Stevens Johnson syndrome and toxic epidermal necrolysis

• Stevens Johnson syndrome : Stevens & Johnson, 1922
• Toxic epidermal necrolysis : Lyell, 1956

Stevens Johnson Syndrome, SJS, Toxic epidermal necrolysis, TEN, Lyell syndrome, Epidermolysis necroticans combustiformis, Epidermolysis acuta toxica.

Rare, serious, potentially lethal, mucocutaneous disease, which is usually triggered by the ingestion of drugs. There is detachment of the epidermis and the appearance of necrosis. Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) correspond to one clinical picture. In 100% there is cheilitis and stomatitis. What differs is the extensive spread to the rest of the skin

• Division
  • Stevens Johnson syndrome: 10% of the body surface, mucous membranes are affected (eyes, oral cavity, genital)
  • SJS/TEN overlap syndrome: > 10% to < 30% of body surface area, mucous membranes are affected (eyes, oral cavity, genital).
  • TEN: > 30% of body surface, mucous membranes are affected (eyes, oral cavity, genital).

• Incidence (for SJS, SJS/TEN and TEN): 2-7/1,000,000/per annum
• SJS:TEN = approx. 3:1
• 100-fold increased incidence in HIV-positive patients
• Women > men

• Medicines:
  • Allopurinol
  • Anticonvulsants
    • Phenobarbital
    • Primidone
    • (Ox)-carbamazepine
    • (Fos)-phenytoin
    • Lamotrigine
  • Nevirapine
  • NSAIDs
    • Oxicam
      • Piroxicam
      • Tenoxicam
      • Meloxicam
    • Diclofenac
    • COX-2 inhibitors
      • Etoricoxib
  • Paracetamol
  • Metamizole
  • Sulfasalazine
  • Amifostine
  • Antibiotics
    • Azithromycin
    • Penicillins
      • Amoxicillin
      • Ampicillin
  • Sulphonamides
    • Sulfadiazine
    • Sulfadoxine
    • Sulfamethoxazole
    • Clarithromycin
    • Erythromycin
    • Cephalosporins
      • Cefadroxil
      • Cefixime
      • Ceftriaxone
      • Cefuroxime
    • Doxycycline
    • Fluoroquinolones
      • Ciprofloaxcin
      • levofloxacin
      • Pefloxacin
    • Rifampicin
• Infections
  • Mycoplasma pneumoniae
  • Cytomegalovirus infections
• Vaccinations
• Contrast media
• Nutrients
• Bone marrow transplants
• Radiotherapy

• Predisposing factors
  • HIV infection
  • Genetics:
    • HLA: HLA-B*1502, HLA-A*3101, B*5801, HLA-B*1502, HLA-A*3101, HLA-B*5801.
    • Polymorphisms

• Prodromal stage:
  • Deteriorated AZ, fever
  • Influenza-like symptoms
    • Facultative:
      • Photophobia
      • Conjunctival pruritus
      • Pain on swallowing
      • Myalgias
      • Arthralgias
      • Purulent rhinitis
      • Joint pain
      • Generalised lymphadenopathy
      • Liver and spleen involvement
• Mucocutaneous symptoms
  • Mostly appear after 1-3, but sometimes after up to 14 days.
  • Lesions usually begin on the face or trunk before spreading to other body locations.
  • The capillitium is not affected, but palmoplantar involvement is also seen in some cases.
  • The duration of mucocutaneous symptoms is reported to be 8-12 days.
• Mucocutaneous:
  • In 90% of cases, the oral mucosa is affected
    • Erosions and ulcerations.
    • Hemorrhagic crusts on the lips.
  • The eyes (conjunctivits, sometimes purulent) are almost always affected
    • Incrusted lesions on the upper and lower eyelids.
    • Corneal ulcer, panophthalmitis, photophobia, synechiae, symblepharon.
  • Genital erosions
    • Synechiae and stenosis may develop in the labia, urethra.
    • Urethritis, urinary retention, cystitis.
  • Involvement of the pharynx may be observed in almost all patients.
  • Rarely, the trachea, bronchus, oesophagus and intestine may also be involved.

