COMMENT
Tumor necrosis factor α inhibition in the treatment of TEN was first utilized in the 1990s with PTX and thalidomide.9,10 In 1994, PTX in addition to antioxidant therapy was found to successfully treat a 26-year-old woman with TEN attributed to anticonvulsant therapy.9 Other reports of PTX in the treatment of TEN were not found; however, there is a case series describing the successful treatment of 2 pediatric patients with Stevens-Johnson syndrome (SJS) and SJS-TEN overlap with PTX.25 Thalidomide, however, proved detrimental to patients with TEN as evidenced by an increased mortality in the 1998 trial.10 Paradoxically, the treatment group was found to have increased rather than decreased TNF-α concentrations, which was hypothesized to be the cause of increased mortality. This finding furthered the theory that TNF-α is an important mediator in TEN pathogenesis and a potential novel target in disease management.10
Since the PTX case report and the thalidomide trial, many physicians have reported the beneficial effects of biologic TNF-α inhibitors in the course of TEN; however, most of the literature is composed of case reports and case series describing a small number of patients. Therefore, the beneficial effects of anti–TNF-α therapy in TEN cannot be conclusively derived. Furthermore, cases using TNF-α inhibitors in combination with or after other systemic agents complicate the effects of TNF-α inhibitors themselves. Most of these case reports and case series describe the beneficial effects of TNF-α inhibitors in TEN; however, it is important to remember that cases in which these agents were ineffective are less likely to be published. The strongest evidence for TNF-α inhibitor use in the treatment TEN comes from the Paradisi et al14 case series, which showed a decrease in expected mortality with etanercept monotherapy in a relatively large cohort of patients. However, when evaluated prospectively by Paquet et al,24 there was no benefit seen by adding infliximab to NAC therapy and possibly an increased mortality in the group treated with both agents.
In the cases reviewed, a total of 32 patients were treated with infliximab or etanercept, and of these patients there were 4 deaths (12.5%).16,22,24 Three deaths were attributed to infection and 1 was attributed to disseminated intravascular coagulation. Furthermore, infection complicated the hospital course of 9 (28.1%) patients.13,15,22,24 The bacteria cultured from these patients included methicillin-resistant S aureus, P aeruginosa, E coli, Enterobacter aerogenes, and K pneumoniae. Patients who received TNF-α antagonists in combination with or after other systemic immunosuppressants appeared to have a higher incidence of infections. All patients treated with TNF-α antagonists in TEN should undergo careful evaluation and monitoring for infections due to the immunosuppressant effect of these drugs.
In our review, a total of 3 pediatric/adolescent patients received a TNF-α inhibitor for the treatment of TEN.13,17,21 Two patients received infliximab as a second-line medication after failure of IVIG to arrest progression of disease13,17 and one patient received infliximab as a second-line medication after dexamethasone.21 Each of these patients recovered without any reported infections or long-term complications.
Although excluded from this review, both infliximab and etanercept have been reported to show benefit in acute generalized exanthematous pustulosis/TEN overlap.26,27 Interestingly, in postmarketing surveillance, rare reports have implicated both infliximab and etanercept in causing both SJS and TEN.28 Also, there have been case reports of adalimumab causing SJS, but no cases of it causing TEN were identified.29,30
CONCLUSION
Rapid discontinuation of the culprit drug and aggressive supportive care remain the primary treatment of TEN. Tumor necrosis factor α inhibitors as monotherapy or as second-line agents show promise in the treatment of this complex disease state in both the adult and pediatric populations. The risks of these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-α inhibition in the treatment of TEN.