SJS involves skin detachment over less than 10% of the body surface area. TEN is more severe, with detachment over more than 30%. SJS/TEN overlap is the intermediate form (10–30% involvement).

sjsStevens-Johnson syndrome (SJS) is a rare, serious disorder of the skin and mucous membranes. It's considered a medical emergency and is often a severe reaction, usually to a medication or, less commonly, an infection.

SJS is part of a spectrum of disease that also includes Toxic Epidermal Necrolysis (TEN), with SJS being the less severe end:

SJS involves skin detachment over less than 10% of the body surface area.

TEN is more severe, with detachment over more than 30%.

SJS/TEN overlap is the intermediate form (10–30% involvement).

1. Frank Chambliss Johnson Albert Mason Stevens

2. EPIDEMIOLOGY Estimates of incidence for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN range from two to seven cases per million people per year incidence of SJS/TEN is much higher among HIV-infected individuals and patients with active cancer more common in women

3. ETIOLOGY Medications are the leading trigger following agents or groups of agents were most commonly implicated Allopurinol Aromatic antiseizure medications and lamotrigine Antibacterial sulfonamides (including sulfasalazine) Nevirapine Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs)

4. anticancer therapies have been associated with SJS/TEN, including thalidomide [23], capecitabine [24], afatinib [25], vemurafenib [26], tamoxifen [27], and immune checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) Mycoplasma pneumoniae infection

5. RISK FACTORS For Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) include HIV infection, genetic factors, underlying immunologic diseases or malignancies, and, possibly, physical factors (such as ultraviolet light or radiation therapy). HIV infection —  100-fold higher risk of SJS/TEN Malignancy  —  active malignancy have an increased risk of SJS/TEN (risk is highest for patients with hematologic cancers) HLA types — The risk of drug-induced SJS/TEN has been associated with certain human leukocyte antigen (HLA) types

6. HLA types  ●HLA-B*15:02-increased risk for SJS/TEN due to carbamazepine and other aromatic anticonvulsants (eg, oxcarbazepine, phenytoin, phenobarbital) ●HLA-B*15:11 –carbamazepine-induced SJS/TEN HLA-A*31:01 carbamazepine-induced severe cutaneous drug reactions ●HLA-A*24:02 –  carbamazepine, lamotrigine, and phenytoin ●HLA-B*13:01 dapsone-induced severe skin reactions, HLA-B*58:01 –allopurinol-induced SJS/TEN

7. PATHOPHYSIOLOGY Antigen presentatio n and production of tumor necrosis factor (TNF) -alpha by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocyte proliferation andenhances 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.

8. PATHOPHYSIOLOGY The d eath of kerkeratinocytes causes separation of the epidermis from the dermis. Once apoptosis ensues, the dying cells provoke recruitment of more chemokines . This can perpetuate the inflammatory process, which leads to extensive e pidermal necrolysis.

9. HISTOLOGY EPIDERMIS stratum basale basement membrane contains collagens and laminins attached epidermis to dermis

10. EPIDERMIS stratum basale basement membrane EPITHELIAL CELLS BASEMENT MEMBRANE LAMINA PROPIA

11. MHC CLASS 1 CD8 +TCELL PEPTIDE DOESN’T RECOGNIZE CELL AS FOREIGN

12. MHC CLASS 1 CD8 +TCELL PEPTIDE MHC CLASS 1 CD8 +TCELL PEPTIDE

13. stevens-johnson syndrome and toxic epidermal necrolysis GRANZYMES (granulysin) PERFORIN TNF a INF y

14. Granulysin most highly expressed cytotoxic molecule IL-15 has a key role in promoting and maintaining long-lasting cytotoxic T cell and NK cell responses.

15. TRIGGERS anticonvulsants like carbamazepine antibiotics likes sulfonamides immunomodulators like nevirapin and sulfasalazine nsaids like piroxicam METABOLITE peptide are RECOGNIZED as FOREIGN by the CYTOTOXIC T CELLS MEDICATIONS INFECTIONS mycoplasma pneumonia cytomegalovirus

16. steven johnson toxic epidermal necrolysis if not treated and the risk of fatality increases with severity

17. stevens-johnson syndrome and toxic epidermal necrolysis STEVEN JOHNSONS SYNDROME OVERLAP STEVEN JOHNSONS SYNDROME & TOXIC EPIDERMAL NECROLYSIS TOXIC EPIDERMAL NECROLYSIS 10% of the BODY SURFACED AFFECTED 10 - 30% of the BODY SURFACED AFFECTED >30% of the BODY SURFACED AFFECTED STEVEN JOHNSONS SYNDROME 10% of the BODY SURFACED AFFECTED STEVEN JOHNSONS SYNDROME TOXIC EPIDERMAL NECROLYSIS

18. SYMPTOMS BOTH MUCOSAL LINGS AND SKIN are AFFECTED FEVER EARLY :FLU LIKE SYMPTOMS

19. CLINICAL PRESENTATION Prodrome Fever, often exceeding 39°C (102.2°F), and influenza-like symptoms precede by one to three days the development of mucocutaneous lesions [102]. Photophobia, conjunctival itching or burning, and pain on swallowing may be early symptoms of mucosal involvement. Malaise, myalgia, and arthralgia are present in most patients.

