Adalimumab combination with corticosteroid therapy for Stevens–Johnson syndrome/toxic epidermal necrolysis

Abstract

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe acute mucocutaneous reactions associated with considerable mortality and poor prognosis. Corticosteroids and intravenous immunoglobulin (IVIG), as a traditional remedy, have been widely used in the treatment of SJS/TEN. Recent studies have reported the potential therapeutic benefits of tumor necrosis factor-alpha (TNF-α) antagonists on the disease. However, the optimal treatment remains unknown. This study is to compare the effectiveness and safety of TNF-α antagonist adalimumab conjunction with corticosteroid to traditional remedy on SJS/TEN. In this single-center, retrospective, observational study, we enrolled 53 SJS/TEN patients received either traditional remedy (Corticosteroids and IVIG) or a combination therapy (TNF-α antagonist conjunction with corticosteroid). The primary endpoint was duration of hospitalization and re-epithelization time, and the secondary endpoints including exposure time to high-dose steroids, and major adverse event incidence. 26 patients received traditional remedy and 27 patients received combination remedy. In comparison to traditional remedy, the combination remedy reduced the hospitalization duration (25 ± 4.7 vs. 22 ± 5.2 days; P = 0.032), re-epithelization time (19 ± 2.5 vs.17 ± 3.4 days; P = 0.019), and exposure time to high-dose steroids (18 ± 4 vs. 16 ± 2 days; P = 0.025). Obviously, TNF-α levels in the combination group showed a significant decreased on the discharge day comparing to the traditional group (3.9 ± 1.8 vs. 5.8 ± 2.2, p = 0.001). The major adverse event incidences were no significant statistically difference (P > 0.05) within 6 months of follow-up after hospital discharge, and no death happened between two groups. The combination remedy (adalimumab conjunction with corticosteroid) could be an optimal treatment to promote disease recovery without increasing adverse events and morality in SJS/TEN patients.

Introduction

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are life-threatening mucocutaneous reactions mainly cased by medications characterized by exfoliation of the skin accompanied by hemorrhagic crusting of lips and erosions of genital mucosa and erosions [1]. Patients with epidermal detachment involving 10–30% of the extent of the body surface area (BSA) regarded as SJS/TEN^2,3. The mortality rate of SJS/TEN has been reported higher than 22% and the SCORTEN prognostic score has proved effective and widely used in SJS/TEN patients for predicting prognosis [4].

The pathogenesis of SJS/TEN remains unclearly. Keratinocyte necrosis and epidermal damage are the key histopathological features of SJS/TEN which may be attributed to cytotoxic T lymphocyte-mediated inflammatory processes [5]. Results have showed that culprit drugs or their metabolites presented by human leukocyte antigen (HLA) molecules on antigen-presenting cells can trigger T cell activation and amplify the immune responses in SJS/TEN^5,6. Several cytotoxic mediators released by T cells and natural killer cells, including granulysin, perforin, and granzyme, have been confirmed as key drivers of widespread keratinocyte apoptosis [7]. Additionally, recent studies have demonstrated a significant increase in tumor necrosis factor-alpha (TNF-α) levels in both blisters and patient serum which may induce Fas-mediated keratinocyte apoptosis in SJS/TEN⁸.

The current treatment strategy for SJS/TEN, involving corticosteroid therapy, supplemented by cyclosporine, intravenous immunoglobulins (IVIG), or tumor necrosis factor inhibitors (TNFi), mainly based on expert consensus rather than high-quality evidence [9]. Several case reports have reported the potential of TNFi in SJS/TEN treatment. A randomized controlled trial revealed that TNFi, etanercept as a monotherapy can accelerate skin healing and reduce TNF-α and granulysin levels in blister fluid [2]. Moreover, other clinical studies and systematic reviews provide additional support for the safety and therapeutic benefits of TNFi in SJS/TEN^9–12. Despite these advances, the optimal therapeutic approach for SJS/TEN remains underexplored.

In this study, we compared the effectiveness and safety of patients with SJS/TEN treated with adalimumab conjunction with corticosteroid to traditional remedy on SJS/TEN. These findings aim to enhance the current understanding and management of SJS/TEN.

