**6.2 Care support**

Medical staff should use protective equipment when in contact with patients to avoid oral and respiratory infections. It is important to avoid holding or pulling the patient strongly and to limit injury to the epidermis (blood pressure measuring tape, electrocardiogram) [73]. Bacteria, viruses, and Candida fungi from three skin lesions should be cultured. Herpes infection should be excluded, especially in the case of severe mucous membrane lesions. Systemic antibiotics should be used if there is evidence of infection. In patients who have diarrhea or are unable to move, avoid getting dirty stools into skin lesions. Pay attention to using pain relievers if the pain is severe [1, 74].

Skin lesions should be washed with sterile warm water or physiological saline or with an antiseptic solution such as chlorhexidine (1/5000). A moisturizer with fatty properties such as vaseline, paraffin all over the skin, including the area that is growing granules should be applied. Scaly skin could be improved with topical antimicrobial drugs. Peeled epidermal fragments should be kept as a bio-bandage. The blisters should be aspirated and drained. Areas of skin that have lost the epidermis should be covered with non-stick gauze. Necrotic and infected epidermal fragments should be removed.

Eye mucosa is often damaged in SJS/TEN, if not detected, timely treatment can leave complications such as corneal ulceration, eye corner adhesions, pterygium adhesions, blindness [68]. Patients with SJS/TEN should be examined, treated, and monitored by an ophthalmologist from the acute stage of the disease until the disease has recovered. The mucous membrane of the vulva, vagina needs to be regular checkups and cleaning with antiseptic solutions, moist gauze. Topical corticosteroids can reduce inflammation [75]. Oral mucosa needs to be cleaned with antiseptic solutions such as chlorhexidine. Lips and mouth should be covered with moist gauze, corticosteroid solution can be applied to rinse the mouth, oral hemorrhages need to be controlled [76].

Peripheral and central lines should be placed in preserved areas. The fluid balance will be monitored by a catheter. The amount of fluid to compensate could be calculated by referring to the formula of Shiga and Cartotto [77]:2 ml kg−1 body weight/% of epidermal area detachment, necrotic.

If the patient can drink, oral rehydration should be maintained. Patients with SJS/ TEN need more nutrition than usual. If the mouth is severely damaged, eating is difficult, a nasogastric tube should be placed or parenteral nutrition. In the acute phase, the required calorie intake is 20–25 kcal kg−1 per day. During the recovery phase, the calorie requirement is 25–30 kcal kg−1 per day [1].

Patients with SJS/TEN have pain in the skin, especially at epidermal detachment sites. There are no studies on analgesic regimens in SJS/TEN. Therefore, analgesics according to the World Health Organization tiers can be used. Paracetamol or

synthetic opiate pain relievers (tramadol) should be used, but not non-steroidal antiinflammatory analgesics because of the risk of kidney and stomach damage. Some care procedures such as bathing and changing clothes require the use of analgesics.

Other treatments including proton pump inhibitors, anticoagulants, and drugs to treat leukopenia, anemia (granulocyte colony-stimulating factor, G-CSF) should be used appropriately.

#### **6.3 Specific medicines**

## *6.3.1 Intravenous immunoglobulin*

The basis for the use of IVIG in SJS/TEN are studies that show the role of Fas-FasL interaction in the mechanism of apoptosis of squamous cells [78]. FasL is a transmembrane protein of the TNF family that is expressed on the surface of cytotoxic T cells and natural killer cells. When cytotoxic T cells are activated, FasL is expressed, binds to its receptor on the target cell, activates the intracellular caspase, leading to uncontrolled destruction of the target cell. In addition, Fas can be separated from the cell membrane by metalloproteinase enzymes, producing soluble Fas from FasL, still maintaining the ability to bind to Fas receptors, causing apoptosis [6, 79]. High concentrations of normal immunoglobulin inhibit Fas-Fas ligand and apoptosis interactions through activation of anti-Fas antibodies.

In a systematic review and meta-analysis published by Huang in 2012 (all studies included at least 8 IVIG-treated SJS/TEN patients), cumulative estimates of risk mortality were determined, comparing IVIG and supportive care alone in patients with TEN and overlapping SJS/TEN. Statistical analysis was performed on the raw data to compare the clinical differences between high- and low-dose treatment in adult patients, and between pediatric and adult patients receiving IVIG. The mortality rate in the group of TEN and overlapping SJS/TEN patients treated with IVIG was 19.9%. Pediatric patients treated with IVIG had a lower mortality rate than adults (0% vs. 21.6%, p = 0.01). Adult patients treated with high dose IVIG had a lower mortality rate than those treated with low dose (18.9% vs. 50%, p = 0.02). However, the multivariable logistic regression model showed that IVIG dose was not correlated with mortality. But these results should be interpreted with caution due to limitations in the study design [79]. Following Huang's publication, a further study performed by Firoz et al. including 23 TEN patients treated with IVIG, demonstrated that IVIG did not improve survival compared with supportive care simply [80]. In 2013, Lee et al. published a retrospective analysis of 64 patients with overlapping SJS/TEN and TEN receiving IVIG. Based on the actual mortality compared with the SCORTEN estimated mortality, IVIG therapy showed no benefit. In addition, there was no difference between the high dose (>3 g/kg) and the low dose (<3 g/kg) [81].