20. Cutaneous lesions — The skin lesions typically begin with ill-defined, coalescing, erythematous macules with purpuric centers, although many cases of SJS/TEN may present with diffuse erythema . The skin is often tender to the touch, and skin pain can be prominent and out of proportion to the cutaneous findings. Atypical target lesions with darker centers may be present. As the disease progresses, vesicles and bullae form, and within days the skin begins to slough. -Nikolsky sign (may be positive. ) -The Asboe-Hansen sign or "bulla spread sign" may also be present.

21. No ocular involvement – 0 (none) ●Conjunctival hyperemia – 1 (mild) ●Either ocular surface epithelial defect or pseudomembrane formation – 2 (severe) ●Both ocular surface epithelial defect and pseudomembrane formation – 3 (very severe)

22. Genital erosions are frequent. In women, vulvovaginal involvement may present with erosive and ulcerative vaginitis, vulvar bullae, vaginal synechiae, and may lead to long-term anatomic sequelae. These include labial and vaginal adhesions and stenosis, obstructed urinary stream and urinary retention, recurrent cystitis, or hematocolpos

23. lab values neutropenia is present in approximately one-third of patients and is correlated with a poor prognosis Serum urea nitrogen >10 mmol/L and glucose >14 mmol/L are considered markers of disease severity

24. DIAGNOSIS Based on symptoms Biopsy of affected area * Definitive

25. Laboratory and imaging studies to request Complete blood count with differential, metabolic panel Bacterial and fungal cultures chest radiograph

26. DIFFERENTIAL DIAGNOSIS Erythema multiforme Staphylococcal scalded skin syndrome Generalized bullous fixed drug eruption Erythema multiforme usually presents with typical target lesions or raised, atypical, targetoid lesions that are predominantly located on the extremities is caused by epidermolytic toxins produced by certain strains of staphylococci. SSSS presents with generalized erythema rapidly followed by the development of flaccid blisters and desquamation Generalized bullous fixed drug eruption is an extremely rare form of fixed drug eruption characterized by widespread red or brown macules or plaques with overlying, large, flaccid bullae

27. Treatment overview Hospitalization Trigerring Medications Treat Triggering Infection Systemic Immune modulators -antihistamine -IVIG -Corticosteroids

28. Acute phase progressive worsening of the cutaneous detachment and mucositis followed by disease arrest and re-epithelization. Due to extensive skin detachment Management during this phase is focused on supportive care and prevention of short- and long-term complications.

29. management Chronic phase – occurs during the convalescent and recovery stage of SJS/TEN. Physical and psychologic sequelae may occur

30. Prompt identification and withdrawal of the causative drug — Prompt identification and withdrawal of the offending agent may improve the prognosis. In a 10-year, observational study of 113 patients with TEN or SJS, early withdrawal of the causative drugs with short half-lives reduced the risk of death by 30 percent for each day before the development of blisters and erosions (odds ratio [OR] 0.69, 95% CI 0.53-0.89) [7]. However, in drugs with long half-lives , there was an increased risk of death , independent of early or late withdrawal (OR 4.9, 95% CI 1.3-18.9).

31. Causality attribution is generally determined by two principles: Temporal sequence Most causative drugs are started 5 to 28 days (occasionally up to two months) prior to the onset of symptoms Drug notoriety – The majority of SJS/TEN cases are caused by a few high-risk medications An algorithm for determining drug causality has been formulated and is useful for the determination of the culprit drug

32. Assessment of the extent of skin detachment

33. Assessment of prognosis SCORTEN score severity of illness score of toxic epidermal necrolysis (SCORTEN)

34. Assessment of prognosis ABCD-10 age, serum bicarbonate level, cancer, dialysis, involvement of >10 percent BSA [ABCD-10] Comparisons between the two prognostic scores suggest that the performance of SCORTEN remains superior and should be considered as the default prognostic tool

35. Red cell distribution width to hemoglobin ratio (RDW/Hb) study evaluating the association between inflammatory markers and in-hospital mortality in 192 patients with SJS/TEN showed that red cell distribution width to hemoglobin ratio (RDW/Hb ) had a similar predictive accuracy as SCORTEN