Methods

This retrospective, observational study was conducted at (hospital name) from January 2020 to June 2024, and it was approved by the Clinical Research Ethics Board of Department of Dermatology, Hangzhou Third Hospital, Hangzhou (Approval number 2025KA031). 53 patients diagnosed with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) whose extent of epidermal detachment as a percentage of body surface area (BSA) at 10-30% were enrolled. Exclusion criteria included autoimmune bullous diseases, acquired immunodeficiency syndrome, active hepatitis B virus infection, active tuberculosis, severe infections, lymphoma, heart failure, and pregnancy. All patients were thoroughly informed about the potential risks and benefits of adalimumab treatment. Clinical data were independently reviewed and verified by two physicians. The primary endpoint was duration of hospitalization and re-epithelization time, and the secondary endpoints including exposure time to high-dose steroids, and major adverse event incidence.

Demographic information, clinical characteristics, treatments, and prognoses were analyzed. The clinical severity of SJS/TEN was assessed via the SCORTEN system. Patients were discharged upon achieving complete re-epithelialization of the skin and at least 50% healing of oral mucosal lesions. Medications administered during hospitalization, including corticosteroids, intravenous immunoglobulin (IVIG), and adalimumab, as well as patient prognosis, were also studied. The IVIG was administered at an average dose of 0.4 g/kg/day for a duration of 3 to 5 days. The initial methylprednisolone dosage corresponded to 1 to 2 mg/kg/day of prednisolone. The patients who did not respond to the initial treatment well, the methylprednisolone dosage was increased by 50% from the initial dosage. Patients who received at least 1 dose of adalimumab were included in the studies.

Serum tumor necrosis factor-alpha (TNF-α) levels were measured in the clinical laboratory at Sun Yat-sen Memorial Hospital using a chemiluminescent assay kit (Siemens LKNF1, Siemens, Llanberis, United Kingdom) on the IMMULITE 1000 system (Siemens Healthcare Diagnostics Inc, Camberley, United Kingdom) following the manufacturer’s protocols.

Severe adverse events potentially associated with adalimumab were serious infections, significant hepatic dysfunction (liver enzyme levels exceeding three times the upper normal limit), infections with hepatitis viruses or tuberculosis, development or progression of malignancies, and hematological abnormalities (leukemia, lymphoma, and hepatosplenic T-cell) occurring within six months post-treatment.

Statistical analyses were conducted using SPSS version 25.0 (IBM, Armonk, NY, USA). Normally distributed data were presented as mean ± standard deviation (SD) and other data were reported as median and range. Quantitative variables were analyzed using the student’s two-tailed t-test or the Mann-Whitney U test, while qualitative variables were compared using the chi-squared test. A P value < 0.05 was considered statistically significant.

Results

From January 2020 to June 2024, the study enrolled 53 patients diagnosed with SJS/TEN. Of these, 26 patients received traditional remedy (receiving corticosteroids and IVIG) and 27 patients received combination remedy (adalimumab conjunction with corticosteroid). All the patients completed the study, and their baseline characteristics, clinical manifestations and prognosis are showed in Table 1. The included patients’ mean age 52.12, with a mean body mass index (BMI) of 23.78 kg/m². NSAIDs (32.1%) and antibiotics (26.4%) were the first causative drugs in the participants. Of notedly. Carbamazepine (20.8%) was also the one of the implicated drugs causing SJS/TEN. Chinese medicine (13.2%) and other drugs (7.6%) were also leading to SJS/TEN. Clinically, fever was observed in 42 patients (79.3%), with a peak temperature of 39.2 °C. Liver injury was appeared in 35 patients (66%), and mucositis was showed in 45 patients (85%), predominantly affecting eyes and oral cavity. 16 patients (30.2%) had a history of malignant tumor, with the most common malignancies being lung cancer (17%), gastrointestinal cancer (9.4%), and prostate cancer (5.7%). The median SCORTEN was 3.815. There was no statistical significance on the baseline characteristics of the participants in traditional group and combination group.

Table 1.

