Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Venue: Internal Medicine Department,
Delta State University Teaching Hospital (DELSUTH), Oghara, Nigeria
June 2023.

1. STEVEN JOHNSON SYNDROME (SJS) AND TOXIC EPIDERMAL NECROLYSIS (TEN) BY DR. SUAME PRECIOUS MATTHEW Venue: Internal Medicine Seminar Room, Delta State University Teaching Hospital (DELSUTH), Oghara , Nigeria June 2023.

2. Outline Introduction Brief history Epidemiology Classification Etiology Pathophysiology Clinical presentation Differential Diagnoses Investigations Treatment Prognosis Complications

3. Introduction The acute life threatening condition is characterized by epidermal sloughing and mucositis secondary to extensive keratinocytic apoptosis. They can be distinguished from Erthema Multiforme varying only in the area of involvement of skin surface.

4. Brief history The syndrome was first described in 1922, when the American pediatricians Albert Mason Stevens and Frank Chambliss Johnson reported the cases of 2 boys aged 7 and 8 years with "an extraordinary, generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis." Both cases had been misdiagnosed by primary care physicians as hemorrhagic measles.

5. Epidermiology The incidence rate is 2-7 cases per million population per year. Stevens-Johnson syndrome has been described worldwide in all races, although it may be more common in whites. Women more commonly affected than men, 2:1 occurrence ratio. Interestingly, the disease is not limited to humans; cases have been reported in dogs, cats, and monkeys. SJS occurs with a worldwide distribution similar in etiology and occurrence to that in the United States. However, a study from Germany reported only 1.1 cases per 1 million person-years. Cases have been reported in children as young as 3 months.

6. Classification The only difference between them is degree of skin involvement with SJS involving less than 10% of total body surface while TEN involving more than 30%. Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) Detachment of 10-30% BSA.

7. Etiology Various etiologic factors have been implicated as causes of Stevens-Johnson syndrome. Drugs most commonly are blamed. The 4 etiologic categories are as follows: Infectious Drug-induced Malignancy-related Idiopathic.

8. Drug induced Antibiotics are the most common cause of Stevens-Johnson syndrome, followed by analgesics, NSAIDs, psycholeptics , and antigout drugs. antibiotics, penicillins and sulfa drugs are prominent; ciprofloxacin has also been reported.

9. Drug induced… The following anticonvulsants have been implicated: Phenytoin Carbamazepine O xcarbazepine Valproic acid Lamotrigine Barbiturates

10. Drug induced… Antiretroviral drugs implicated in Stevens-Johnson syndrome include nevirapine and possibly other non-nucleoside reverse transcriptase inhibitors. Indinavir(a protease inhibitor) has been mentioned.

11. Drug induced… Stevens-Johnson syndrome has also been reported in patients taking the following drugs: Allopurinol Mirtazapine TNF-alpha antagonists Sertraline Pantoprazole Tramadol

12. Infectious cause Viral diseases that have been reported to cause Stevens-Johnson syndrome include the following: Herpes simplex virus AIDS Coxsackie viral infections Influenza Hepatitis Mumps

13. Infectious cause… Bacterial etiologies include the following: Group A beta-hemolytic streptococci Diphtheria Brucellosis Lymphogranuloma venereum Mycobacteria Mycoplasma pneumonia Rickettsial infections Tularemia Typhoid

14. Infectious cause… Possible fungal causes include: coccidioidomycosis, dermatophytosis and histoplasmosis. Malaria and trichomoniasis have been reported as protozoal causes.

15. Genetic factors There is strong evidence for a genetic predisposition to severe cutaneous adverse drug reactions such as Stevens-Johnson syndrome and TEN. Carriage of certain human leukocyte antigens has been associated with increased risk.

16. Idiopathic Stevens-Johnson syndrome and TEN is idiopathic in 25-50% of cases.

17. Pathophysiology Pathogenesis is often associated with type III hypersensitivity reactions (immune complex reaction) induced by soluble complexes of antigen or its metabolites with IgM and IgG antibodies and delayed-type hypersensitivity reactions (hypersensitivity reactions type IV is a reaction that is mediated by specific T lymphocytes).

18. Pathophysiology… Antigen presentation and production of tumor necrosis factor (TNF)-alpha by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocyte proliferation and enhances the cytotoxicity of the other immune effector cells. A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic lymphocytes. The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin.

19. Pathophysiology… The death of keratinocytes causes separation of the epidermis from the dermis. Once apoptosis ensues, the dying cells provoke the recruitment of more chemokines. This can perpetuate the inflammatory process, which leads to extensive epidermal necrolysis.

20. Clinical presentation Typically begins with a nonspecific upper respiratory tract infection. This usually is part of a 1-14 day prodrome during which fever, sore throat, chills, headache, and malaise may be present. Vomiting and diarrhea are occasionally noted as part of the prodrome. Mucocutaneous lesions develop abruptly. Clusters of outbreaks last from 2-4 weeks. The lesions are typically nonpruritic.

21. Clinical presentation… Ocular : C onjunctivitis, blepharoconjunctivitis , iritis, iridocyclitis, eyelid edema, in severe cases erosion and perforation of the cornea that can lead to blindness. Ocular mucosa injury is the trigger that causes ocular cicatricial pemphigoid, a chronic inflammation of the ocular mucosa which causes blindness. Foreign body sensation. Decreased vision.

22. Burn sensation Photophobia Diplopia   The time required from onset until the occurrence of ocular cicatricial pemphigoid vary from a few months to 31 years.