#### *6.3.2 Systemic corticosteroid therapy*

Corticosteroids have been used to treat SJS/TEN for many years. Advocates emphasize the anti-inflammatory role of high doses of corticosteroids in the early stages of the disease. Opponents argue that systemic corticosteroids increase the risk of infection. Retrospective analysis of EuroSCAR data showed a lower mortality rate in the German group of patients receiving corticosteroids than in the supportive care group alone. To limit the side effects of long-term corticosteroid use, some authors use very high doses for a short time (pulse therapy) [82]. In the study by Kardaun and Jonkman, 12 patients treated with intravenous dexamethasone 100 mg or 1.5 mg/kg for 3 days had a lower mortality rate compared with the estimated mortality according to the SCORTEN [83]. Hirahara et al. had 8 patients with SJS/TEN treated with intravenous methylprednisolone 1000 mg for three consecutive days, followed by dose reduction with oral prednisolone or 2 days of methylprednisolone at half the initial dose. No patient died although the SCORTEN estimated mortality was 1.6. Serum biomarkers IFN-γ, TNF-α, IL-6, and IL-10 were measured in 5/8 patients. On the fourth day post-treatment, the mean concentrations of these cytokines decreased compared with pre-treatment, but only significantly changed for interferon-gamma (IFN-γ) and IL-6. On day 19, there was a significant reduction in both IFN-γ, TNF-α, and IL-6, whereas IL-10 levels were higher than before treatment [84].

#### *6.3.3 Cyclosporine*

Cyclosporine is an immunosuppressive drug, indicated in many diseases such as rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, anti-rejection in organ transplantation. The mechanism of action of the drug is to reduce the function of lymphocytes by forming a complex with cyclophilin to inhibit the activation of calcium channel phosphatase, thereby reducing the production of cytokines by T lymphocytes.

Its inhibitory effect on lymphocytes defines cyclosporine as the theoretical standard drug of action in SJS/TEN [1]. A study by Valeyrie-Allanore showed that in 29 SJS/TEN patients treated with cyclosporine (1.5 mg/kg/day in 2 divided doses for the first 10 days, then reduced to 1 mg/kg/day days for the next 10 days, the last 10 days is 0.5 mg/kg/day) is effective. No patient died, although the SCORTEN estimated number of deaths was 2.75/29 [85]. Singh reported 11 patients with SJS/ TEN who were treated with cyclosporine 3 mg/kg/day for 7 days, followed by dose reduction. This group was compared with 6 corticosteroid-treated SJS/TEN patients. In the cyclosporine group with a shorter hospital stay, the epithelialization rate was faster. Cyclosporine was more effective than corticosteroids when comparing SCORTEN estimated mortality. Kirchhof retrospectively studied 64 SJS/TEN patients treated with cyclosporine or IVIG (dose varied from patient to patient). Comparison of SCORTEN estimated mortality with actual mortality suggests a benefit of cyclosporine over IVIG [86]. Cyclosporine is well-tolerated, despite treatment in patients prone to hemodynamic instability and prerenal hypovolemia. It contributed to improved patient survival. Disease progression was slow and halting in the majority of patients [85, 87].

#### *6.3.4 Other methods of treatment*

Other therapies were used in SJS/TEN but in small sample sizes, no comparisons were made. Plasmapheresis is used in difficult-to-treat cases, and some reports have shown it to be effective [88, 89]. The immunoregulatory and regenerative role of G-CSF is used in the treatment of SJS/TEN (helps to stop hypersensitivity, stimulate epithelialization, control neutropenia) [90]. Biologics such as TNF-alpha antagonists have been conducted to improve the prognosis of SJS/TEN [23, 52]. Paradisi reported 10 patients with SJS/TEN treated with etanercept with a single dose of 50 mg subcutaneously. The study did not have a control group. All patients responded with a mean time of epithelialization of 8.5 days. Although the SCORTEN estimated mortality rate was 50%, no patient died [91].
