Erythema Multiforme and Stevens-Johnson Syndrome

Erythema multiforme is clinically a circumscribed and well-defined condition. Its salient and diagnostically most important feature are the iris-like lesions, ranging 

Drug-induced erythema multiforme is histologically and even clinically related to fixed drug eruptions. There also seems to be some relationship to Lyell s syndrome, as transitional cases have been observed (Schuppli 1972). 

The etiology is by no means the same in all cases. Erythema multiforme can be caused by various totally unconnected factors. The eruption most commonly arises after infections with herpesviruses or streptococci. In comparison with these, drugs are relatively seldom the cause. However, if drug-induced rashes of erythema multiforme type are included, much larger numbers will be recorded (e.g., ampicillin rashes). 

According to Wereide (1967) the incidence of sulfonamide-induced Stevens-Johnson syndrome in Norway is one case from two million single doses, i.e., one case from one ton of sulfonamide (Hjorth 1968). 

Among other drugs which have been blamed are penicillins, streptomycin, barbiturates, oral antidiabetics, hydantoins, diuretics, quinine, and smallpox vaccine (Betson and Alfordt 1961 Dugois et al. 1957 Lutz 1951 Saxl 1972 Schuppli 1972 Strempel 1959 Tullett 1966, Vayre and Combey 1955 Watts 1962 WoRiNGER and Levy 1949 Yaffee 1959, 1960). 

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Less frequent are skin rashes, tinnitus and liver function disturbances. Erythema multiforme and Stevens-Johnson syndrome have been reported. 

Unithiol has been reported to have a low overall incidence of adverse effects (< 4%). Self-limited dermatologic reactions (drug exanthems or urticaria) are the most commonly reported adverse effects, although isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. Because rapid intravenous infusion may cause vasodilation and hypotension, unithiol should be infused slowly over an interval of 15-20 minutes. 

The patient is sensitized to the medication, causing a hypersensitive reaction (rash, urticaria, papules, or vesicles) or erythema multiforme and Stevens-Johnson syndrome, which is life threatening. Reaction can take minutes, hours, or a day. Medications known to cause dermatitis are ... 

The following drugs have been most often associated with erythema multiforme and Stevens-Johnson syndrome allopurinol, lamotrigine phenytoin, barbiturates, carbamazepine, estrogens/progestins, gold, NSAIDs, penicillamine, sulfonamides, tetracycline, and tolbutamide. 

As with all drugs in this class, the most common side effect of delavirdine is rash, which occurs in 18 to 36% of subjects. Rash usually is seen in the first few weeks of treatment and often resolves despite continued therapy. The rash may be macular, papular, erythematous, or pruritic and usually involves the trunk and extremities. Fewer than 5% of patients discontinue delavirdine because of rash. Severe dermatitis, including erythema multiforme and Stevens-Johnson syndrome, has been reported but is rare. Elevated hepatic transaminases also have been reported, but delavirdine use is not associated with fatal hepatitis. Neutropenia also may occur rarely. 

Allergic reactions include rash, fever, hepatitis, agranulocytosis, purpura, aplastic anaemia, peripheral neuritis and polyarteritis nodosa. Rarely, severe skin reactions including erythema multiforme bullosa (Stevens-Johnson syndrome) and toxic epidermal necrolysis (LyelTs syndrome) occur. 

In a spontaneous reporting system of individuals who had been exposed to Fansidar in 27 countries, an estimated 117 million users, there were 126 reports 87 cases of erythema multiforme or Stevens-Johnson syndrome and 39 cases of toxic epidermal necrolysis 86% of the cases were reported in Europe or North America (13). The fatality rates were 36% for toxic epidermal necrolysis (95% Cl = 21, 53) and 9% for erythema multiforme/ Stevens-Johnson syndrome (4, 18). The overall SCAR risk was 1.1 (0.9, 1.3) per million. For developing countries with mainly single-dose use, the risk was estimated at 0.1 (0.0, 0.1) per million. For Europe and North America, with mainly prophylactic use, the risks were 10 (8,12) and 36 (23, 48) per million respectively. 

Vancomycin can cause the severe forms of erythema multiforme, both Stevens-Johnson syndrome (involvement of 10-30% of the skin surface) (68) and toxic epidermal necrolysis (more than 30% of the skin surface involved) both conditions include mucosal involvement. 

Penicillin is a potent topical sensitizer and may cause contact dermatitis (Levine 1960 a Fellner 1976) it is therefore no longer used in ointments. Several other cutaneous manifestations of penicillin allergy, such as fixed drug eruption, erythema multiforme, the Stevens-Johnson syndrome, exfoliative dermatitis, epidermal necrolysis, erythema nodosum and cutaneous necrotizing angiitis have been described (Fellner 1976 Soter and Austen 1978 Wintraub et al. 1979 De Swar-TE 1972). The precise immunological mechanisms of these various forms of cutaneous reactions are usually not known. 

Erythema multiforme, liver damage, and Stevens-Johnsons syndrome occur rarely. 