• Cutaneous manifestation:
  • Epidermal detachments, erosions and sometimes ulcers
  • Cocardiform plaques and macules
  • Often scarlatiniform, truncal exanthema
  • Development of vesicles and bullae
    • Nikolski phenomenon I (blisters can be triggered on healthy skin or non-blistered skin can be displaced when lateral pressure is applied)
    • Nikolski phenomenon II (pre-existing blisters can be displaced on lateral pressure)
    • Asboe-Hansen sign (the blister expands laterally on pressure
  • Coarse lamellar desquamation/the skin peels off flat
  • Necrosis
  • Perhaps onycholysis
  • Reepithelialisation occurs after a few days

• Lab
  • Elevated ESR, CRP, leukocytosis
  • Egg-wise electrophoresis (Increased α- & γ-globulin fraction)
  • Anemia (approx. 15%)
  • Lymphopenia (frequent)
  • Neutropenia
    • occurs in about 1/3 of all patients
    • Often masked by systemic glucocorticoids
    • Correlates with a poor prognosis
  • Eosinophilia (20%)
  • Elevated transaminases (approx. 15%)
  • Proteinuria and haematuria (5%)
  • Bacteraemia (approx. 27%)
  • Characteristics of a severe course:
    • Urea >10 mmol/L
    • Glucose >14 mmol/L
    • ALT (up to 2-3 times the normal value)

• Anamnesis (medication history)
• Clinical image
• Biopsy
  • Frozen section procedure. Important to make a distinction from SSSS. Thus has a pronounced therapeutic consequence!
  • Direct immunofluorescence
• Using the algorithm of drug causality for epidermal necrolysis (ALDEN)
• Laboratory
  • BB, creatinine, electrolytes, electrophoresis
• Bact. Swabs, blood cultures, cultures of urinary catheters and PEG tubes, if applicable, should be repeated every 2 days!

Subepidermal blister cleft, necrotic keratinocytes in the epidermis at the blister roof, otherwise unchanged str. corneum, ↑ eosinophils in the epidermis, spiny cells with ballooned degeneration. In the corium lymphohistiocytic infiltrate, mainly arranged perivascularly.

• Hypoalbuminemia
• Electrolyte imbalances
• Hypovolaemic shock
• Insulin resistance
• Catabolic metabolic state
• Multi-organ failure
• Bacterial infections
• Septic shock (often S. aureus and P. aeruginosa)
• Pneumonia or interstitial pneumonitis
• Necrosis of oesophagus, small intestine and colon with perforation

• The mucosal area usually shows painful erosions

• Estimation of body surface infestation:
  • 1 patient's palm is approximately 1% of body surface area in children and adults
  • Rule of nines: rule for measuring body surface area
    • Head ≙ 9% of the body surface
    • 1 arm ≙ 9% of the body surface
    • Breast & Abdomen ≙ 9% & 9% (= 18%) of the body surface
    • 1 leg ≙ 18% (!) of the body surface
    • Genital ≙ 1% of the body surface

• SCORTEN (severity of illness score for toxic epidermal necrolysis)
  • Scale designed to predict the probability of mortality
• Mortality (for SJS, SJS/TEN and TEN): approx. 30%.
• Mortality (for SJS): 10%
• Mortality (TEN): >30%
  

