Cyclosporine Use in Epidermal Necrolysis Is Associated with an Important Mortality Reduction: Evidence from Three Different Approaches

Abstract

Several immunomodulatory agents are used in the treatment of epidermal necrolysis, but evidence of their efficacy is limited. The Autonomous Community of Madrid has two reference burn units to which all patients with epidermal necrolysis are referred. One burn unit has mostly used cyclosporine (CsA), and the other has used non-CsA therapies (mainly high-dose intravenous immunoglobulin). The allocation of patients to one or the other burn unit was mainly based on proximity, resembling a random assignment. Thus, we took advantage of this "natural experiment" to estimate the mortality risk ratio (MRR) of CsA (n = 26) compared with non-CsA (n = 16) treatment using hospital as an instrumental variable over the period from 2001 to 2015. We also computed the observed versus expected (O/E) MRR in a case series of 49 CsA-treated patients (including 23 patients from other regions treated in Madrid), and using the Score for Toxic Epidermal Necrolysis (i.e., SCORTEN) scale to estimate the expected values. The instrumental variable-based MRR of CsA versus non-CsA was 0.09 (95% confidence interval = 0.00-0.49). The O/E analysis also showed a reduction in mortality risk (MRR = 0.42; 95% confidence interval = 0.14-0.99). We identified five other case series of CsA-treated patients providing MRR and meta-analyzed their results. The pooled MRR (including from this study) was 0.41 (95% confidence interval = 0.21-0.80). All three approaches consistently show that CsA reduces the mortality in epidermal necrolysis patients.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Multicenter Retrospective Study of 377 Adult Patients from the United States

“…Emerging data from Europe, including a meta-analysis and systematic review, report a mortality benefit from treatment with cyclosporine (Arévalo et al, 2000;Gonzalez-Herrada et al, 2017;Kirchhof et al, 2014;Lee et al, 2017;Reese et al, 2011;Valeyrie-Allanore et al, 2010;Zimmermann et al, 2017), whereas a more recent retrospective cohort study showed no benefit (Poizeau et al, 2018). Etanercept has also been reported beneficial in a small case series (Paradisi et al, 2014) and, recently, in a randomized trial (Wang et al, 2018).…”

Efficacy and safety of cyclosporine in Stevens-Johnson syndrome and toxic epidermal necrolysis

“…The study also reported that there were no differences with respect to the development of renal failure requiring dialysis, bacteremia, and mechanical ventilation between those who received cyclosporine and those who did not. González-Herrada et al (2017) took advantage of a "natural experiment" by comparing two reference burn units in Madrid; one that utilizes cyclosporine in SJS/TEN treatment, whereas the other does not. Of 49 patients treated with cyclosporine, 11.8 were expected to die based on their SCORTEN score, however only five deaths were observed.…”

Intravenous cyclosporine in treatment of Stevens–Johnson syndrome/toxic epidermal necrolysis: A case series

“…Its management includes offending agent withdrawal, supportive care, and use of systemic immunomodulators to halt disease progression. Cyclosporine is an immunosuppressant with favorable activity in SJS/TEN, producing near‐complete disease stabilization in 3 days and complete re‐epithelialisation by 12 days (González‐Herrada et al, ). Multiple studies demonstrate its efficacy, with two meta‐analyses reporting significant reduction in mortality in SJS/TEN (Ng, De Deyn, Venkatanarayanan, Ho, & Yeo, ; Zimmermann et al, ).…”

“…Multiple studies demonstrate its efficacy, with two meta‐analyses reporting significant reduction in mortality in SJS/TEN (Ng, De Deyn, Venkatanarayanan, Ho, & Yeo, ; Zimmermann et al, ). Although most studies used oral cyclosporine, intravenous form has been utilized less frequently with success in few studies (González‐Herrada et al, ). Intravenous cyclosporine has added advantage of predictable bioavailability vis‐à‐vis oral cyclosporine (Morse, Holdsworth, Venuto, Gerbasi, & Walshe, ).…”