Rzany B, Mockenhaupt M, Baur S, Schroder W, Stocker U, Mueller J, Hollander N, Bruppacher R, Schopf E. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992) structure and results... 

Pruritus and skin rashes can occur (15). Much more rarely, toxic epidermal necrolysis has occurred after a total dose of 1800 mg, and Stevens-Johnson syndrome and erythema multiforme have also been reported (16). 

Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J, Schopf E. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 1996 135(1) 6-11. 

Postmarketing and other experience these data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, and Stevens-Johnson syndrome. 

Albendazole, thiabendazole and mebendazole are also used in human medicine for the treatment of helminthiasis. Thiabendazole is frequently associated with anorexia, nausea, vomiting and dizziness at therapeutic doses. It may also cause diarrhoea, drowsiness and headache. It has resulted in erythema multiforme, hallucinations, sensory disturbances and Stevens-Johnson syndrome. Mebendazole is without significant toxicity although it may cause abdominal pain and diarrhoea. Like mebendazole, albendazole is well tolerated and only occasionally results in abdominal pain, diarrhoea, nausea, dizziness and headache. Very rarely, it may cause signs of hepatotoxicity including increases in liver enzymes, jaundice and cholestasis and it is usually recommended that its use be avoided in patients with cirrhosis. Albendazole has been reported to cause pseudomembranous colitis and dystonia in children. 

NSAIDs can induce a number of other adverse reactions, including bleeding disorders, anemia, thrombocytopenia, erythema nodosum, erythema multiforme, fixed drug eruptions, toxic epidermal necrolysis, Stevens-Johnson syndrome, leukocytocla-sitc vasculitis, recurrent fever with exanthema and, of course, the well-known gastric cytotoxicity. 

Stevens-Johnson syndrome—a severe expression of erythema multiforme (also known as erythema multiforme major). It typically involves the skin and the mucous membranes with the potential for severe morbidity and even death. 

Dermafo/og/c. Alopecia, balanitis, erythema multiforme, erythema nodosum, fixed drug eruptions, hyperpigmentation of the nails, injection site erythema and injection site pain, maculopapular and erythematous rashes, photosensitivity, pruritus, skin and mucus membrane pigmentation, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis. 

Rash In controlled clinical trials, rash occurred in 21% of patients treated with atazanavir. Discontinue atazanavir if severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving atazanavir. 

Skin - Severe, occasionally fatal dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported within days of methotrexate administration. 

Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, and anaphylaxis occur rarely. 

Adverse reactions to cefuroxime have been generally mild and transient in nature. As with other cephalosporins there have been rare reports of erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis (exanthematic necrolysis) and hypersensitivity reactions including skin rashes, urticaria, pruritus, drug fever, serum sickness and very rarely anaphylaxis. 

However the reported adverse effects include mild gastrointestinal reactions (nausea, vomiting, abdominal cramps and diarrhoea). Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. The other side effects are allergic in nature viz. skin rash, itching, bronchospasm, hypotension, erythema multiforme, Steven-Johnson syndrome. Other side effects viz. haemolytic anaemia, hypoprothrombine-mia, seizures and thrombophlebitis have been rarely reported. 

Immune vasculitis can also be induced by drugs. The sulfonamides, penicillin, thiouracil, anticonvulsants, and iodides have all been implicated in the initiation of hypersensitivity angiitis. Erythema multiforme is a relatively mild vasculitic skin disorder that may be secondary to drug hypersensitivity. Stevens-Johnson syndrome is probably a more severe form of this hypersensitivity reaction and consists of erythema multiforme, arthritis, nephritis, central nervous system abnormalities, and myocarditis. It has frequently been associated with sulfonamide therapy. Administration of nonhuman monoclonal or polyclonal antibodies such as rattlesnake antivenin may cause serum sickness. 

Steven-Johnson syndrome (SJS, erythema multiforme) and toxic epidermal necrolysis (TEN or Lyell syndrome) with apoptosis of keratinocytes and bullous detachment of the epidermis from the dermis. When more than 30% of the body surface is affected, TEN is present. Its course is dramatic and the outcome not rarely fatal. 

Other Medical Conditions. Other systemic disorders can be affected by or contraindicate the use of topically applied medications. Examples include myasthenia gravis, which can be worsened with topical timolol, and erythema multiforme (Stevens-Johnson syndrome), which can be caused or exacerbated by topical ocular sulfonamides and related antiglaucoma drugs such as carbonic anhydrase inhibitors. 

The most freqnently reported reactions to topically applied snlfonamides are local irritation, stinging, and binning. Contact dermatitis is common with topical application of these dmgs, and they can cause more serious dermatologic problems such as erythema nodosum, erythema multiforme (Stevens-Johnson syndrome), and exfoliative dermatitis. In addition to hypersensitivity reactions, topical administration of snlfonamides can lead to local photosensitization, which can result in sunburn on the Ud margins or skin of the face. 

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