23. Clinical presentation… The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema. The center of these lesions may be vesicular, purpuric, or necrotic. The typical lesion has the appearance of a target; this is considered pathognomonic. these lesions have only two zones of color. The core may be vesicular, purpuric, or necrotic; that zone is surrounded by macular erythema. Lesions may become bullous and later rupture, leaving denuded skin. The skin becomes susceptible to secondary infection.

24. Clinical presentation… Genital lesions: may be non-specific urethritis, balanitis and/or vaginal ulcers.

25. Clinical presentation… The following signs may be noted on examination: Fever Tachycardia Hypotension Altered level of consciousness Epistaxis Conjunctivitis Corneal ulcerations Erosive vulvovaginitis or balanitis Seizures Coma

26. Differential Diagnosis Erythema multiforme Staphylococcal scalded skin syndrome(SSSS) Irradiation Trauma Progressive systemic sclerosis (scleroderma) Porphyria cutanea tarda Epidermolysis bullosa acquisita Linear Ig A bullous disease

27. Differential Diagnoses…. Paraneoplastic pemphigus Bullous systemic lupus erythematosus Corynebacterium diphtheria conjunctivitis Sebaceous cell carcinoma Adenoviral conjunctivitis Intraepithelial epithelioma Atopic keratoconjunctivitis

28. Investigations There are no specific laboratory studies that can definitively establish the diagnosis of Stevens Johnson syndrome. Serum levels of the following are typically elevated in patients with Stevens-Johnson syndrome: Tumor necrosis factor (TNF)-alpha Soluble interleukin 2-receptor Interleukin 6 C-reactive protein However, none of these serologic tests is used routinely in diagnosing and managing Stevens-Johnson syndrome.

29. Investigations… Skin biopsy: Sub-epithelial blisters characterized by degenerating, necrotic basal keratinocytes. Chronic inflammatory infiltrates in connective tissue stroma. Complete blood count (CBC): anemia, lymphopenia, neutropenia, eosinophilia. Liver function tests (LFT): elevated transaminases, hypoalbuminemia

30. Investigations… Renal function: microalbuminuria, renal tubular enzymes in urine, reduced glomerular filtration, rising creatinine and urea, hyponatremia Pulmonary function: bronchial mucosal sloughing on bronchoscopy, interstitial infiltrates on chest x-ray

31. Treatment Management of patients with Stevens-Johnson syndrome is usually provided in intensive care units or burn units. No specific treatment for as the disease is usually self-limiting ; therefore, most patients are treated symptomatically.

32. Treatment… General Care of a patient with Stevens-Johnson syndrome/toxic epidermal necrolysis includes: Cessation of the suspected causative drug(s). Fluid replacement (crystalloid) Nutritional assessment: may require nasogastric tube feeding Temperature control: warm environment, emergency blanket Pain relief Supplemental oxygen and in some cases, intubation with mechanical ventilation Sterile/ aseptic handling  

33. Treatment… Skin care requires daily examination of skin and mucosal surfaces for infection, Use of non-adherent dressings, and avoidance of trauma to the skin. Gentle removal of necrotic skin/mucosal tissue. Culture of skin lesions, axillae, and groins every two days. Manage oral lesions with mouthwashes. Address tetanus prophylaxis.

34. Treatment… Antibiotics may be required for secondary infection but are best avoided prophylactically. It is unknown whether systemic corticosteroids are beneficial, but they are often prescribed in high doses for the first three to five days of admission. Granulocyte colony-stimulating factor (G-CSF) may be of benefit in patients with severe neutropenia. Other drugs reported effective include, ciclosporin, TNF-alpha inhibitors, N-acetylcysteine, and intravenous immunoglobulins. Their role remains controversial.

35. Treatment… Treatment of acute ocular manifestations usually begins with lubrication of the ocular surface. As inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon lysis.

36. Prognosis Individual lesions typically should heal within 1-2 weeks, unless secondary infection occurs. Most patients recover without sequelae. Mortality is determined primarily by the extent of skin sloughing. When body surface area (BSA) sloughing is less than 10%, the mortality rate is approximately 1-5%. However, when more than 30% BSA sloughing is present, the mortality rate is between 25% and 35%, and may be as high as 50%. Bacteremia and sepsis appear to play a major role in increased mortality.

37. Prognosis… The SCORTEN score (a severity-of-illness score for toxic epidermal necrolysis) calculates the risk for death on the basis of the following variables: Age >40 years Malignancy Heart rate >120 Initial percentage of epidermal detachment >10% Blood urea nitrogen (BUN) level >10 mmol/L Serum glucose level >14 mmol/L Bicarbonate level < 20 mmol/L

38. Prognosis… Each variable is assigned a value of 1 point. Mortality rates are as follows: 0-1 points, ≥3.2% 2 points, ≥12.1% 3 points, ≥35.3% 4 points, ≥58.3% 5 or more points, ≥90%

39. Prognosis… Other negative prognostic factors include: persistent neutropenia (defined as neutropenia lasting more than 5 days), hypoalbuminemia (usually < 2 g/dL), and persistent azotemia. Survivors of Stevens-Johnson syndrome may experience numerous long-term ocular sequelae due to cicatrization .

40. Complications 50% progress to severe ocular disease. Ocular complications of Stevens-Johnson syndrome include the following: Chronic cicatrizing conjunctivitis Corneal epithelial defects Corneal stromal ulcers Corneal perforation Endophthalmitis

41. Complications… Other complications may include the following: Esophageal strictures. Renal tubular necrosis, renal failure, penile scarring, vaginal stenosis. R espiratory failure. Cutaneous Scarring and cosmetic deformity, recurrences of infection through slow healing ulcerations.

42. References Oxford Handbook of clinical medicine, 8 th edition. Slideshare.com