36. Transfer to a referral center — Patients with BSA detachment of ≥10 percent, rapidly progressive disease, or worsening biochemical/organ function should be transferred and managed in specialized centers, such as specialized dermatology units, burn centers, or intensive care units

37. ACUTE MANAGEMENT Supportive care cornerstone of management and includes wound care, fluid and electrolyte management, nutritional support, temperature management, pain control, infection prevention and management, ocular care, and organ support, if needed

38. Wound care Surgical approach devitalized epidermis is removed via operative debridement, manual scrubbing, or the use of whirlpools [30] Conservative approach the detached/detachable epidermis is left in situ as a biologic dressing, and additional nonadhesive dressings may be used to promote healing.

39. Fluid and temperature management Fluid and electrolyte imbalances occur secondarily to increased water loss from the denuded dermis and decreased oral intake in patients with extensive oral mucosal involvement. Strict intake/output monitoring should be instituted. Fluid replacement is essential to prevent end-organ hypoperfusion and shock. Room temperature should be maintained between 82.4 to 89.6°F (28 to 32°C) to prevent excessive caloric expenditures due to epidermal loss and to prevent hypothermia [2,23,38]. Heated-air body warmers may also be used.

40. Nutrition — Nutritional supplementation should be initiated early to support metabolic disturbances and promote healing. The estimated caloric requirement is 20 to 25 kcal/kg per day during the early, catabolic phase of SJS/TEN and 25 to 30 kcal/kg per day during the anabolic, recovery phase of the disease .

41. Pain control — SJS/TEN is an extremely painful condition, and the pain is exacerbated by mobilization and wound care procedures. Every effort should be taken to optimize pain control.

42. Prevention and treatment of infections Patients with SJS/TEN are at high risk of infection. Up to 30 to 50 percent of patients with SJS/TEN develop bacteremia, and sepsis is the most common cause of death [40-42]. BSA involvement of ≥10 percent, hemoglobin levels ≤10 g/dL, and existing cardiovascular disease are associated with increased risk of developing bacteremia [41]. Br J Dermatol. 2016 Jun;174(6):1194-227.

43. Prevention Sterile handling Sterile handling is essential. In specialized centers, patients are nursed in reverse isolation procedure rooms Skin antisepsis Antiseptic solutions containing octenidine, polyhexanide, or chlorhexidine or silver nitrate preparations may be used for disinfection.

44. Repeated cultures of the skin, as well as blood, catheters, gastric, and urinary tubes, should be obtained at regular intervals (eg, every 48 hours) to allow early detection of infections [41,42]. Positive skin cultures may predict blood culture positivity from the same organisms. Repeated bacterial cultures

45. Surveillance for clinical signs of sepsis Signs of bacteremia include hypothermia, confusion, hypotension, and reduced urinary output [41,42]. Hypothermia and elevated procalcitonin ≥1 mcg at the time of blood culture have been shown to be predictive of the blood culture positivity [41].

46. Treatment – Antibiotic choice should be directed by culture results whenever possible Commonly isolated pathogens include S. aureus and P. aeruginosa

47. Management of acute respiratory involvement Up to 40 percent of patients with SJS/TEN may develop acute respiratory complications [44]. Risk factors for mechanical ventilation include serum bicarbonate <20 mmol/L, serum urea >10 mmol/L, baseline detached BSA >10 percent, white blood cell count >12,000/mm3, hemoglobin <8 g/dL, bacteremia, and shock/organ failure on admission [45-47].

48. Management of acute respiratory involvement Concerns on the following: Bronchoscopy Oral intubation Noninvasive ventilation

49. Management of urogenital involvement — Urogenital involvement occurs in up to 70 percent of patients with SJS/TEN It may present acutely as erosions of the scrotum/labia and penis/vulva and may result in dysuria and urinary retention. Nonadhesive dressings should be applied to urogenital erosions to reduce pain and prevent adhesions. Moderate-potency topical corticosteroids can be applied daily until resolution of the acute phase of illness . Estrogen cream and barrier creams may also promote re-epithelization .

50. Management of urogenital involvement FEMALE In female patients, additional local vulvar care includes gentle water washes or sitz baths. If vaginal involvement is suspected, an intravaginal potent corticosteroid ointment should be applied, and silicone vaginal dilators can be used to prevent strictures and adhesions [49]. Menstrual suppression during the acute phase of illness in female patients of reproductive age is recommended to reduce the risk of vaginal adenosis and endometriosis [49,50]. To prevent periurethral stricture, patients with vulvovaginal involvement should receive a urinary catheter.

