to lead to SJS, erythema multiforme and toxic epidermal necrolysis include sulfonamides (antibiotics), penicillins (antibiotics), barbiturates (sedatives), lamotrigine and phenytoin (e.g. Dilantin) (anticonvulsants). Combining lamotrigine with sodium valproate increases the risk of SJS.
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. Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.
SJS has also been consistently reported as an uncommon side effect of herbal supplements containing ginseng. SJS may also be caused by cocaine usage.
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.[10][11][12] A study in Europe suggested that the gene marker is only relevant for East Asians.[13][14] Based on the Asian findings, similar studies were performed in Europe which showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (B*5801 allele - phenotype frequency 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."
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.
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.
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.
Other agents have been used, including cyclophosphamide and cyclosporine, but none have 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. Also, an extensive physical therapy program ensues after the patient is discharged from the hospital.
Prognosis
SJS proper (with less than 10% of body surface area involved) has a mortality rate of around 5%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account. Other outcomes include organ damage/failure, cornea scratching and blindness.
Epidemiology
Stevens-Johnson syndrome is a rare condition, with a reported incidence of around 2.6 to 6.1 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 three to two sex ratio.
- Typically, the disease process begins with a nonspecific upper respiratory tract infection.
- This usually is part of a 1- to 14-day prodrome during which fever, sore throat, chills, headache, and malaise may be present.
- Vomiting and diarrhea are occasionally noted as part of the prodrome.
- Mucocutaneous lesions develop abruptly. Clusters of outbreaks last from 2-4 weeks. The lesions are typically nonpruritic.
- A history of fever or localized worsening should suggest a superimposed infection; however, fever has been reported to occur in up to 85% of cases.
- Involvement of oral and/or mucous membranes may be severe enough that patients may not be able to eat or drink.
- Patients with genitourinary involvement may complain of dysuria or an inability to void.
- A history of a previous outbreak of Stevens-Johnson syndrome (SJS) or of erythema multiforme may be elicited. Recurrences may occur if the responsible agent is not eliminated or if the patient is reexposed.
- Typical symptoms are as follows:
- Cough productive of a thick purulent sputum
- Headache
- Malaise
- Arthralgia
- Physical
- The center of these lesions may be vesicular, purpuric, or necrotic.
- The typical lesion has the appearance of a target. The target is considered pathognomonic. However, in contrast to the typical erythema multiforme lesions, these lesions have only two zones of color. The core may be vesicular, purpuric, or necrotic; that zone is surrounded by macular erythema. Some have called these targetoid lesions.
- Lesions may become bullous and later rupture, leaving denuded skin. The skin becomes susceptible to secondary infection. Extensive sloughing is shown in the image below.
Note extensive sloughing of epidermis from Stevens-Johnson syndrome. Courtesy of David F. Butler, MD.
- Urticarial lesions typically are not pruritic.
- Infection may be responsible for the scarring associated with morbidity.
- Although lesions may occur anywhere, the palms, soles, dorsum of the hands, and extensor surfaces are most commonly affected. Desquamation on the foot is shown in the image below.
Sheetlike desquamation on the foot in a patient with toxic epidermal necrolysis. Courtesy of Robert Schwartz, MD.
- The rash may be confined to any one area of the body, most often the trunk.
- Mucosal involvement may include erythema, edema, sloughing, blistering, ulceration, and necrosis. An example of this type of involvement is shown in the image below.
Hemorrhagic crusting of the mucous membranes in toxic epidermal necrolysis. Similar lesions are seen in Stevens-Johnson syndrome. Courtesy of Robert Schwartz, MD.
- Although some have suggested the possibility of Stevens-Johnson syndrome (SJS) without skin lesions, most believe that mucosal lesions alone are not enough to establish the diagnosis. Some are now calling cases without skin lesions "atypical" or "incomplete." This group of authors suggested that the combination of urethritis, conjunctivitis, and stomatitis made the diagnosis of SJS in a patient with Mycoplasma pneumoniae -induced signs and symptoms.
- The following signs may be noted on examination:
- Fever
- Orthostasis
- Tachycardia
- Hypotension
- Altered level of consciousness
- Epistaxis
- Conjunctivitis
- Corneal ulcerations
- Erosive vulvovaginitis or balanitis
- Seizures, coma
- The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema.
Causes
- Drugs and malignancies are most often implicated as the etiology in adults and elderly persons.
- Pediatric cases are related more often to infections than to malignancy or a reaction to a drug.
- Oxicam NSAIDs and sulfonamides are most often implicated in western nations. In Southeast Asia, allopurinol is most common.
- A medication such as sulfa, phenytoin, or penicillin had previously been prescribed to more than two thirds of all patients with Stevens-Johnson syndrome (SJS). The anticonvulsant oxcarbazepine (Trileptal) has also been implicated. Hallgren et al reported ciprofloxacin-induced Stevens-Johnson syndrome in young patients in Sweden and commented on several others. Metry et al reported Stevens-Johnson syndrome in 2 HIV patients treated with nevirapine and mentioned one other in the literature. The authors speculated that the problem may extend to other non-nucleoside reverse transcriptase inhibitors. Indinavir has been mentioned.
- More than half of the patients with Stevens-Johnson syndrome report a recent upper respiratory tract infection.
- The 4 etiologic categories are (1) infectious, (2) drug-induced, (3) malignancy-related, and (4) idiopathic.
- Viral diseases that have been reported include herpes simplex virus (HSV), AIDS, coxsackie viral infections, influenza, hepatitis, mumps, lymphogranuloma venereum (LGV), rickettsial infections, and variola.
- Bacterial etiologies include group A beta streptococci, diphtheria, Brucellosis, mycobacteria, Mycoplasma pneumoniae, tularemia, and typhoid. An "incomplete" case was recently reported after Mycoplasma pneumoniae infection.
- Coccidioidomycosis, dermatophytosis, and histoplasmosis are the fungal possibilities.
- Malaria and trichomoniasis have been reported as protozoal causes.
- In children, Epstein-Barr virus and enteroviruses have been identified.
- Antibiotic etiologies include penicillins and sulfa antibiotics. Anticonvulsants including phenytoin, carbamazepine, valproic acid, lamotrigine, and barbiturates have been implicated. Mockenhapupt et al stressed that most anticonvulsant-induced SJS occurs in the first 60 days of use. In late 2002, the US Food and Drug Administration (FDA) and the manufacturer Pharmacia noted that Stevens-Johnson syndrome (SJS) had been reported in patients taking the cyclooxygenase-2 (COX-2) inhibitor valdecoxib. In 2007, the US FDA reported SJS/TEN in patients taking modafinil (Provigil). Allopurinol has recently been implicated as the most common cause in Europe and Israel.
- The most recent additions to possible drug-induced cases include the antidepressant mirtazapine and the TNF-alpha antagonists infliximab, etanercept, and adalimumab.
- Various carcinomas and lymphomas have been associated.
- Stevens-Johnson syndrome (SJS) is idiopathic in 25-50% of cases.
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