toxic epidermal necrolysis

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Combination therapy: Etanercept and intravenous immunoglobulin for the acute treatment of StevensJohnson syndrome/toxic epidermal necrolysis Christopher H. Pham a,b, T. Justin Gillenwater a,b, Eric Nagengast b, Meghan C. McCullough b , David H. Peng a,c , Warren L. Garner a,b, * a

Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA 90033, United States Division of Plastic Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, 1510 San Pablo Street, Suite 415, Los Angeles, CA 90033, United States c Department of Dermatology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Ezralow Tower, Suite 5301, Los Angeles, CA 90033, United States b

article info

abstract

Article history:

Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is an autoim-

Accepted 22 December 2018

mune condition with significant morbidity and mortality.

Available online xxx

Methods: A retrospective review was performed at a single institution. All patients admitted to the LAC+USC burn unit from May 1st 2015–January 1st 2018 with a histologic diagnosis of SJS/TEN were reviewed. Patient characteristics and outcomes were recorded. These

Keywords:

outcomes were compared to our previously published cohort.

Burns

Results: Thirteen total consecutive SJS/TEN patients were treated with etanercept. Compared

Dermatology

to non-etanercept treated patients, etanercept-treated patients did not experience a

Plastic surgery Toxic epidermal necrolysis Stevens-Johnson syndrome

significant difference in mortality (15.4% vs. 10%, P=0.58), ICU days (6.9 vs. 15.1, P=0.08), length-of-stay (9.8 vs 16.4, P=0.11), or infections (38.5% vs. 57.5%, P=0.58). The standardized mortality ratio in etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65). In general, etanercept-treated patients had higher SCORTENs (3 vs. 2, P=0.03) and longer delays to presentation (5.2 vs. 2.7 days, P<0.01). Conclusions: Etanercept can be considered in the treatment of SJS/TEN patients in addition to IVIg, and supportive care in a burn unit. © 2019 Elsevier Ltd and ISBI. All rights reserved.

1.

Introduction

Stevens-Johnson necrolysis (TEN)

syndrome (SJS)/toxic is a life-threatening

epidermal cutaneous

autoimmune disease that is poorly characterized. The etiology of this disease is not well understood but is thought to be a response to exogenous stimuli, most commonly secondary to drug reactions and microbial infections [1].

Abbreviations: SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; SMR, Standardized mortality ratio; TNF, Tumor necrosis factor; IVIg, Intravenous immunoglobulin. * Corresponding author at: Plastic and Reconstructive Surgery, Burn and Critical Care, Univ. of Southern California, LAC+USC Burn Center, 2051 Marengo St., Los Angeles, CA 90033, United States. E-mail address: [email protected] (W.L. Garner). https://doi.org/10.1016/j.burns.2018.12.018 0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.

Please cite this article in press as: C.H. Pham, et al., Combination therapy: Etanercept and intravenous immunoglobulin for the acute treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis, Burns (2019), https://doi.org/10.1016/j.burns.2018.12.018

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Most practitioners use the previously validated “severityof-illness score” (SCORTEN) [2] for estimating the mortality of SJS/TEN and to compare outcomes between different treatment modalities. During the last several years there has been controversy regarding the best treatment for these patients and our institution recently published our 15-year experience with this disease and documented a mortality rate of 10% [3]. Our treatment algorithm [3] includes a multi-disciplinary team of burn surgeons, dermatologists, ophthalmologists, critical care nurses, and registered dietitians. We employ aggressive fluid resuscitation (titrated to a urine output of 0.5–1.0 cc/kg/ hr), mechanical debridement to remove sloughed epidermis and exudate, wound care with a nondaily silver dressing (Exsalt, Exciton Technologies), and enteral nutrition to optimize wound healing. Corticosteroids, intravenous immunoglobulin (IVIg), cyclosporine, and supportive care have all been documented as treatment modalities for SJS/TEN, with controversy surrounding all modalities except supportive care. Corticosteroid use has been shown to provide ocular benefits in SJS/TEN [4], but some have argued there is an association with higher mortality [5,6]. Meta-analysis has also questioned the role of IVIg [7]. In addition to supportive care, some have successfully reported treating SJS/TEN with Infliximab [8–15], a TNF-alpha monoclonal antibody that inhibits binding at its receptor, and with etanercept, a TNF-alpha decoy receptor [16–21] Here, we present a series of patients treated with etanercept, IVIg, and supportive care and believe that it may lead to improved outcomes.

