Stevens-johnson syndrome L51.1

Acute clinical picture, usually characterized by febrile, respiratory prodromes and a general feeling of illness, which is characterized 1-14 days later by severe erosive mucositis of at least two mucosal regions (e.g. conjunctiva, oral mucosa, genital mucosa). In addition, there is often a generalized, mostly truncal exanthema with red, small (0.2-0.4 cm) to (due to confluence) large (>20 cm) spots and patches, sometimes with a hint of cocardia, on which subepithelial firm blisters and flat skin detachments (towel-like pushed together exfoliations) develop.

As there are fluid transitions between SJS and toxic epidermal necrolysis(TEN) (SJS-TEN overlap), SJS is defined as a disease in which the skin detachment is < 10% of the KOF (around 60% of all patients with SJS belong to this group)

Skin detachment between 10 and 30% is defined as a transitional form of SJS/TEN (SJS-TEN overlap) (25% of patients).

Skin detachment > 30% is diagnosed as toxic epidermal necrolysis (TEN ) (15% of patients).

SJS, SJS/TEN and TEN are regarded as one entity(epidermal necrolysis) with different expressivity and severity, whereby all clinical variants are characterized by hemorrhagic, erosive mucosal infestation.

The SJS and TEN are rare overall. The incidence in Germany is expected to be 1.8/1 million people/year in the USA with 1.9/1 million people/year. Additive risk factor is the HIV infection. The risk of contracting the disease is 1000 times higher than in the normal population.

Stevens-Johnson syndrome as well as TEN are considered to be T-cell mediated reactions. Recent data suggest that certain alleles of human leukocyte antigens (HLA: HLA-A 3101;HALA-B5801) are involved in the activation chain of CD8+ cytotoxic T cells and NK cells. CD8+ T lymphocytes are the epidermal inflammatory infiltrate in the early phase of the disease. This leads to the release of cytokines that induce apotosis of keratinocytes. Thus, the cationic cytokine granulysin in the bladder fluid correlates with the severity of the disease. Furthermore, the interaction of Fas and Fas ligands on epidermal keratinocytes plays a crucial role in the induction of apoptosis. Soluble FasL (see Fas ligand below) is detectable in serum in patients with severe drug reactions (Hertel M 2018).

The sole or co-triggers are (Creamer D et al. 2016):

• Medicines: >75% ( NSAIDs especially ibuprofen and naproxen, allopurinol, sulfonamides (the combination of trimethoprim/sulfmethoxazole is used in various drugs) The combination of trimethoprim/sulfmethoxazole is cited in various studies as the most frequent cause! (Micheletti RG et al. 2018), anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine, valproic acid), penicillins, doxycycline, tetracycline, cephalosporins; tyrosine kinase inhibitors).
• Bacterial infections: <25% (Mycoplasma, Yersinia, Chlamydia, various types of cocci)
• Viral infections: Enteroviruses, Adenoviruses, Measles, Mumps, Influenza viruses, Retroviruses (HIV)
• Fungal infections, coccidia, histoplasm
• Malignant tumors
• After vaccinations ( measles, mumps, rubella)
• Idiopathic.

In larger studies the mean age was around 50 years.

SJS is initially characterized by uncharacteristic, febrile, catarrhal prodromal symptoms, possibly with purulent rhinitis or conjunctivitis. Mucosal changes (stomatitis, cheilitis: 100% of cases): After a latency of a few days (up to 14 days), an acute, painful enanthema develops, which usually spreads to more than one region of the mucous membrane. Rapid development of extensive, fibrin-covered erosions and ulcers.

Skin manifestations: In parallel to the mucosal changes, skin manifestations of varying extent develop, from a few single lesions resembling shooting disks to an extensive, scarlatiniform exanthema. Within 1-2 days, large, flaccid, easily rupturing blisters form all over the body (this can lead to a smooth transition to toxic epidermal necrolysis, see above). Later drying of the blister covers and appearance of coarse lamellar desquamation.

An important clinical-diagnostic finding is the positive Nikolski phenomenon, the displacement of the skin surface under tangential pressure!

Lips (90% involvement): flat, firmly adherent hemorrhagic crusts appear.

Eyes (90% of cases): Purulent conjunctivitis

Genitals (70% involvement): Frequent involvement as painful, erosive vulvitis and balanitis (balanoposthitis).

Respiratory tract: 40% of patients develop acute pulmonary complications, 25-40% require mechanical ventilation therapy.

Joint involvement is rarer

Generalized lymphadenopathy and hepato-splenomegaly may also occur.

Increase in acute phase indicators (ESR, CRP, leukocytosis). Inconstantly present eosinophilia (20%), anemia (15%), increased liver enzymes (15%), proteinuria and hematuria (5%).

The histological picture of SJS corresponds to that of classical acute cytotoxic interface dermatitis with plexus-like (orthokeratotic) stratum corneum, pronounced intra- and subepidermal edema up to blistering. Later extensive epidermal necrosis. Mostly rather spindly lymphocytic infiltrate. Numerous dyskeratotic keratinocytes.

