PracticalDermatology

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) belong to a spectrum of severe diseases involving the skin and mucous membranes, characterized by necrosis of keratinocytes with subsequent development of painful blisters and sloughing of skin. SJS and TEN share the same pathogenesis and are distinguished from one another by the extent of cutaneous involvement, with SJS affecting less than 10% of total body surface area (BSA) and TEN greater than 30% involvement. Cases affecting from 10% to 30% BSA are described as SJS/TEN overlap syndrome. SJS/TEN most commonly manifests as an adverse reaction to drugs¹ and has a significantly higher incidence among those with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).² The current mainstay of treatment is supportive care, although immunomodulating therapies have shown promising ability to reduce mortality.³ Here, we present a case in which a patient with SJS demonstrated rapid improvement of symptoms following treatment with etanercept and cyclosporine.

CASE REPORT

A 53-year-old female with a history of chronic kidney disease (CKD) stage III, poorly controlled diabetes mellitus type II and HIV presented to the emergency department complaining of abdominal pain lasting 2 months. The patient was admitted and subsequent workup demonstrated acute-on-chronic renal failure with suspected uremic gastritis. A renal biopsy was performed with results pending, during which time intermittent hemodialysis was initiated with tunneled dialysis catheter placement. The patient had been prescribed anti-retroviral therapy, which she had been taking inconsistently. Her CD4 count was 193 on admission, marking a progression from HIV to AIDS. Given her low CD4 count, the patient received trimethoprim/sulfamethoxazole (TMP/SMX) for prophylaxis against opportunistic infections.

On day 4 of admission, the patient became febrile to 39.2° centigrade and was empirically treated with vancomycin and piperacillin/tazobactam. The fever resolved within 48 hours, and infectious work-up was unremarkable. Two days after the initiation of these antibiotics, the patient developed a small blister on her bottom lip. The following day, a large area of denuded skin was noted in her gluteal cleft. A day after that, the patient complained of extremely painful bullae on her left foot and hand, as well as larger areas of denuded skin on her lower abdomen and inner and posterior thighs. At that point, a dermatology consult was emergently requested to rule out SJS.

Figure 1 (Superficial lip erosion): A prominent erosion with hyperkeratotic crusting is observed over the left lower lip.

Physical examination confirmed painful, fluid-filled blisters with an erythematous base overlying the bilateral dorsal feet, thighs, left hand, and lower abdomen. Mucosal involvement was limited to a small superficial erosion over the left lower lip (Figure 1). The pannus folds, gluteal cleft, and one patch on the right lateral thigh were denuded with positive Nikolsky sign, indicating epidermal necrosis (Figures 2A and 3A). The total involved BSA was less than 10%. A clinical diagnosis of SJS was made at that point. SCORETEN-score, the prognostic scoring system for SJS, was determined to be 2. Two stat punch biopsies of a larger blister on the right thigh were sent to pathology and rapidly processed. Microscopically, one showed extensive keratinocyte necrosis involving the upper half the epidermis, accompanied by evident apoptosis and scattered lymphocytes (Figure 3). TMP/SMX prophylaxis was then discontinued, and the patient was started on cyclosporine 3 mg/kg/day intravenously (IV) for a 10-day course and was given a one-time dose of etanercept 50 mg subcutaneously as well. Given the patient’s history of CKD, the initial presentation of acute renal failure requiring dialysis, and the known nephrotoxicity of cyclosporine, cyclosporine was administered only after approval from the nephrology team. Notably, hemodialysis does not significantly alter the clearance of cyclosporine. Precautions were taken to prevent dehydration from insensible fluid losses as well as to prevent cutaneous infection. The cutaneous lesions stabilized after the first day of this new drug regimen, and no new lesions developed. In less than 24 hours after initiating treatment, the patient reported that her skin lesions were no longer painful. Healthy granulation tissue and re-epithelization were noted within days (Figures 2B, 2C, and 3B). Three days after starting IV cyclosporine therapy, the patient was switched to an oral microemulsion of the same dose. Renal biopsy results were most consistent with diabetic nephropathy without changes of HIV nephropathy. The patient was eventually sent home 9 days after the initiation of therapy and was provided with one dose of oral cyclosporine to complete her 10-day course.

Figure 2 (Progression of gluteal involvement). The left gluteal region exhibited epidermal sloughing and vesicle formation, originally documented as a decubitus ulcer (A).
Large patches of denudation developed along the gluteal region (B). Marked re-epithelization along the gluteal region was noted eight days after initiation of therapy (C).