2.

Methods

After obtaining Institutional Review Board approval (Protocol Number: HS-15-00173), we performed a retrospective chart review from May 1st 2015–January 1st 2018 to examine all consecutive patients admitted to the LAC+USC burn unit diagnosed with SJS/TEN, confirmed by histology, and treated with etanercept. The histologic diagnosis of SJS/TEN was confirmed when full-thickness epidermal necrosis with a lymphocytic infiltrate was observed. The culprit drug or

infection was determined through a thorough history and application of the ALDEN method [22]. The culprit drug was identified when an ALDEN score greater than or equal to 4 [22] was calculated; otherwise, the culprit drug was listed as “Undetermined” (Table 1). Patient characteristics (age, sex, medical co-morbidities), disease characteristics (greatest total body surface area involvement, time-to-burn unit, causative agent, SCORTEN), and treatment modalities (steroids, IVIg, etanercept) were examined. The primary outcome was mortality and secondary outcomes included rates of hospital complications, total ICU days, and total hospital days. Hospital complications included respiratory failure (defined as undergoing intubation), renal failure (receiving hemodialysis (HD) or continuous renal replacement therapy (CRRT)), shock (hypotension receiving vasopressor support), infection (defined as a positive culture), or ocular involvement with an ophthalmology consult. The etanercept-treated cohort was compared against our previously published cohort of patients not treated with etanercept. All patients — etanercept and non-etanercept — received IVIg and wound care with silver-impregnated products, with the only difference in treatment being the presence or absence of etanercept. Etanercept is routinely given within the first 24h of admission at our burn center. All data was analyzed using IBM SPSS Statistics Software Package. Categorical data (e.g., patient characteristics) were compared by Fischer’s Exact and chi-squared tests and considered significant when P<0.05 (95% confidence interval, CI). Continuous variables were compared by twotailed t-tests. Linear and logistic regressions were used to estimate the effect of etanercept on the outcomes of interest. The family of tests used to test hypotheses around the effect of etanercept were considered significant when P<0.005 (Bonferroni Correction, 0.05/10 hypotheses). Per a previously published method [3,23,24], standardized mortality ratios (SMR) were calculated using the observed mortalities and expected mortalities as predicted by SCORTEN. Because of the lack of a control cohort, SMRs between etanercept and non-etanercept treated patients cannot be compared with statistics and, instead, are reported with their respective 95% confidence intervals.

Table 1 – Patient characteristics.

Age (years) Male Female Total body surface area (%) SCORTEN Total ICU stay (days) Total length-of-stay (days) Time-to-burn unit (days) Causative agent (%) Antibiotics Antiepileptics Allopurinol Undetermined *

Etanercept-treated

Non-etanercept

44.8 21.1 5 (38.5%) 8 (61.5%) 54.3 3 6.9 9.8 5.2

45.9 20.0 18 (45%) 22 (55%) 46.3 2.1 15.1 16.4 2.7

5 (38.5%) 3 (23.1%) 1 (7.7%) 4 (30.8%)

19 (47.5%) 8 (20%) 6 (15%) 7 (17.5%)

P 0.9

0.3 0.03* 0.08 0.11 <0.01*

Denotes statistical significance (P <0.05).

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3.

Results

Thirteen patients with a histologic diagnosis of SJS/TEN were treated with etanercept, IVIg, and supportive care during the study period and compared to our previously published cohort [3] of 40 patients only treated with IVIg and supportive care. There was no significant difference between age, sex, or cause of SJS/TEN between cohorts (Table 1). In general, etanercept-treated patients had significantly more severe presentations characterized by higher SCORTENs (3 vs. 2.1, P=0.03) and longer delays before presenting to our burn unit (5.2 vs. 2.7 days, P<0.01). There was a trend toward more skin involvement (54.3% vs. 46.3%, P=0.30) in etanercept-treated patients although this did not reach statistical significance (Table 1). There was no difference in mortality between etanercept and non-etanercept treated patients (15.4% vs. 10%, P=0.58) (Table 2). Using the predicted mortality from individual patient SCORTENs, the standardized mortality ratio (SMR) for etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65) (Table 2). Etanercept-treated patients tended toward fewer ICU days (mean, 6.9 vs. 15.1 days, P=0.08) and a shorter total LOS (mean, 9.8 vs. 16.4 days, P=0.11) although these findings were not statistically significant (Table 1). Logistic and linear regressions (Table 3) to estimate the effects of etanercept did not show significant differences in any outcome. Although not