1. Arvalo JM, Lorente JA, Gonz??lez-Herrada C , Jim??nez-Reyes J. Treatment of Toxic Epidermal Necrolysis with Cyclosporin A. The Journal of Trauma: Injury, Infection, and Critical Care 2000;48:473-8.
2. Assier H. Erythema Multiforme With Mucous Membrane Involvement and Stevens-Johnson Syndrome Are Clinically Different Disorders-Reply. Arch Dermatol 1996;132:711.
3. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W , Roujeau J-C. Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis. Arch Dermatol 2002;138.
4. Bachot N, Revuz J , Roujeau J-C. Intravenous Immunoglobulin Treatment for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Arch Dermatol 2003;139.
5. Bastuji-Garin S. Clinical Classification of Cases of Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, and Erythema Multiforme. Arch Dermatol 1993;129:92.
6. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A , Gamelli RL. Toxic Epidermal Necrolysis: Does Immunoglobulin Make a Difference? Journal of Burn Care & Rehabilitation 2004;25:81-8.
7. Chung W-H, Hung S-I, Yang J-Y, Su S-C, Huang S-P, Wei C-Y et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nature Medicine 2008;14:1343-50.
8. Côté B. Clinicopathologic Correlation in Erythema Multiforme and Stevens-Johnson Syndrome. Arch Dermatol 1995;131:1268.
9. Dietrich A, Kawakubo Y, Rzany B, Mockenhaupt M, Simon JC , Schopf E. Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis*. Experimental Dermatology 1995;4:313-6.
10. Elias PM , Levy SW. Bullous impetigo. Occurrence of localized scalded skin syndrome in an adult. Arch Dermatol 1976;112:856-8.
11. Fagot J-P, Mockenhaupt M, Bouwes-Bavinck J-N, Naldi L, Viboud C , Roujeau J-C. Nevirapine and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. AIDS 2001;15:1843-8.
12. Fouchard N, Bertocchi M, Roujeau J-C, Revuz J, Wolkenstein P , Bastuji-Garin S. SCORTEN: A Severity-of-Illness Score for Toxic Epidermal Necrolysis. Journal of Investigative Dermatology 2000;115:149-53.
13. Garcia-Doval I, LeCleach L, Bocquet H, Otero X-L , Roujeau J-C. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. Arch Dermatol 2000;136.
14. Gubinelli E, Canzona F, Tonanzi T, Raskovic D , Didona B. Toxic epidermal necrolysis successfully treated with etanercept. The Journal of Dermatology 2009;36:150-3.
15. Halebian PH, Corder VJ, Madden MR, Finklestein JL , Shires GT. Improved Burn Center Survival of Patients with Toxic Epidermal Necrolysis Managed without Corticosteroids. Annals of Surgery 1986;204:503-12.
16. Halevy S, Ghislain P-D, Mockenhaupt M, Fagot J-P, Bouwes Bavinck JN, Sidoroff A et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. Journal of the American Academy of Dermatology 2008;58:25-32.
17. Hebert AA , Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. Journal of the American Academy of Dermatology 2004;50:286-8.
18. Hess Schmid M , Elsner P. Ungewöhnliche hämorrhagische Variante eines Stevens-Johnson-Syndroms bei einem HIV-infizierten Patienten. Der Hautarzt 1999;50:52-5.
19. Hewitt J , Ormerod AD. Toxic epidermal necrolysis treated with cyclosporin. Clin Exp Dermatol 1992;17:264-5.
20. Hunger RE, Hunziker T, Buettiker U, Braathen LR , Yawalkar N. Rapid resolution of toxic epidermal necrolysis with anti-TNF-α treatment. Journal of Allergy and Clinical Immunology 2005;116:923-4.
21. Kamanabroo D. Plasmapheresis in Severe Drug-Induced Toxic Epidermal Necrolysis. Arch Dermatol 1985;121:1548.
22. Kardaun SH , Jonkman MF. Dexamethasone Pulse Therapy for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. Acta Derm Venereol 2007;87:144-8.
23. Laffitte E, Nenadov Beck M, Hofer M, Hohl D , Panizzon RG. Severe Stevens-Johnson syndrome induced by contrast medium iopentol (ImagopaqueR). Br J Dermatol 2004;150:376-8.
24. Leckie MJ. Stevens-Johnson syndrome in association with hydroxychloroquine treatment for rheumatoid arthritis. Rheumatology 2002;41:473-4.
25. Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S et al. A European study of HLA-B in Stevens???Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenetics and Genomics 2008;18:99-107.
26. Lyell A. TOXIC EPIDERMAL NECROLYSIS: AN ERUPTION RESEMBLING SCALDING OF THE SKIN. Br J Dermatol 1956;68:355-61.
27. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bavinck JNB et al. Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Assessment of Medication Risks with Emphasis on Recently Marketed Drugs. The EuroSCAR-Study. Journal of Investigative Dermatology 2008;128:35-44.
28. Nassif A, Bensussan A, Bachot N, Bagot M, Boumsell L, Roujeau J-C et al. Drug Specific Cytotoxic T-Cells in the Skin Lesions of a Patient with Toxic Epidermal Necrolysis. Journal of Investigative Dermatology 2002;118:728-33.
29. Ng CY, Yeh YT, Wang CW, Hung SI, Yang CH, Chang YC et al. Impact of the HLA-B58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions. J Invest Dermatol 2016.
30. Paul C, Wolkenstein P, Adle H, Wechsler J, Garchon HJ, Revuz J et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996;134:710-4.
