Severe Cutaneous Adverse Reactions to Drugs

Faith L. Chia; Khai Pang Leong

Disclosures

Curr Opin Allergy Clin Immunol. 2007;7(4):304-309. 

In This Article

Immunosuppression

A Cochrane review on interventions in TEN in 2002 bleakly concluded that there was 'no reliable evidence on which to base treatment for TEN'. Throughout the literature, there has only been one randomized controlled trial using thalidomide in the treatment of TEN, but it was terminated early due to excessive mortality in the study arm. Since then, although there have been many more studies published, the literature is still dominated by uncontrolled trials, retrospective studies, case series and anecdotal reports.

Systemic Corticosteroids

The use of corticosteroids in the management of TEN remains controversial. The use of corticosteroids as an anti-inflammatory agent must be tempered with the risk of increasing the already high risk of septic complications. Current available data do not allow for the recommendation of corticosteroids as a therapy for TEN, particularly if major skin loss has already occurred. High-dose corticosteroid, however, may have a place for use in patients who present with early TEN during the erythrodermic stage before skin loss occurs. Even so, the use should be limited to the first 48 h to avoid serious complications.[31,32,33]

Unlike in TEN, the potential benefit of corticosteroids is less controversial for SJS. A prospective analysis of 67 consecutive patients with SJS treated with corticosteroids concluded that prompt treatment with systemic steroids reduces morbidity and improves outcomes of SJS patients.[34]

Intravenous Immunoglobulin

In a landmark paper in 1998, Viard et al.[35] reported that commercial preparations of intravenous immunoglobulin (IVIg) contained natural antibodies to Fas (CD95) that were able to block the binding of FasL to Fas. In vitro, this potently inhibited cell death mediated by recombinant FasL. IVIg may affect the lymphocytes as well because in a child with TEN due to lamotrigine, it was shown that the high levels of CD8, CLA and CD69 in blister-fluid lymphocytes decreased 24 h after IVIg infusion.[36]

There are many case reports and nine studies with 10 or more patients with TEN treated with IVIg, the largest of which is a retrospective multicentre study of 48 patients.[37] Seven of these nine studies showed a trend towards a benefit on the mortality rate of TEN with high-dose IVIg.[38*,39*]

Of the three studies that did not show any benefit on mortality,[40,41,42] two were retrospective and only one was a prospective noncomparative evaluation of IVIg therapy at 2 g/kg in 34 patients with SJS and TEN from a single center.[40] Progression of disease and mortality rates were not significantly different from that predicted by SCORTEN (11 deaths, 32% versus 8 deaths, 24%). The mean interval between onset and IVIg administration was 4 days. The mean age of the survivors was 37.6 years compared to 66.4 years in those who perished. Significantly, two out of 12 patients with HIV died.

Patients who received IVIg within the first 4 days of onset of eruption appear to have a shorter time to cessation of progression and to complete re-epithelialization compared to those who received it later. Statistical significance was not reached probably due to the small sample size of 16 patients. The authors concluded that most benefit would be derived from IVIg if it was given within 4 days of onset of symptoms.[43]

The use of IVIg in children with SJS/TEN has been uniformly favourable.[44] TEN in children, however, has been reported to have a better spontaneous prognosis than in adults, with more rapid re-epithelialization and lower mortality.[45]

There have been a few cases of SJS/TEN who were treated with both corticosteroids and IVIg, both in the paediatric as well as adult populations. The experience suggests that these patients take a longer time to respond than those who have not received corticosteroids.[37,44]

In addition to lack of controlled studies, it is difficult to compare the existing ones because of variation in patient characteristics, treatment protocols, IVIg dosages, commercial IVIg brands and intervals between TEN onset and initiation of treatment. Despite the lack of randomized controlled trials, the majority of trials point towards a beneficial effect of IVIg on TEN, especially when it is administered early in the disease course and in sufficiently high total dose (beyond 2 g per kg bodyweight). Based on this, we support the use of IVIg in TEN, while acknowledging that further work needs to be done in the form of randomized controlled trials.[38*]

Anti-tumour Necrosis Factor Agents

Thalidomide was tested in a double-blind placebo controlled trial with the rationale of inhibiting TNF-α production. It was discontinued early, however, due to unexpectedly high mortality in the thalidomide group. The increased mortality could be attributed to a paradoxical increase in TNF-α production as thalidomide also acts as a costimulator of CD8+ cytotoxic T cells in vitro, or alternatively because TNF could be antiapoptotic in TEN.[46]