Table 2 – Mortality and standardized mortality ratio. SCORTEN

Etanercept-treated (N)

Non-etanercept (N)a

0–1 2 3 4 5 Unable to determine Mortality (%)

0 5 4 3 1 –

11 11 7 3 1 7

2 (15.4)

4 (10)

SMR (95% CI)

0.44b (0.21, 0.65)

0.60b (0.23, 0.97)

a b

Adapted from McCullough et al. Denotes statistical significance (95% CI).

Table 3 – Multivariate regression of Etanercept on outcomes: normal linear regression for continuous variables; logistic regression for dichotomous variables. Mortality, HD/CRRT, and ocular complications could not be included in the regression due to a lack of data. No significant values (P<0.005, Bonferroni correction). Outcome Total ICU stay (days) Total LOS (days) Infection Intubation Vasopressor use

Effect estimate (Std. Error) 7.1 (4.6) 12.8 (6.7) 3.6 (2.3) 1.2 (1.5) 1.1 (2.3)

statistically significant, we noted that etanercept tended toward reducing total LOS by 12.8 days (P=0.07). There were no significant differences in infectious complications between etanercept-treated and non-etanercept treated patients (38.5% vs. 57.5%, P=0.58) (Table 4). There were also no significant differences in the incidence of respiratory failure with intubation (15.4% vs. 47.5%, P=0.59), hypotension receiving vasopressor support (23.1% vs. 17.5%, P=0.50), renal failure undergoing HD or CRRT (15.4% vs. 5%, P=0.38), or ocular complications in patients treated with etanercept (15.4% vs. 35%, P=0.10) (Table 4).

4.

Discussion

We described and compared the characteristics and outcomes of patients treated with etanercept in addition to IVIg and supportive care against a previously published [3] cohort treated only with IVIg and supportive care for the treatment of SJS/TEN. The two cohorts were similar in age, sex, and cause of disease (Table 1). Although we did not detect a significant difference in mortality between groups, this must be analyzed in the context of significantly higher SCORTENs (P=0.03), and longer delays-to-presentation at the burn unit (P<0.01) in etanercepttreated patients. The higher SCORTENs and longer delays to transfer in the etanercept-treated patients may be explained by stochasticity as a result of our sample size rather than a demographic change. Among our etanercept-treated patients (mean SCORTEN 3, expected 35.3% mortality), the SMR was 0.44 and statistically significant (95% CI, 0.21, 0.65). When comparing the SMRs of our etanercept vs. non-etanercept cohort, the etanercept-treated cohort had a lower SMR (0.44 vs. 0.60) (Table 2). Thus, it appears that patients treated with etanercept, IVIg, and supportive care appeared to have some improvement in mortality compared to those treated with IVIg and supportive care alone. Although it did not reach statistical significance, we also noted that patients treated with etanercept tended toward fewer ocular complications. We currently employ amniotic membrane transplantation (AMT) on all patients with ocular involvement due to data demonstrating a significant effect on preventing vision loss in patients treated with AMT [25]. Detailed visual acuity data was not available in our study, but we note that only one patient in our entire SJS/TEN database developed blindness. Of the two patients (XX and YY) that died in our etanercepttreated cohort, one (XX) had a SCORTEN of 5 (expected mortality >90%), 90% TBSA involvement, and died from Vancomycin-resistant enterococcal sepsis. The other (YY)

Table 4 – Hospital complications. No significant values (P<0.005, Bonferroni correction).