Baseline characteristics of the participants in traditional group and combination group

characteristics	Total group (N = 53)	Traditional group (N = 26)	Combination group (N = 27)	P value
Age, years, M ± SD	52.15 ± 5.2	51.2 ± 6.2	52.5 ± 5.7	0.430
Male Sex, n (%)	21 (39.62)	9 (34.62)	12 (44.44)	0.464
Body mass index, kg/m2, M ± SD	23.78 ± 2.4	22.92 ± 4.3	23.47 ± 3.6	0.615
Clinical manifestations, n (%)
Fever	42 (79.3)	20 (37.7)	22 (41.5)	0.682
Mucositis	45 (84.9)	22 (41.5)	23 (43.4)	0.953
Liver injury	35 (66)	19 (35.8)	16 (30.2)	0.288
SCORTEN, M ± SD	3.815 ± 2.7	3.54 ± 2.3	3.89 ± 3.1	0.644
Causative drugs, n (%)
NSAIDs	17 (32.1)	7 (13.2)	10 (18.9)	0.430
Carbamazepine	11 (20.8)	6 (11.3)	5 (9.4)	0.682
Antibiotics	14 (26.4)	6 (11.3)	8 (15.1)	0.588
Chinese medicine	7 (13.2)	5 (9.4)	2 (3.8)	0.203
Others	4 (7.6)	1 (1.9)	3 (5.7)	0.316
Malignant tumor	16 (30.2)	6 (11.3)	10 (18.9)	0.268
Lung cancer	9 (16.9%)	4 (7.5)	5 (9.4)	0.761
Gastrointestinal cancer	5 (9.4)	1 (1.9)	4 (7.5)	0.172
Prostate cancer	3 (5.7)	2 (3.8)	1 (1.9)	0.529
Combined with IVIG	26 (49.1)	26 (49.1)	0	0.000
Combined with Adalimumab	27 (50.9)	0	27 (50.9)	0.000
Times of Adalimumab injection	1.78 ± 0.15	0	1.78 ± 0.15	0.000

Comparing to the traditional cohort, the re-epithelization time was obviously shorter, in the combination cohort (17 ± 3.4, P = 0.019). For the combination cohort, the length of hospitalization was also significantly shorter, 22 ± 5.2 days vs. 25 ± 4.7days for the traditional cohort (P = 0.032). Additionally, combination therapy markedly reduced the exposure time to high-dose steroids. In the combination group, exposure time to corticosteroid duration was (16 ± 2) days vs. (18 ± 4) days in the traditional group (P = 0.025). Interestingly, the total dose of corticosteroids was lower in the combination group (1345 ± 234 mg vs. 1603 ± 425 mg, p = 0.008). One patient in the combination group appeared infection in the 6 months of follow-up. However, the major adverse event incidence and observed mortality rates were not statistically significant difference within 6 months of follow-up after hospital discharge between two groups. The detail was showed in Table 2.

Table 2.

Comparison of therapy outcomes between traditional group and combination group

Outcomes	Traditional group (N = 26)	Combination group (N = 27)	P value
Hospitalization duration, d, M ± SD	25 ± 4.7	22 ± 5.2	0.032
Re-epithelization time	19 ± 2.5	17 ± 3.4	0.019
Exposure time to high-dose steroids	18 ± 4	16 ± 2	0.025
Total dose of corticosteroids	1603 ± 425 mg	1345 ± 234 mg	0.008
Adverse events n = 1 (%)	0	1	0.317
Infections,	0	1	0.317
Lung infection	0	0
Disseminated intravascular coagulation	0	0
Gastrointestinal bleeding	0	0

Serum TNF-α levels were measured in both groups on the day of admission and discharge. Serum TNF-α levels were 35 ± 1.6 and 36 ± 2.2 separately in both group on the day of admission (p = 0.065). Obviously, TNF-α levels in the combination group showed a significant decreased on the discharge day comparing to the traditional group (3.9 ± 1.8 vs. 5.8 ± 2.2, p = 0.001), which was presented in Table 3.

Table 3.