51. Management of ocular involvement — . Repeated ophthalmic evaluation of all patients with suspected SJS/TEN should be performed even if ocular involvement is not visible at the onset of the disease, as it may follow cutaneous involvement. Examination should be performed daily until the ocular condition stabilizes [24]. The entire ocular surface should be carefully examined. Examination should include fluorescein staining to document the presence of membranes and loss of surface epithelium.

52. Ophthalmic therapy — The principles of ophthalmic care are to reduce destructive inflammation at the ocular surface and lid margin; prevention of conjunctival adhesions; infection prophylaxis; and prompt identification and management of blinding complications of corneal exposure, ulceration, and infection Saline rinses Lubricants Topical corticosteroids/antibiotics Adhesion separation Amniotic membrane transplantation

53. Additional supportive measures Stress ulcer prophylaxis Disseminated intravascular coagulation Prevention of deep vein thrombosis Hyperglycemia Neutropenia

54. ADJUNCTIVE PHARMACOLOGIC THERAPIES There is no established pharmacologic treatment for SJS/TEN. A variety of systemic immunosuppressive or immunomodulating agents, such as systemic corticosteroids, intravenous immune globulin (IVIG) [70], cyclosporine [71], plasmapheresis [72], and anti-tumor necrosis factor (TNF) agents [73], have been utilized Evidence on the efficacy of immunomodulatory treatments is largely derived from observational studies and has been summarized in several meta-analyses Hierarchy ranking of treatments showed that cyclosporine was the most effective treatment, followed by corticosteroids plus IVIG and etanercept [77].

55. Cyclosporine There is increasing evidence from multiple case series and meta-analyses suggesting that the cyclosporine administered during the acute phase may be associated with reduced mortality [71,76,78,86-90]. The use of cyclosporine early in the course of the disease has consequently been advocated by some experts [91]. We suggest using c yclosporine 3 to 5 mg/kg/day as adjunctive therapy w ithin 24 to 48 hours of symptom onset.

56. Systemic corticosteroids prednisolone 60 to 250 mg/day for 2 to 12 days , intravenous dexamethasone 1.5 mg/kg/day for three days , and intravenous methylprednisolone 250 to 1000 mg/day for three days [80]. ●However, in a subsequent, updated review of patients recruited in the RegiSCAR study for whom treatment details were available (n = 442), there was no observed benefit or harm with corticosteroids (hazard ratio [HR] 1.3, 95% CI 0.8-1.9) [4]. ●In a systematic review of 31 pediatric case series with 128 patients, no deaths were reported among the 20 patients who received either prednisolone/prednisone (1 mg/kg/day) or methylprednisolone (4 mg/kg/day) for five to seven days [84]. Complications occurred in five patients (mild skin infections in three children and bronchiolitis in two children).

57. Intravenous immune globulin 2 to 4 g/kg over two to five days There is little evidence: ●A 2012 systematic review and meta-analysis of 17 observational studies including 113 patients treated with IVIG and 130 patients treated with supportive care only found no difference in the risk of death between the two groups (OR 1.00, 95% CI 0.58-1.75) [97]. However, a subgroup analysis showed a statistically nonsignificant reduction in the mortality risk for patients treated with high-dose IVIG (total dose ≥2 g/kg) compared with those treated with <2 g/kg (OR 0.49, 95% CI 0.11-2.30). ●In a subsequent, single-institution study of 64 cases of TEN and SJS/TEN overlap (mean SCORTEN 2.6) treated with IVIG, the overall mortality rate was 31 percent (SCORTEN-predicted mortality 28 percent, SMR 1.1, 95% CI 0.6-1.6) [98]. Mortality was similar among patients treated with <3 g/kg IVIG and those treated with ≥3 g/kg IVIG (31 and 26 percent, respectively). ●A 2017 meta-analysis using individual data from 1209 patients, of whom 215 received IVIG in addition to supportive treatment, found that IVIG treatment was not associated with a decreased risk of death compared with supportive treatment alone (OR 0.99, 95% CI 0.64-1.54) [78].

58. PROGNOSIS Mortality — The overall mortality rate among patients with SJS and TEN is approximately 25 percent, ranging from 10 percent for SJS to >30 percent for TEN [4]. Mortality is considerably lower in children, ranging from 0 to 9.5 percent among centers Patients who develop acute renal failure requiring renal replacement therapy also have an increased mortality risk [124]. Older age (>70 years) and presence of comorbidities (eg, liver cirrhosis, metastatic cancer) are also associated with an increased risk of death [125]. Disease severity (ie, the extent of cutaneous involvement) is the main risk factor for mortality within 90 days of disease onset [4].

59. Nice to know facts Nail changes occur in up to 70 percent of survivors and include Beau lines and onychomadesis