image of silk fabric and dry skin


N. Mittmann, PhD1,2,4; B.C. Chan, MSc3; S. Knowles, BScPhm1,5; N. H. Shear, MD2,4,6

1. Division of Clinical Pharmacology, 2. Department of Medicine , 3. HOPE Research Centre,
4. Department of Pharmacology, 5. Department of Pharmacy, 6. Division of Dermatology,
University of Toronto, Toronto, ON, Canada

ABSTRACT

Intravenous immunoglobulin (IVIG) has been proposed as a treatment for toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS). A number of retrospective and prospective studies have been conducted, with varying levels of evidence for the efficacy of IVIG. Recent publications provide opposing conclusions. A multi-center, comparative, long-term analysis needs to be conducted to determine the role of IVIG in the management of patients with SJS/TEN.

Key Words:
Intravenous immunoglobulin, IVIG, toxic epidermal necrolysis, TEN, Stevens-Johnson Syndrome, SJS

The terms erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have become entangled and confusing over time. Current concepts support EM as a specific disease that is different from the SJS/TEN spectrum. SJS and TEN represent different degrees of a severe, acute mucocutaneous reaction that often can be caused by drugs.1 TEN or SJS is diagnosed objectively according to a consensus-derived definition.2 The differentiation between SJS and TEN is determined based on the percentage of body surface area (BSA) affected: SJS is characterized by mucous membrane erosions and blisters on less than 10% of the total BSA, whereas TEN involves more than 30% of the total BSA.2 Important prognostic factors for SJS/TEN include the percentage loss of BSA, age, heart rate, cancer/hematologic malignancy, urea, bicarbonate, and glucose serum levels.3

Clinical Features

SJS/TEN is most commonly characterized by skin changes (scattered 2-ring target-like lesions with a dark red centre and lighter red halo, red macules with central blistering that can coalesce to larger areas of denuded skin), hemorrhagic mucositis (mouth, eyes, genitals, and respiratory tract), and systemic symptoms (fever, malaise, possible internal organ involvement).1 In severe TEN cases, fingernails and toenails, eyebrows and cilia may be lost as well. There may be extensive involvement of the gastrointestinal tract and respiratory tract. Sepsis and respiratory distress are the most common complications and ultimately the direct causes of death.

Survivors of SJS/TEN may experience numerous long-term sequelae; the most disabling are those involving the eyes. Cicatrization of conjunctival erosions may lead to inverted eyelashes, photophobia, burning sensation in the eyes, watery eyes, a siccalike syndrome, and corneal and conjunctival neovascularization. As many as 40% of survivors of TEN have residual, potentially disabling lesions on the eye and/or surrounding area, that may cause blindness.

Epidemiology

TEN affects between 0.4–1.2 cases per million people every year.4-7 SJS is seen more frequently, affecting 1–6 cases per million people every year.5,7 SJS may prove fatal in approximately 5% of patients. Prognosis is worse in TEN, where there is more epidermal sloughing which increases the severity of the condition with mortality rates ranging from 20%–40% for extensive sloughing.

Pathogenesis

The pathogenesis of drug-induced SJS/TEN is unknown, although several theories have been developed. Reactive metabolites of oxidative drug metabolism have been shown to lead to covalent binding that can stimulate an immune response. For some drugs there have been clear associations with HLA-B haplotypes in specific populations.8,9 Epidermal death is due in part to apoptosis that is triggered by a death signal (Fas-ligand) and in vitro antibodies to Fas-ligand can block the process.

Drug-related SJS/TEN

Many cases of SJS/TEN are related to drug exposure. The drugs most frequently cited as causes of SJS and TEN are anticonvulsants, antibiotics (especially sulfonamides), allopurinol, and NSAIDs (e.g., piroxicam).4 Other causes, especially for SJS, include infections, neoplasia, and autoimmune diseases.

Treatment of SJS/TEN

There is currently no specific treatment for TEN and SJS.10 Discontinuation of the suspected drug is the first step in the management of these patients, with supportive care (e.g., wound care, hydration, and nutritional support) forming the basis of treatment. Immunosuppressives (e.g., cyclosporin, cyclophosphamide) are often recommended,10 although the use of corticosteroids in SJS and TEN remains controversial. Other therapeutic modalities that have been attempted include hyperbaric oxygen,11 granulocyte colony stimulating factor,12-14 and plasmapheresis.15
Intravenous immunoglobulin therapy (IVIG) may improve outcomes and reduce mortality and morbidity in this population. Considered by many clinicians as a treatment option, it is produced from the plasma of thousands of healthy blood donors. The pooled plasma is fractionated and purified to produce a final product containing predominantly IgG (90%–98%) as well as traces of IgA, IgM, CD4, CD8, HLA molecules and cytokines.16 Albumin also appears in IVIG in quantities ranging from trace amounts to 3000ìg/mL.17-19

A number of retrospective and prospective studies have been conducted to examine the efficacy and safety of IVIG in SJS/TEN patients. A recent review of IVIG use in TEN and SJS examined studies with sample sizes of 10 or more patients.20 Nine studies were included consisting of 134 TEN or SJS/TEN overlap patients and 22 SJS patients. The overall mortality rate of all the studies reviewed was 20.5%, and 22.4% for TEN-specific studies. In a subanalysis of these controlled trials, mortality rate for patients receiving IVIG were 27% compared with 30% for the predicted/control group. Further subanalyses revealed significantly higher average IVIG dose in studies with a positive “effect” conclusion than studies with an “ineffective” conclusion. The authors concluded that there was not strong enough evidence to support IVIG use in TEN or SJS patients. Seven of the nine publications analyzed did not report adverse effects with IVIG treatment. Of the two studies that did report adverse effects, one reported higher complications in the IVIG group. In the other report, there were higher plasma creatinine levels in IVIG patients, especially in elderly patients and in patients with past kidney function impairment.20

An updated review stratified results according to TEN and SJS and examined more studies.21 In total, 14 studies in patients with TEN and 3 in patients with SJS were evaluated. The majority of studies reported positive results (11 out of 14),9,22-31 while three cohort studies did not observe statistically significant improvement with IVIG administration.32-34 For SJS, two of the three studies reported positive results.23,35 The remaining study showed no significant differences in mortality, progression of detachment or speed of re-epidermalization.32 In the pediatric population there were also positive results for IVIG response and adverse events.9,25,28,32,35 Because of the heterogeneity of the studies, a meta-analysis could not be conducted for IVIG in TEN or SJS.

It is important to note that all IVIG studies have examined clinical outcomes based on treatment in adults with doses ranging from 0.2g/kg/day to 2g/kg/day for 1–5 days’ duration. There is no information available on the impact of multiple dosing strategies.

The Toxic Epidermal Necrolysis Website Registry

Recently, a website for TEN and SJS has been launched (www.tenregistry.org) in Canada. At present, this new website is a pilot initiative that was created as an online resource to provide up-to-date information on SJS/TEN to clinicians, patients, and the public. The overall future objective of the website is to create a prospective, longitudinal database or registry of SJS/TEN patients across Canada and globally. At present, cases of suspected TEN or SJS should be reported to the adverse drug reaction monitoring agency. Reports to the adverse drug reaction monitoring centre may provide a signal for drugs that may cause SJS/TEN. Submitted reports of SJS/TEN will aid in determining the epidemiology, prognosis, and the possible causes, and will help plan health policy, especially for newly marketed drugs.

Conclusion

Based on the available data, IVIG may have a positive impact on the treatment of individuals with TEN and SJS. A large, multi-center, long-term analysis needs to be conducted to determine the role of IVIG in the management of these patients.

References

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