Stevens-Johnson Syndrome ( SJS ) and Toxic Epidermal Necrolysis ( TEN ) : an update

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed-type hypersensitivity reactions triggered by drugs, and sometimes by infections.1 They are characterised by widespread epidermal necrosis of the skin and mucosa and are associated with substantial morbidity. They are classified according to body surface area affected.2 SJS and TEN are typically severe and potentially fatal in the acute phase due to the necrosis of external and internal body surfaces which may predispose the patient to life-threatening complications such as sepsis and multi-organ failure.1 In South Africa, the majority of patients who present with SJS and TEN are young to middle aged women who are HIV positive, and the most commonly implicated drugs are nevirapine and co-trimoxazole.3


Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed-type hypersensitivity reactions triggered by drugs, and sometimes by infections.1They are characterised by widespread epidermal necrosis of the skin and mucosa and are associated with substantial morbidity.They are classified according to body surface area affected.2SJS and TEN are typically severe and potentially fatal in the acute phase due to the necrosis of external and internal body surfaces which may predispose the patient to life-threatening complications such as sepsis and multi-organ failure.1In South Africa, the majority of patients who present with SJS and TEN are young to middle aged women who are HIV positive, and the most commonly implicated drugs are nevirapine and co-trimoxazole.3SJS and TEN rarely occur without any prior drug use, and in the rare instances that they do occur, the drug history reveals longterm medication use which cannot be linked directly to the adverse reaction experienced.⁴Other instances where SJS and TEN have occurred include vaccination, exposure to industrial chemicals and fumes, consumption of natural remedies and traditional Chinese herbal medications, and also infections by Mycoplasma pneumoniae and the herpes simplex virus.⁵ The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd58

Clinical presentation
SJS and TEN generally develop within the first eight weeks after starting a new medication.⁵Initial symptoms include fever and malaise, followed by the development of a generalised, tender cutaneous eruption consisting of macules, papules, atypical target lesions, and vesicles or bullae.⁸Mokenhaupt, (2016) further characterises these conditions by a cutaneous erythema with blister formation and haemorrhagic erosions of the mucous membranes such as stomatitis, balanitis, colpitis (vaginitis), severe conjunctivitis and blepharitis.The most widely accepted definition of these conditions is based on skin detachment, with SJS being defined when the denuded cutaneous surface covers less than 10% of the body surface area (figure 1) and TEN being defined when over 30% of the body surface is denuded (figure 2).⁹Epidermal detachment between 10 -30% constitutes SJS-TEN overlap. 1

Complications
The most documented pulmonary complications of SJS are obstructive lung diseases which include bronchiolitis, bronchiectasis, and chronic obliterative bronchitis.These patients often present with a cough, dyspnoea, wheezing, purulent sputum and sometimes a fever.1 Gastrointestinal and hepatic complications that have been commonly documented are oesophageal strictures which usually appear one month after the onset of SJS/TEN,1 but Teo and Walsh 10 (2016) also report that intestinal ulcers, chronic cholestasis, ischaemic hepatitis and the vanishing bile duct syndrome have also been documented.
Oral mucous membrane involvement is seen in the majority (70 -100%) of patients with SJS and TEN and includes tooth decay, severe dental growth abnormalities as a result of bacterial infection due to low saliva production and ulceration with fibrinous exudative inflammation which leads to reepithelialisation and healing.1 Some dental hypoplasia has also been documented in these patients. 10Otorhinolaryngologic involvement includes hypopharyngeal stenosis, nasal septal synechiae, pinna synechiae, 10 acute laryngitis, epiglottitis, and ulceration of the nasal cavity which resolve with supportive therapy and airway management.1 Gynaecologic complications involve vulva and vaginal adenosis, a fusion of the labia minora and majora, and labial synechiae and renal complications involve glomerulonephritis and chronic renal insufficiency. 10