Staphylococcal scalded skin syndrome (SSSS); graft-versus-host disease; paraneoplastic pemphigus, erythema exsudativum multiforme.

Regular antiseptic wound treatment with antiseptic solutions or gels should be carried out to reduce the risk of infection. The antiseptics should be warmed. Solutions containing polihexanide and octenidine are recommended.

• In the case of minor skin detachment, the epidermis should be left in situ.
• If blisters form, they should be relieved by puncture. The blister cover remains in situ.
• In the case of extensive skin detachment, careful removal of the detached skin should be considered.

If no systemic treatment with glucocorticoids is given, topical glucocorticoid externals can be applied for a maximum of 5 days (glucocorticoids class III/IV in adults and corticoids class III in children and adolescents). They should be applied to lesional but not yet eroded areas of skin.

For the treatment of eroded areas of the skin, they should be applied to non-stick, non-adherent silicone spacers or greasy gauze to cover the wound. Silver-containing topicals and wound dressings are also used in acute care (silver sulphadiazine). Limitations include the increased risk of absorption of silver-containing particles (monitoring of leukocytes, liver and kidney values) and the possible causal triggering of toxic epidermolysis by sulfmethoxazole or sulfasalazine when silver sulfadiazine is used.

The frequency of topical antiseptic treatment is based on the frequency of dressing changes.

Topical antibiotics and antibiotic wound washes should be avoided.

Lip and oral mucosa involvement (frequent infestation): White kerosene or an ointment containing dexpanthenol should be applied to the erosive lip skin several times a day. Alternatively, white beeswax or a local anesthetic ointment would be indicated. Antiseptic mouthwashes should be carried out regularly. Rinsing with dexpanthenol or ointment solutions is also useful. Prophylactic administration of antibiotics or antiviral substances is not necessary.

Eye involvement (50-80% involvement): Preservative-free wetting agents should be used 1-2 hourly during the day to care for the ocular surfaces, regardless of severity. Ocular ointments should be used at night. If the ocular surface is intact, a preservative-free topical corticosteroid (e.g. 1% prednisolone) should be applied. If anti-inflammatory topical treatment is necessary for >2-4 weeks, a switch to topical calcineurin inhibitors(Ciclosporin A, Tacrolimus) is recommended.

Genital involvement (up to 70%): In patients with erosive involvement of the genital mucosa or dysuria, a urinary catheter (Foley catheter) should be inserted. Gentle cleansing of the urogenital area with sterile water and physiological saline solution. Basic protective care (e.g. white kerosene ointment) should be applied several times a day. Topical corticosteroids can be applied for a maximum duration of 5 days (glucocorticoids class III/IV in adults and corticoids class III in children and adolescents). They should be applied to lesional but not yet eroded areas of skin. Covering the lesions with non-adherent fat gauze is recommended.

If the female genitals are involved, vaginal stents/phantoms should be used to avoid synechiae. Menstrual suppression may be considered.

Anal region involvement: Antiseptic sitz baths e.g. with potassium permanganate (light pink) and glucocorticoid creams (see above). Administration of mild laxatives to soften the stool; if necessary, switch to a strained or liquid diet; parenteral nutrition if necessary.

Caution! Eye involvement: treatment by an ophthalmologist. Symblepharon formation is possible!

SJS is generally considered a serious illness that requires intensive medical care. In this respect, transfer to a surgical intensive care unit is recommended in order to guarantee continuous monitoring of vital parameters.

Regular antiseptic wound treatment with antiseptic solutions or gels should be carried out. For minor

Glucocorticoids internally like prednisolone i.v. (e.g. Solu Decortin H) in high doses 80-500 mg/day, balance out according to clinic. With good clinical improvement transition to glucocorticoids p.o. like prednisolone (e.g. Decortin Tbl.) 50-100 mg/day.

Evaluation: Glucocorticoids in medium to high dosage, given initially and briefly quoad vitam have a beneficial effect (Schneck J et al. 2008).

Opinions differ on the early use of IVIG therapy. Neither at study level nor in meta-analyses were positive effects on mortality detectable (Huang YC et al. 2012).

Prophylactic antibiotic coverage with broad-spectrum antibiotics such as cefotaxime (e.g. claforan) 2-3 times/day 2 g i.v. is recommended. Sufficient pain medication is required.

The course of the disease is 4-6 weeks. The mortality of untreated patients is reported to be 5-15% (<10% for SJS; about 30% for TEN).

The risk of mortality is significantly higher in patients >70 years of age with KO > 20% than in younger patients of comparable severity.

Depending on the expressivity and localisation of the skin and mucous membrane changes, different terms were used in the past, the originality of which is doubted today:

• Erythema multiforme major
• Dermatostomatitis Baader
• Stevens-Johnson-Fuchs syndrome (syndrome muco-cutaneo-ocular fox)
• Fiessinger-Rendu syndrome (Ectodermosis érosive pluriorificielle).

The terms now only have a historical meaning. Today, they are understood together with Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) as a disease spectrum with varying degrees of severity.

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16. www.awmf.org