The use of anti-TNF monoclonal antibody in the treatment of TEN was first reported from Germany in a 56-year-old woman treated with cotrimoxazole. One dose of intravenous infliximab 5 mg/kg body weight, administered 4 days after the onset of symptoms, resulted in the halting of disease progression within a few hours.[47] In a more recent case report, a 69-year-old woman received a single dose of infliximab 5 mg/kg within 3 days of onset of symptoms, with cessation of epidermal detachment in 24 h and complete re-epithelialization after 5 days.[48] In patients with TEN, TNF-α is strongly expressed in keratinocytes and macrophages of lesional skin, and higher concentrations are found in cutaneous blister fluid. In this case, expression of TNF-α in the skin was examined before and 24 h after anti-TNF-α therapy, demonstrating that TNF-α protein and mRNA expressions by inflammatory cells in the dermis was markedly reduced after infusion, reaching levels lower than normal. This promising new treatment of TEN has to be evaluated in larger groups of patients.

Other Agents

Ciclosporin is an immunosuppressant that has antiapoptotic properties. There have been several case reports and one case series of 11 patients documenting treatment of TEN with ciclosporin.[49] All the patients had severe TEN, and ciclosporin was administered at 3-5 mg/kg/day until the patient had re-epithelialized, except in the case series where it was given for 4 weeks. There appeared to be a shorter time to arrest of disease progression with no greater risk of septic complications. The patients in the case series, however, were compared to historical controls who received cyclophosphamide and prednisolone, keeping in mind that steroids are no longer recommended for TEN. Since then, there have been no further studies on ciclosporin.

Redondo et al.[50] described the use of intravenous N-acetylcysteine in the treatment of two patients with hypersensitivity syndrome and TEN from anticonvulsants. They postulated that N-acetylcysteine could be beneficial as it is a known precursor of glutathione, a molecule involved in the detoxification pathway of several drugs including anticonvulsants. N-acetylcysteine also inhibits the production of TNF-α and IL-1β in vitro. Following this, two more patients with TEN were treated with intravenous N-acetylcysteine 300 mg/kg/day with complete re-epithelialization in 7 days.[51] More recently, N-acetylcysteine was used together with IVIg with rapid recovery in a HIV positive patient with TEN and toxic hepatitis from the antiretroviral drug nevirapine.[52]

Although the authors of both papers suggested that N-acetylcysteine was safe to use aside from the possibility of increased clearance of other drugs other than the culprit drug, a surprisingly high incidence of angiooedema (75%) was found in a small series of patients with anticonvulsant hypersensitivity syndrome treated with intravenous N-acetylcysteine 2 g at 6-hourly intervals.[53] Also, a randomized trial showed lack of effectiveness of N-acetylcysteine in prevention of hypersensitivity reactions to trimethoprim-sulfamethoxazole in patients with HIV infection.[54]

Ocular Manifestations and Management

The majority (60 to 88%) of patients with SJS and TEN have ocular involvement.[55] This may range from mild (lid oedema, conjunctival injection or chemosis) to moderate (conjunctival membrane/pseudomembrane, corneal erosion or epithelial defect) to severe manifestations that are vision threatening (conjunctival fornix fore-shortening, sympblepharon, corneal infiltrate or ulceration).[56] Although the majority of patients have mild manifestations, long-term sequelae occur in almost half of all patients, the most common being dry eyes, conjunctival or corneal scarring and symblepharon.[57]

Early ophthalmological consultation should be sought for all patients to ensure best outcome, with judicious use of topical lubricants, steroids and antibiotics. Patients with ocular adhesions require daily lysis and sweeping of the fornix. Therapeutic gas permeable contact lenses may be used for patients with corneal epithelial defects.

As with systemic treatment, the efficacy of topical treatments has not been evaluated in any randomized controlled prospective study. According to current knowledge, the use of systemic or topical steroids apparently fails to prevent long-term complications.[56] Cases of corneal opacification would benefit from corneal transplant with or without limbal stem cell transplantation. A recent paper[58] suggested that cultivated limbal stem cell transplant for SJS resulted in better clinical results and vision than conventional limbal stem cell transplant.

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