Figure 3 (Progression of pannus fold involvement): Areas of denuded skin along the pannus folds and medial thighs were noted, along with patches of bright red erythema on the anterior thighs (A). Eight days after initiation of cyclosporine and one dose of etanercept, excellent re-epithelization was observed (B).

DISCUSSION

This case of SJS presents numerous features that we believe are important to emphasize. First, the early recognition of SJS (only 4 days after exposure to the inciting antibiotics) allowed for rapid intervention, which likely improved the patient’s outcome. Second, this case illustrates the potential efficacy of cyclosporine and etanercept in the treatment of SJS. Our patient demonstrated a rapid improvement in symptoms with the initiation of cyclosporine and etanercept: no new lesions presented within 24 hours of treatment, and the existing lesions began to heal shortly thereafter. Lastly, another unique feature of this case was the use of cyclosporine–a drug with known nephrotoxic side effects–in a patient with CKD. This decision was made after consultation with the nephrology team. The dose of cyclosporine was relatively low, and no significant worsening of renal function was appreciated. Finally, the current literature supporting the use of cyclosporine and etanercept is often retrospective in nature and confounded by the fact that many of the patients in these studies had received a multitude of agents, including corticosteroids and intravenous immunoglobulins (IVIG).⁴ Thus, it is difficult to attribute clinical improvement to any specific agent. Our patient, in contrast, received only cyclosporine and etanercept, making us confident that the observed clinical improvement can be directly attributed to these agents.

While the pathogenesis of SJS is not completely understood, the current leading hypothesis involves an inappropriate cytotoxic T-cell and natural killer cell response, ultimately resulting in keratinocyte apoptosis through Fas-Fas ligand and/or perforin/granzyme pathways.⁵ CD8+ cells have been found in blister fluid along with the detection of both Th1 and Th2 cytokines. It has been hypothesized that drug-associated antigens bind with major histocompatibility complexes, forming compounds that trigger uncontrolled immune reactions.

Standard management of SJS/TEN involves early withdrawal of the offending drug and referral to the ICU or a burn center if needed. The SCORETEN prognosis system may be used for this decision, and supportive care emphasizes wound care, control of insensible fluid losses, prevention of wound infections, and pain management. There have been no systemic therapies with definitive evidence of improvement in mortality when compared to supportive care alone, however, this could be due to a paucity of appropriately designed studies. Given the understanding of T-cells in their role in the pathogenesis of the disease, clinicians have attempted immunomodulating therapies such as systemic corticosteroids, IVIG, cyclosporine, and tumor necrosis factor (TNF) modulating drugs. In a 2008 retrospective study of 281 patients with SJS from Europe, no statistically significant reduction in mortality was found among patients treated with systemic corticosteroids or with IVIG, compared with those receiving only supportive care. However, while not reaching the level of statistical significance, corticosteroids did seem to yield promising results, leaving researchers with the hope that future randomized control studies may prove its utility.⁶ Unfortunately, such studies are difficult to conduct due to the relative rarity of the disease and because a large number of patients would need to be enrolled to prove the efficacy of such therapies. As a result, most of the data supporting the use of immunomodulating therapies comes from retrospective observational studies.

Although limited by small sample sizes, studies investigating the treatment of SJS/TEN with etanercept and/or cyclosporine have yielded promising results. Cyclosporine is an immunosuppressive agent that works by inhibiting the transcription of the cytokine interleukin-2 (IL-2) via inhibition of calcineurin. IL-2 is crucial for the activation and proliferation of T-cells, thus supporting the idea that cyclosporine may be beneficial in controlling the unregulated T-cell induced damage seen in SJS/TEN. Cyclosporine is known to induce nephrotoxicity. Given that our patient had stage III CKD and was in acute renal failure requiring intermittent hemodialysis, special consideration and consultation with nephrology was undertaken before the initiation of therapy. The nephrology team approval on the use of cyclosporine was largely based on the relatively low dose and short duration of treatment. A standard dose of 3 to 5 mg/kg/day has been used for treatment of SJS/TEN, which is lower than the standard dosing used for solid organ transplant. In addition, a renal biopsy during this admission had demonstrated poor kidney reserve, making the benefits of treating SJS outweigh the risk of potentially worsening her already poor renal function.