Comparison of the TNF-α level in traditional group and combination group

	TNF-α level on admission	TNF-α level on the day of discharge
Traditional group (N = 26)	35 ± 1.6	5.8 ± 2.2
Combination group (N = 27)	36 ± 2.2	3.9 ± 1.8
P value	0.065	0.001

Discussion

In our study, we found that TNF-α antagonist adalimumab conjunction with corticosteroid reduces the hospitalization duration, re-epithelization time, and exposure time to high-dose steroids. Moreover, the combination remedy does not increase major adverse event incidence and mortality rate within 6 months of follow-up after hospital discharge.

Recent studies have identified upregulated TNF-α levels as a key factor in the pathogenesis of SJS/TEN, primarily by inducing keratinocyte apoptosis [13]. Binding of TNF-α to TNF receptor 1 triggers distinct cell death pathways: apoptosis when caspase-8 is activated and necroptosis when caspase-8 is inactivated [14]. Additionally, cytotoxic CD8 + T cells contribute to the pathological process by releasing TNF-α alongside granulysin and soluble FasL [15, 16]. TNF-α is a multifunctional cytokine which serves as a key regulator of inflammatory responses and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. It is essential for maintaining a normal immune response by activating and modulating immune system functions. Elevated levels of TNF-α have been detected in both the serum and blister fluid of SJS/TEN patients, underscoring its pivotal role in disease pathogenesis [17]. TNF-α inhibitors have been reported as potential therapeutic options for SJS/TEN, with evidence suggesting their ability to halt disease progression and improve survival rates [11, 18].

TNF-α inhibitors have demonstrated significant success in clinical applications for conditions such as Crohn’s disease (CD) and RA [19, 20]. They are increasingly used in acute GVHD with fair results, especially in those who resemble SJS/TEN [21, 22]. These therapeutic agents function either as antagonists, preventing the interaction of TNF-α with its receptors (TNFR1/2), or as agonists, inducing reverse signaling and promoting apoptosis in TNF-α-producing immune cells [23]. Approved TNF-α inhibitors include etanercept, infliximab, adalimumab, golimumab, and certolizumab [17]. Adalimumab exhibits distinct molecular characteristics, mechanisms of action, and clinical application methods compared to other TNF-α inhibitors. Unlike etanercept, a soluble recombinant fusion protein that competitively binds soluble TNF-α and inhibits TNF receptor activation, adalimumab is a fully human monoclonal antibody. It directly neutralizes the specific region of the secreted TNF-α molecule while demonstrating reduced immunogenicity [11]. Additionally, adalimumab is administered subcutaneously as a single dose for SJS/TEN, offering a less frequent and potentially safer treatment regimen compared to other TNF-α inhibitors [24]. In this study, adalimumab combination of corticosteroids significantly accelerated skin lesion recovery, reduced the hospitalization duration, re-epithelization time, and corticosteroid exposure without increasing the incidence of major treatment-related adverse events.

Several limitations of this study should be acknowledged. First, as a single-central observational analysis, it is inherently less robust than multicenter, double-blind, controlled trials. Second, SJS/TEN patients with severe complications were excluded, and we were unclear whether such individuals would obtain benefits from TNF-α antagonist conjunction with corticosteroid treatment. Third, there was variability in the combination treatment protocols, including differences in dosage and timing of administration. Additionally, the small sample size and incomplete data on serum TNF-α levels further limit the generalizability of the findings. To solve these gaps, prospective randomized clinical trials are necessary to confirm the therapeutic benefits of TNF-α antagonist conjunction with corticosteroid and establish optimal dosing regimens for managing SJS/TEN effectively.

Conclusion

Our study indicates that the combination of corticosteroids with tumor necrosis factor inhibitors (TNFi) significantly reduced the hospitalization duration, re-epithelization time, and corticosteroid exposure without increasing the incidence of major treatment-related adverse events. This study provided valuable supports on the treatment of SJS/TEN patients. Considering the study’s limitations, A larger-scale, multi-center randomized controlled trials are essential to advancing treatment protocols and improving outcomes for SJS/TEN patients.

Author contributions

Jia Liu and Taoye Li wrote the main manuscript text，Mengyun Zhou and Tianhong Xu helped tables. All authors reviewed manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.