31. Pereira FA, Mudgil AV , Rosmarin DM. Toxic epidermal necrolysis. Journal of the American Academy of Dermatology 2007;56:181-200.
32. Prins C. Treatment of Toxic Epidermal Necrolysis With High-Dose Intravenous Immunoglobulins. Arch Dermatol 2003;139:26.
33. Redondo P, Felipe I, Pena A, Aramendia JM , Vanaclocha V. Drug-induced hypersensitivity syndrome and toxic epidermal necrolysis. Treatment with N-acetylcysteine. Br J Dermatol 1997;136:645-6.
34. Revuz J , Roujeau JC. [Lyell's staphylococcal syndrome or bullous impetigo?]. Nouv Presse Med 1980;9:1097.
35. Revuz JE , Roujeau JC. Advances in toxic epidermal necrolysis. Seminars in Cutaneous Medicine and Surgery 1996;15:258-66.
36. Roujeau J-C. Genetic Susceptibility to Toxic Epidermal Necrolysis. Arch Dermatol 1987;123:1171.
37. Roujeau J-C. Toxic Epidermal Necrolysis (Lyell Syndrome). Arch Dermatol 1990;126:37.
38. Roujeau J-C, Chosidow O, Saiag P , Guillaume J-C. Toxic epidermal necrolysis (Lyell syndrome). Journal of the American Academy of Dermatology 1990;23:1039-58.
39. Roujeau J-C, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T et al. Medication Use and the Risk of Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis. New England Journal of Medicine 1995;333:1600-8.
40. Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 1996;135:6-11.
41. Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. Journal of Clinical Epidemiology 1996;49:769-73.
42. Saiag P, Caumes E, Chosidow O, Revuz J , Roujeau J-C. Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. Journal of the American Academy of Dermatology 1992;26:567-74.
43. Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 2010;88:60-8.
44. Schneck J, Fagot J-P, Sekula P, Sassolas B, Roujeau JC , Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. Journal of the American Academy of Dermatology 2008;58:33-40.
45. Schöpf E. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. Arch Dermatol 1991;127:839.
46. Shay E, Kheirkhah A, Liang L, Sheha H, Gregory DG , Tseng SCG. Amniotic Membrane Transplantation as a New Therapy for the Acute Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Survey of Ophthalmology 2009;54:686-96.
47. Stern RS. Improving the Outcome of Patients With Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. Arch Dermatol 2000;136.
48. Ting W, Stone MS, Racila D, Scofield RH , Sontheimer RD. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): a case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions. Lupus 2004;13:941-50.
49. Tougeron-Brousseau B, Delcampe A, Gueudry J, Vera L, Doan S, Hoang-Xuan T et al. Vision-Related Function After Scleral Lens Fitting in Ocular Complications of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. American Journal of Ophthalmology 2009;148:852-9.e2.
50. Trent JT, Kirsner RS, Romanelli P , Kerdel FA. Analysis of Intravenous Immunoglobulin for the Treatment of Toxic Epidermal Necrolysis Using SCORTEN. Arch Dermatol 2003;139.
51. Trent JT, Ma F, Kerdel F, Fien S, French LE, Romanelli P et al. Dose of intravenous immunoglobulin and patient survival in SJS and toxic epidermal necrolysis. Expert Review of Dermatology 2007;2:299-303.
52. Watanabe H, Koide R , Iijima M. Toxic Epidermal Necrolysis Arising as a Sequela of Drug-induced Hypersensitivity Syndrome. Acta Dermato Venereologica 2012;92:214-5.
53. Wetter DA, Davis MDP, Yiannias JA, Gibson LE, Dahl MV, El-Azhary RA et al. Effectiveness of Intravenous Immunoglobulin Therapy for Skin Disease Other Than Toxic Epidermal Necrolysis: A Retrospective Review of Mayo Clinic Experience. Mayo Clinic Proceedings 2005;80:41-7.
54. Wolff K , Tappeiner G. Treatment of Toxic Epidermal Necrolysis. Arch Dermatol 2003;139.
55. Wolkenstein P, Carri??re Vr, Charue D, Bastuji-Garin S, Revuz J, Roujeau J-C et al. A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Pharmacogenetics 1995;5:255-8.
56. Wolkenstein P, Chosidow O, Flechet M-L, Robbiola O, Paul M, Dume L et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis 1996;35:234-6.
57. Wolkenstein P, Latarjet J, Roujeau J-C, Duguet C, Boudeau S, Vaillant L et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. The Lancet 1998;352:1586-9.
58. Wolkenstein PE, Roujeau JC , Revuz J. Drug-Induced Toxic Epidermal Necrolysis. Clinics in Dermatology 1998;16:399-408.
59. Bastuji-Garin S et al. (2000) SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 115: 149-153
60. Nirken, M. (2016). Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. Uptodate.com. Retrieved 22 May 2016, from http://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis?source=search_result&search=stevens-johnson-syndrom&selectedTitle=1%7E150
61. High, W. (2016). Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. Uptodate.com. Retrieved 22 May 2016, from http://www.uptodate.com/contents/stevens-johnson-syndrome-andtoxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae?source=search_result&search=stevens-johnsonsyndrom&selectedTitle=2%7E150