P 0.13 0.07 0.11 0.42 0.62

Infection Intubation Pressors HD/CRRT Ocular

Etanercept-treated

Non-etanercept

5 (38.5) 2 (15.4) 3 (23.1) 2 (15.4) 2 (15.4)

23 (57.5) 19 (47.5) 7 (17.5) 2 (5) 14 (35)

P 0.58 0.59 0.5 0.38 0.1

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had a SCORTEN of 4 (expected 58.3% mortality), 70% TBSA involvement, had a six-day delay to presentation to the burn unit, renal failure with CRRT, and passed from complications from sepsis. Possible explanations for their poor outcomes may be explained by recent data showing that in patients with SJS/TEN, septicemia and renal failure are independently associated with an increased risk of death by 30 (adjusted odds ratio=30.45, P<0.05) and 300 (adjusted odds ratio=300.28, P<0.05) [26]. In addition, patient YY also received multiple doses of high-dose corticosteroids at an outside hospital, which has been controversially associated with significantly higher mortality in SJS/TEN patients [5]. SJS/TEN has been associated with class I HLA alleles and exhibits a drug-specific, class I restricted T cell response [27]; however, despite advances in the understanding of the pharmacogenomics of SJS/TEN, its precise pathophysiology remains unclear. Strong evidence suggests that granulysin is the primary cytotoxic mediator in the pathophysiology of SJS/ TEN [28] and is released by CD8+ T cells, natural killer T cells, and natural killer cells. TNF-alpha has been previously shown to activate granulysin promoter activity [29]. Therefore, etanercept’s therapeutic mechanism in SJS/TEN may be through reductions in granulysin levels in serum and blister fluid [30]. Through a similar mechanism, cyclosporine — which reduces levels of CD4+/D8+ T cells in the epidermis and has also provides concurrent inhibition of TNF-alpha demonstrated significant reductions in SJS/TEN mortality (SMR=0.320, 95% CI 0.119–0.552, P=0.002) [31]. The most convincing data supporting the use of etanercept in treating SJS/TEN comes from the TSCAR Consortium [30], which published a 96 patient randomized controlled trial comparing etanercept vs. corticosteroids. The TSCAR Consortium demonstrated that etanercept-treated patients had lower observed rates of mortality (when compared to SCORTEN) and faster time-to-healing when compared to patients receiving steroids [30] Although our study was smaller than the TSCAR Consortium study [30], our cohort had more severe disease presentations (3 vs. 1.9, SCORTEN) and was treated with IVIg and supportive care instead of corticosteroids and supportive care. Some have questioned the efficacy of TNF-alpha inhibitors in the treatment of SJS/TEN due to a prior RCT showing an increased mortality with the use of thalidomide, a potent TNFalpha inhibitor [32]. TNF-alpha levels in patients treated with thalidomide tended to be paradoxically higher than the placebo group, possibly explaining the increased mortality; however, Wang et al. [30] showed that there were significant reductions in TNF-alpha levels in the serum and blister fluid of SJS/TEN patients. Our current algorithm is to provide weight-based IVIg for three days and a one-time subcutaneous injection (50mg) of etanercept on a case-by-case basis, pending contraindications such as active tuberculosis infection, sepsis, or a history of chronic viral hepatitis. While others have documented the use of etanercept for SJS/TEN [16–21] and the associated outcomes, this is the largest published study to date. In addition, we were able to use a large (N=40) previously published [3] cohort at the same institution to compare outcomes before and after the routine adoption of etanercept to our treatment algorithm

to draw comparisons between outcomes while controlling for variation in institutional practices and patient population. Limitations of this study include the retrospective design and small sample size, which limit our conclusions to the quality of documentation and statistical power. Also, although one meta-analysis has argued no survival benefit when IVIg is compared to supportive care (OR=0.99, 95% CI 0.64, 1.54) [7], we noted that the meta-analysis was biased due to lack of randomization, blinding, and possible publication bias in the included studies. We continue to use IVIg in our protocol because of historically positive outcomes at our institution [3]. In conclusion, our study provides new insights into the combination therapy of etanercept and IVIg in SJS/TEN patients with severe disease. Etanercept can be used on a case-by-case basis and patients should be screened prior to use for contraindications such as latent tuberculosis infection or active infection [33,34].

Funding sources None.

Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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