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Cyclosporine reaches the top of the SJS/TEN leaderboard

DII small banner By Warren R. Heymann, MD
Oct. 16, 2017

A, Sheet-like detachment, blisters, and raw erosions on back of patient with Stevens-Johnson syndrome/toxic epidermal necrolysis. B, Postinflammatory hyperpigmentation accentuated in areas where detached epidermis was not left in situ.
Credit: JAAD

The first commentary in DI&I for 2017 (“2017’s Management of Stevens-Johnson/TEN: The Pendulum is Swinging” January 1, 2017) included a New Year’s resolution “to try either cyclosporine or etanercept the next time I see a case of SJ/TEN.” Surprisingly, I have not seen a true new case of SJS/TEN this year. Recently, there have been several articles addressing the role of cyclosporine for SJS/TEN — I am now even more resolute about my resolution.

Although there is great controversy regarding appropriate adjuvant therapies for SJS/TEN, most authorities agree that discontinuation of the presumed offending medication and supportive care is imperative. Scrupulous attention to fluid and electrolyte balance, nutrition, pain control, prevention of secondary infection, and care of ocular surfaces and genitourinary mucous membranes is essential for survival and quality of life. This may be handled best in a burn unit. (1)
Zimmerman et al, performed a meta-analysis of 96 studies comprising 3,248 patients with SJS/TEN, who were treated with supportive care, glucocorticosteroids, intravenous immunoglobulins, cyclosporine, plasmapheresis, thalidomide, cyclophosphamide, hemoperfusion, tumor necrosis factor inhibitors, and granulocyte colony-stimulating factor. The authors determined that glucocorticosteroids and cyclosporine were associated with promising survival benefit. This finding was not observed for other treatments, including IVIG. (2)

Cyclosporine’s benefit for SJS/TEN has also been demonstrated in children. St. John et al described 3 children (ages 17 months, 5 years, and 8 years, respectively) with SJS/TEN who were successfully treated with cyclosporine. The average time cessation of disease progression or new lesion formation after cylcosporine administration was 2.2 days (range 1.5-3 days) and average time to remission or reepithelialization was 13 days (range 10-15 days), which is superior to that of IVIG. The average length of hospital stay was 11.7 days (range 4-19 days). The authors, as appropriately expected, recommend additional trials to evaluate the safety and efficacy of cyclosporine [in children].(3)

A major obstacle in studying SJS/TEN has been conducting a multicenter, randomized trial, given the relative rarity of the entity and variable supportive care in different medical centers. 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, and the other has used non-cyclosporine 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, the authors took advantage of this “natural experiment” to estimate the mortality risk ratio (MRR) of cyclosporine (n = 26) compared with non-cyclosporine (n = 16) treatment using the hospital as an instrumental variable over the period from 2001 to 2015. They also computed the observed versus expected (O/E) MRR in a case series of 49 cyclosporine-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 O/E analysis showed a statistically significant reduction in mortality risk. The authors concluded that cyclosporine reduces the mortality in epidermal necrolysis patients, and “these results should lead to serious consideration of CsA [cyclosporine] as the standard treatment for EN [epidermal necrolysis]”. Although the precise dose of cyclosporine for TEN has not been standardized, it appears that 3 – 5 mg/kg for at least 5 to 7 days is recommended.(4)

Regarding the mechanism of action of cyclosporine in SJS/TEN, St. John et al  (3) offer the following explanation:

SJS/TEN is characterized by widespread keratinocyte apoptosis initiated by natural killer cells, cytotoxic T-cells, and tumor necrosis factor alpha. CsA inhibits T-cell activation, preventing T-cells from producing cytokines critical to the pathogenesis and propagation of SJS/TEN. Thus CsA selectively targets the immunologic changes in SJS/TEN that propagate keratinocyte death and prevents apoptosis. CsA does not affect already-activated and already-released cytokines, accounting for the slight delay in response time for patients treated with CsA. Once a response is initiated, the results are dramatic.

Additionally, as both IL-2 and perforin expression on T cells are highly sensitive to cyclosporine treatment, the drug may have an indirect effect on granulysin, which appears to have an important role in the pathogenesis of TEN. (4)

It will take years for the “perfect” prospective, randomized trial of adjuvant therapy for TEN to be performed. Inevitably, we will be confronted with a SJS/TEN patient long before any such study is concluded. Decisions must be based on the best available evidence at that time. From my perspective, cyclosporine has gone to the top of the leaderboard.

1.Schneider JA, Cohen PR. Stevens-Johnson syndrome and toxic epidermal necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther 2017; 34: 1235-44.
2. Zimmerman S, et al. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis. JAMA Dermatol 2017; 153: 514-22.
3. John S, et al. Successful use of cyclosporine A for Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Pediatr Dermatol 2017; 34: 540-6.
4. González-Herrada C, et al. Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: Evidence from three different approaches. J Invest Dermatol 2017; 137: 2092-2100.

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