Stevens-johnson syndrome L51.1

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

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

For skin detachment between 10 and 30% a transitional form SJS/TEN (SJS-TEN-Overlap) is defined (25% of patients).

If skin detachment > 30%, TEN is diagnosed (15% of patients).

SJS, SJS/TEN and TEN are considered as one entity with different expressivity and expression, all clinical variants being characterized by hemorrhagic, erosive mucosal involvement.

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 mucosa. Rapid development of extensive, fibrin-covered erosions and ulcers.

Skin phenomena: In parallel with the mucous membrane changes, skin phenomena of varying degrees develop, from a few single lesions like a shooting target to a large-area, scarlatiniform exanthema. Within 1-2 days, large, flabby, slightly rupturing blisters develop all over the body (smooth transitions to toxic epidermal necrolysis may occur, 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!

Flat, firmly adhering haemorrhagic crusts appear on the lips.

Eye involvement (90% of cases): Purulent conjunctivitis

Genital mucous membranes: Frequent involvement as painful, erosive vulvitis and balanitis (balanoposthitis).

Less frequent are joint involvement

Generalized lymphadenopathy and hepato-splenomegaly can 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.

In mild forms: moderate to strong topical glucocorticoids such as 0.1% triamcinolone cream(Triamgalen, Delphicort, R259 ), 0.05-1% betamethasone lotion/ointment/cream(Betnesol, Diprosone, Hydrophilic betamethasone valerate emulsion) or clobetasol propionate cream(Clobegalen, Dermoxin, Hydrophilic clobetasol propionate cream (0.05%)).

In severe forms (see also toxic epidermal necrolysis): intensive medical care. Fluid balancing, sufficient volume supply, isolation of the patient, sterile clothing for medical and nursing staff. Positioning on metalline sheet, vacuum mattress if necessary. In case of weeping changes, compresses with polihexanide (Serasept, Prontoderm), quinolinol solution(e.g. Chinosol 1:1000 or R042 ) or 2% potassium permanganate solution, otherwise antiseptic ointments/creams such as 2-5% clioquinol vaseline/ointment (Linola-Sept), silver sulfadiazine (e.g. Flammazine) or better gauze dressings with antibiotic additives such as chlorhexidine (Bactigras).

Infestation of the anal region: Antiseptic sitz baths e.g. with potassium permanganate (light pink) as well as glucocorticoid creams (see above). Passenger administration of mild laxatives to soften stools.

Oral mucosal infestation: Mild rinses or anaesthetic solutions (e.g. Dolo-Dobendan solution, Acoin solution, Parodontal oral ointment, Bepanthen solution, Dexpanthenol solution R066 ).

If necessary, switch to a strained or liquid diet; parenteral nutrition if required.

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

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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