In a 2017 meta-analysis examining 96 studies and 3,428 patients with the goal of comparing immunomodulatory drugs in the treatment of SJS/TEN, researchers found corticosteroids and cyclosporine to be the most beneficial in terms of reducing mortality, but these findings were limited by a low sample size.⁷ Additional meta-analyses have shown similarly promising results, with a 60% to 70% reduction in mortality in those treated with cyclosporine.^8,9 The authors advised that cyclosporine use be further investigated with randomized control trials. A retrospective study from 2017 investigated the differences in outcomes in patients treated for SJS/TEN at a specialized referral center.¹⁰ In all, 24 patients were treated with cyclosporine, and 20 were treated supportively. Among the group treated with cyclosporine, SCORETEN predicted that there would be 7.2 deaths, yet only three deaths were observed. This observed survival benefit did not carry over with the group treated with supportive care alone, as SCORETEN predicted 5.9 deaths, and six deaths occurred. A similarly designed study, also from 2017, showed an observed versus expected (using SCORETEN) mortality risk reduction of 0.41 (95% CI; 0.21-0.80) after including their results in a meta-analysis with five other studies.¹¹

Etanercept is a medication that works as a decoy receptor for TNF-a, thereby reducing systemic inflammation. Granulysin is a cytotoxic protein secreted from CD8+ T-cells and NK cells and is believed to be the key mediator of keratinocyte death observed in SJS/TEN. TNF-a is a known activator of granulysin promoter. Thus, by inhibiting the action of TNF-a, etanercept may theoretically be useful in altering the pathophysiology of SJS/TEN. Unfortunately, there have been very few robust studies investigating the efficacy of etanercept in this disease.

In one case series from 2014, 10 patients with TEN with a SCORETEN-based predicted probability of death of 46.9% were given a single 50 mg subcutaneous injection of etanercept. All 10 patients responded to treatment with a median time to healing of 8.5 days.¹² Another case series from 2019 followed 13 patients who were treated with etanercept, IVIG, and supportive care and compared them with another cohort of 40 patients treated with IVIG and supportive care alone.¹³ There was no statistically significant difference in the overall mortality between the two groups, although the authors did note that the etanercept-treated group had a more severe prognoses as determined by SCORETEN. To account for these baseline differences, the researchers also relied on the SCORETEN mortality predictions and found that the etanercept-treated group had a standardized mortality ratio (SMR) of 0.44 (95% CI; 0.21-0.65), while the non-etanercept group had an SMR of 0.60 (95% CI; 0.23-0.97), indicating some mortality benefit. While not statistically significant (P=.07), the researchers used multivariate linear regression to show that etanercept helped reduce the number of hospital days by 12.8 days.

The most robust study investigating etanercept in the treatment of SJS/TEN is a randomized control study from 2018 that examined 96 patients with SJS/TEN who were treated with either etanercept (25 to 50 mg) subcutaneously twice weekly or with IV prednisolone.¹⁴ These two cohorts were compared with a retrospective supportive care group. Analysis revealed a statistically significant reduction in mortality rate in the etanercept-treated group when compared to the supportive care group (8.3% vs. 26.3%, P=.026). While the corticosteroid treated group also had a reduced mortality rate when compared with the supportive group (16.3% vs. 26.3%), this was not statistically significant. Also, among those patients with 10% or greater BSA affected, researchers found a statistically significant reduction in time needed for complete skin healing in patients treated with etanercept as compared with those treated with corticosteroids.

As mentioned, there have been only a few robust randomized control trials investigating the use of immunomodulating therapies for SJS/TEN. One such study was a double-blind, randomized, placebo-controlled study examining the efficacy of thalidomide in treating TEN.¹⁵ Thalidomide, like etanercept, is an inhibitor of TNF-a. Interestingly, this study was cut short due to the significantly increased mortality observed in the thalidomide treated group. Following this study, the use of thalidomide has been firmly contraindicated for use in SJS/TEN. Despite the similar mechanisms of action shared between thalidomide and etanercept, little explanation has been provided to explain the discrepancy of outcomes observed with the use of these agents.

Our case contributes to the growing body of evidence that supports the use of both cyclosporine and etanercept for the treatment of SJS/TEN. We find that our successful patient outcome due to the combined use of these agents is encouraging and justifies further clinical investigation with well-designed controlled studies.

Financial Disclosures: The authors have no financial disclosures.

Conflict of Interest Statement: The authors state no conflict of interest.

Acknowledgments: The authors have no further acknowledgments or other sources of funding to report.

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