Stevens-johnson syndrome L51.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 23.02.2021

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Synonym(s)

Erythema multiforme major; SJS; SJS/TEN; SJS/TEN overlap; Stevens-Johnson syndromes

History
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Stevens and Johnson, 1922

Definition
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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.

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Occurrence/Epidemiology
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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.

Etiopathogenesis
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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.

Manifestation
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In larger studies the mean age was around 50 years.

Clinical features
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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.

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

Histology
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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.

Differential diagnosis
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Complication(s)
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Bacterial secondary infections (pneumonia, pyoderma, danger of sepsis), fluid losses and electrolyte shifts frequently occur!

Therapy
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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!

General therapy
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The SJS is generally regarded as a serious illness that requires intensive medical care. In this respect, a transfer to a surgical intensive care unit is recommended to guarantee continuous monitoring of vital parameters.

Internal therapy
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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.

Progression/forecast
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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.

Tables
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Substance group

Freiname

Trade name

Sulfonamides

Acetazolamide

Diamox, Glaupax

Sulfamethoxydiazine

Durenate

Sulfacarbamide

Euvernil

Sulfacetamide

Blephamide

Sulfamethoxazole

Bactrim, Eusaprim

Sulfamethyldiazine

Lidaprim

Sulphisomidine

Aristamide

Sulfamerazine

Berlocombin

Sulfadiazine (sulfanilamide)

Sulfadiazine-Heyl

Pyrazolone derivatives

Phenylbutazone

Ambene, butazolidine

Oxyphenbutazone

Phlogont, Tanderil

Metamizole

Novalgin, novamine sulfone

Antibiotics

Tetracyclines

Achromycin, Tefilin, Hostacyclin

Doxycycline

Supracycline

Streptomycin

streptomycin-heyl, streptomycin yeast

Spiramycin

selectomycin, rovamycins

Procaine penicillin G

Jenacillin

Benzathine Penicillin G

Tardocillin, Pendysin

Antiepileptic drugs

diphenylhydantoin/phenytoin

Centropil, Epanutin

Carbamazepine

Tegretal, Timonil

Phenothiazine derivatives

Chlorpromazine

Propaphenin

Fluphenazine

Lyogen, Dapotum

Promethazine

Atosil, Eusedon

Barbiturates

Phenobarbital

Luminal

Thiopental

Pentotal

Hexobarbital

Evipan

Pentobarbital

Neodrome

Antimalarials

quinine

Limptar, Quinine

Disinfectants (halogens)

Iodine

Betaisodona, Braunovidon

Chloramines

Chloramine T, Clorina

Belladonna alkaloids

Atropa belladonna, Atropine sulphate

Atropine, Contramutane

H1-Blocker

Olopatadine

Opatanol

NSAID

Acetylsalicylic acid

ASS

Diclofenac

Voltaren

Ibuprofen

Ibuprofen

Naproxen

Naproxen

Further

Ophiopogonis tuber

Eberu

Note(s)
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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.

Literature
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  1. Bossi P et al (2002) Stevens-Johnson syndrome associated with abacavir therapy. Clin Infect Dis 35: 902
  2. Chantaphakul H et al (2015) Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Ther Med 10: 519-524
  3. Creamer D et al (2016) UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermalnecrolysis
    in adults. J Plast Reconstr Aesthet Surg 69:e119-e153.
  4. Dodiuk-Gad RP et al (2015) Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Update. At J Clin DermatolPubMed PMID: 26481651.
  5. Hebert AA et al (2004) Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol 50: 286-288
  6. Hertl M (2018) Severe cutaneous drug reactions. In: Braun-Falco`s Dermatology, Venerology Allergology G. Plewig et al. (Hrsg) Springer Verlag S 625
  7. Huang YC et al (2012) The efficacy of intravenous immunoglobulin for the treatment of toxic epidermalnecrolysis
    : a systematic review and meta-analysis.Br J Dermatol: 167:424-432.
  8. Johnston GA et al (2002) Neonatal erythema multiforme major. Clin Exp Dermatol 27: 661-664
  9. Laffitte E et al (2004) Severe Stevens-Johnson syndrome induced by contrast medium iopentol (Imagopaque). Br J Dermatol 150: 376-378
  10. Micheletti RG et al (2018) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Multicenter Retrospective Study of 377 Adult Patients from the United States. J Invest Dermatol 138:2315-2321.
  11. Mockenhaupt M (2014) Severe drug-induced skin reactions. Dermatologist 65: 415-423
  12. Pereira FA et al (2007) Toxic epidermal necrolysis. J Am Acad Dermatol 56: 181-200
  13. Schmid MH, Elsner P (1999) An unusual hemorrhagic variant of Stevens-Johnson syndrome in an HIV-infected patient. dermatologist. 50: 52-55
  14. Schneck J et al (2008) Effects of treatments on the mortality of Stevens-Johnson syndrome and toxicepidermal
    necrolysis: A retrospective study on patients included in theprospective
    EuroSCAR Study.J Am Acad Dermatol 58: 33-40.
  15. Stevens AM, Johnson FC (1922) A new eruptive fever associated with stomatitis and ophthalmia: Report of two cases in children. Am J Dis Child 24: 526-533

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Last updated on: 23.02.2021