1.1.3.4 Stevens-Johnson Syndrome

Stevens-Johnson syndrome is a rare disease affecting around 1-2 persons per 1 million. There is a higher risk of development of this serious disease in HIV/AIDS patients and in elderly patients receiving multiple medications. 7−10% of cases in all groups have at least one autoimmune disease. There are new data showing that infections is highest among SJS cases (21.8 %) compared to TEN (17.1 %) and SJS_TEN overlap (11.8%).

Stevens-Johnson syndrome, which is part of a spectrum of severe drug eruptions, affects skin and the oro-genital mucous membranes and conjunctivae. The body surface (BS) involvement ranges in SJS where <10% of BS is affected to toxic epidermal necrolysis (TEN) in which 30% of the BS shows loss of the epidermis. Involvement of 10 to 30% of the BS is referred to as SJS-TEN-overlap syndrome.

Many causes may be implicated. Whereas in erythema exsudativum multiforme (minor and major type) infections such as viruses e.g., the herpes virus and mycoplasma play the important role, much more often in Stevens-Johnson syndrome and toxic epidermal necrolysis, drugs are the inducing agents. Immunologically-induced apoptosis of keratinocytes cascading unchecked into massive epidermal destruction may be the pathogenic mechanism. Besides multidrug exposure in particular in the elderly population, hereditary disposition to severe cutaneous drug reactions is an additional risk. Over 80% of cases are associated with medication exposure, particularly antimicrobials (sulfa antibiotics), antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs). In Chinese and Thai patients, SJS induced by carbamazepine shows a high correlation to HLA-B*1502. This correlation is not found in the European population, but rather an association with HLA class I-allele HLA-A*3101. In all population, SJS is often induced by the very common drug allopurinol. An association with HLA-B*5801 can often be detected in that case. Necrolysis of keratinocytes by TNF alpha and gamma IFN are important mediators of the cell changes. Annexin A 1 promotes via the formyl-peptid- receptor apoptosis of keratinocytes and increased levels of miR-18 a-5p in the skin can be measured, which blocks anti-apoptotic action and therefore promotes cell death.

Drugs with high risk:

• allopurinol,

• carbamazepine,

• lamotrigine, phenytoin, sertraline, nevirapine,

• phenobarbital,

• piroxicam,

• sulfamethoxazole, sulfsalazine and other anti-bacterial sulfonamides.

Drugs with moderate risk: cephalosporins, quinolones, macrolides, NSAIDs (e.g.diclofenac) and tetracyclines.

SJS initially shows a macular exanthem, usually on the trunk. In contrast to erythema exudativum multiforme, the typical target lesions of cockades are not seen. Fever, conjunctivitis, sensitivity to daylight and artificial light and throat pain often precede the skin symptoms.

After skin symptoms have started on the trunk, the face, hands and feet follow. Lesions often become confluent, with formation of atypical target lesions, without the classical erythema multiforme-like characteristics. Erosions and even ulcerations may appear. Up to 10 % of body surface is involved. Generally, erosions are present around more than one mucosal orifice. Later, balanitis may develop and the upper respiratory and the gastrointestinal tract may become affected. Nikolsky I skin sign is positive.

The skin and mucosa of mouth and genitalia are always involved.

SJS is part of the Erythema multiforme – SJS -TEN complex which can be seen as a clinical cascade, however, the course of erythema multiforme in general is milder.

A prognostic scoring system should always be used. Every parameter positively answered is ranked with one scoring point:

Age > 40 years / malignant tumor(s) /skin ablation > 10% BSF / heart frequency > 120 pro min / bicarbonate < 20mmol per litre / urea > 10mmol per litre / hyperglycemia > 252 mg/dl.

Frequent monitoring of electrolytes, kidney and liver parameters, cardiac function is essential.

Cytotoxic T-lymphocytes attack the epidermal keratinocytes, but also mucous epithelia are involved. Apoptosis and necrosis of keratinocytes is the key feature. Disruption of the epidermal / dermal connection leads to formation of bullae. Capillaries in the upper dermal vessel complex are widened and a heavy lympho-mononuclear cell infiltrate is assembled in and around the interstitium.

The course of disease depends on age, comorbidity, body function and body surface involvement, body functional status, earliest time of intervention. Intravenous electrolytes and bicarbonate need to be balanced and the patients should be monitored like burns patients of degree IIa and III.

The mortality of 1 – 5 % is quite high. Long-term sequelae such as scarring of the blepharon, development of an ectropion, phimosis and vaginal synechia are often seen. Superinfection with staphylococci, streptococci and other microbes should be avoided.

Typical clinical features and histology. Scoring is recommended similar as in TEN, however, the SCORTEN is only a rough guide.

All suspicious drugs have to be excluded and discontinued. Drug half-life should be known because it will influence the response rate and time of treatment length to avoid immediate relapse. The systemic use of ciclosporin (3 mg/kg/day) is currently favored. Corticosteroids, intravenous immunoglobulins and TNF alpha blockers are alternative interventions. A recent review showed that cyclosporine was superior to IVIG regarding mortality, and corticosteroids plus IVIG reduced serious complications compared to corticosteroids alone. Symptomatic topical measures are essential to avoid superinfection and scarring, similar to burn patients. Skin-directed treatment is analogous to those in TEN, however, admission to an intensive care unit may not be necessary if less than 10% of BSA is involved.