Non-pharmacological treatment
Early and aggressive supportive care isolated preferably in a Burns Intensive Care Unit may be one of the most important intervention for patients with SJS and TEN, and the offending medication should be identified and stopped immediately to improve prognosis.⁵Room temperature should be increased to between 30 and 32 degrees Celsius, especially if a larger body surface area is involved and bedding on alternating pressure mattress is also recommended.Patients should receive fluid and electrolyte replacement and a solution of albumin⁴ to prevent end-organ hypoperfusion and shock. 11While the patient is in the ICU, necrotic tissue should be debrided and the exposed areas should be covered with an artificial membrane or a biological dressing to promote healing, reduced scarring and discomfort, and prevent infection.Due to the high rate of infection in patients with SJS and TEN, regular blood, skin and urine cultures should be performed.⁵

Pharmacological treatment 1. Systemic corticosteroids
Corticosteroids have been used in the management of SJS and TEN for many years despite high controversy about their use in these patients.Some literature emphasize that early highdose corticosteroids can be used to inhibit inflammation, 11 while some literature state that corticosteroids increase the rate of infections, the risk of masking septicaemia and also delay re-epithelialisation which ultimately prolongs hospital duration and increases mortality.⁴A high dose of pulsed intravenous dexamethasone (1.5mg/kg/day), when given for three days, seems to stop disease progression and promote healing within three weeks. 5

Human intravenous immunoglobulin (IVIg)
Human intravenous immune globulin (IVIg) has been used for both treatment and prophylaxis of SJS and TEN because it has been hypothesised that antibodies in pooled human IVIg inhibit Fas-mediated keratinocyte necrosis.⁴Creamer et al 2016 showed that mortality in patients using IVIg showed no improvement as compared to patients receiving supportive care alone, while Mokwnhaupt (2016) concluded that IVIg is not the best treatment for SJS and TEN.

Cyclosporine
Cyclosporine inhibits apoptosis through the inhibition of down regulation of NF-kB and has reported good results when given at a dose of 3mg/kg/day for ten days.⁵Cyclosporine is used due to its speculated effects on granulysin and its reduction on mortality rate.⁴

Plasmapheresis
Plasmapheresis is the process where non-dialyzable pathogenic components are removed from plasma.The blood is then reconstituted by adding albumin to artificial plasma and re-infused back into the patient. 5

Cyclophosphamide
The benefits of cyclophosphamide in patients with acute TEN was previously reported but is not recommended anymore in the treatment of SJS and TEN due an associated increase in mortality rate. 5

TNF-alpha inhibitors
Infliximab, pentoxiphylline and thalidomide are used in the management of SJS and TEN due to their inhibition of TNFalpha which is said to play a role in SJS and TEN. 5

Granulocyte colony stimulating factor
Granulocyte colony stimulating factor is used to boost neutrophil count in patients with SJS and TEN to reduce the risk of infection caused by neutropenia.⁵

Conclusion
SJS and TEN are severe; T-cell mediated drug reactions which result in rapid irreversible keratinocyte cell death.Although SJS is less severe than TEN, they both have the same aetiology, genetic susceptibility and pathogenesis.Patients most at risk include those taking; allopurinol, sulphonamide anti-infectives (especially co-trimoxazole), carbamezapine, phenytoin, phenobarbital and non-steroidal anti-inflammatory medicines.Due to the rarity of the disease, direct evidence is difficult to mention on any specific treatment, but supportive care in an intensive care or specialist burn unit has been found to be the best management of patients with SJS and TEN.The standard treatment includes analgesia, wound care, fluid replacement, nutritional support and infection control.The benefits of using high-dose corticosteroids, IVIg and plasmapheresis have not yet proven to be effective and therefore further large, registry-based retrospective studies are needed to improve the management of SJS and TEN.The sequelae of the disease is very difficult to predict, so therefore patients should be monitored and followed up for signs of complications after the resolution of the acute phase and also be educated on avoiding the causative medication.