- Viard I,
- Wehrli P,
- Bullani R,
- et al.
Purpose of the Study
Toxic epidermal necrolysis (TEN) is a severe, drug-induced skin disease characterized by epidermal cell death leading to loss of skin. TEN is most frequently induced by sulfonamides, anticonvulsants, or nonsteroidal antiinflammatory drugs and occurs in 0.8 cases per million with a mortality of 30%. Keratinocyte apoptosis (programmed cell death) is abnormally increased in TEN but the mechanism for the increase is unknown. This study evaluated the role of the “death receptor,” fas (CD95), and its ligand, fas ligand (FasL), in TEN and the possible therapeutic use of intravenous gammaglobulin (IVIG) for this disorder.
Seven patients (adults and children) with TEN, 4 controls with drug-induced maculopapular rashes, and 7 healthy controls were evaluated.
Enzyme-linked immunosorbent assay was used to measure serum concentration of soluble FasL; immunohistochemical staining of skin biopsy tissue was used to detect keratinocyte expression of Fas and FasL. The lytic capacity of keratinocyte FasL was evaluated using Fas-sensitive Jurkat cells overlaid on the skin frozen sections. Keratinocyte apoptosis was evaluated by flow cytometric methodology.
Patients with TEN had elevated serum sFasL (concentrations were virtually undetectable in control groups). Keratinocytes expressed increased FasL but similar amounts of Fas compared with controls. The lytic capacity of FasL expressed on keratinocytes was greatly increased, but could be blocked completely by incubation with FasL-blocking antibody. Apoptosis was inducible in human keratinocytes by recombinant sFasL. However, preincubation of keratinocytes with IVIG prevented recombinant sFasL-induced apoptosis. Conversely, incubating the recombinant sFasL with IVIG did not inhibit apoptosis (implicating blockade of Fas receptor as the rescue mechanism). Depletion of anti-Fas immunoglobulin from the IVIG (on an affinity column) also abrogated the ability of IVIG to block Fas-mediated keratinocyte cell death.
In an open, noncontrolled pilot study, 10 patients with TEN received IVIG at doses ranging from 200 to 750 mg/kg/day for 4 days. The progression of skin disease was interrupted in all 10 within 2 days. All experienced healing and a favorable outcome.
Fas-FasL interactions are directly involved in TEN, a disease in which keratinocyte apoptosis is increased and lytic FasL is up-regulated. IVIG, by blocking the Fas receptor, may be an effective treatment.
This study is a wonderful example of research moving from bedside to bench back to bedside. Controlled studies are needed, but an additional indication for IVIG may be on the horizon. In addition, more specific therapies for this disorder, and possibly others, are likely to be developed now that the immunologic mechanism has been elucidated.