What is the data regarding optimal steroid and IVIG dosing for SJS/TENS?

Comment by InpharmD Researcher

The optimal dosing for the treatment of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) with intravenous immunoglobulin (IVIg) and corticosteroids remains uncertain due to limited high-quality evidence. Despite significant variations in dosing regimens, a 2021 meta-analysis suggests a typical IVIg dosage of 3 g/kg, administered over a span of 3 days. This can be combined with corticosteroids, such as prednisone at a range of 0.5-1 mg/kg/day, or pulse methylprednisolone at 1 mg/kg/d for 3 days, potentially yielding mortality benefits. Optimal outcomes from steroid administration were observed with prompt initiation and gradual tapering. Nevertheless, the role of systemic corticosteroids remains controversial due to concerns regarding extended hospitalization and heightened infection risk. Overall, dosing strategies necessitate further investigation and individualization in accordance with the unique characteristics of each patient.

Background

British guidelines on the treatment of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) report conflicting data on the efficacy of intravenous immunoglobulin (IVIg). The data is largely retrospective, and studies tend to be limited by small sample sizes. A pooled analysis suggests IVIg does not significantly lower mortality compared to supportive care (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.58 to 1.75; p= 0.99). However, some data suggests there may be a benefit with IVIg in pediatric patients. When high-dose IVIg was compared to low-dose IVIg for SJS/TEN treatment, there was a significant mortality benefit with the high-dose; however, when the model was adjusted, IVIg did not correlate with reduced mortality. [1]

According to the guideline, corticosteroids have been utilized for the management of SJS/TEN for an extended period. Advocates underscore the significance of administering high-dose corticosteroids early in the disease progression to curb inflammation. However, opponents state that systemic corticosteroid usage heightens the risk of sepsis. In terms of topical corticosteroid application, the expert panel's recommendation pertains to the treatment of ocular manifestations in SJS/TENS. They suggest employing non-preserved dexamethasone 0.1% drops topically under the supervision of an ophthalmologist. This approach aims to mitigate acute-phase ocular surface damage. When dealing with oral involvement, the panel suggests contemplating the use of a topical corticosteroid rinse four times daily, employing a 3-minute betamethasone sodium phosphate 0.5 mg in 10 mL water preparation. Alternatively, during the acute phase, a more potent combination of clobetasol propionate 0.05%, mixed equally with Orabase (Colgate), can be directly applied to the sulci, labial, or buccal mucosa on a daily basis. For addressing urogenital manifestations, it's advised to consider the application of a potent topical corticosteroid ointment once daily to the affected non-eroded urogenital surfaces. [1]

A 2012 meta-analysis cited within the guideline above included seventeen studies that assessed the use of IVIg for SJS/TEN. Overall, the quality of evidence was low, with six of the 17 (35%) papers being controlled (retrospective controls), with the remaining 11 studies being observational and noncontrolled. No randomized or prospectively-controlled studies were identified. Patients were divided into high-dose (total dose of IVIg ≥ 2 g/kg) and low-dose groups (total dose of IVIg <2 g/kg). There was a considerable variation in dosing regimens of IVIg, ranging from 0.05 g/kg to 2.1 g/kg daily over different durations. Most of the non-controlled studies reported IVIg was efficacious for SJS/TEN; however, the overall results of the analysis did not find IVIg to have reduced mortality in SJS/TEN. Additionally, when age, total body surface area, and time to treatment were adjusted in a multivariate logistic regression model, the dosage of IVIg was not significantly related to hospital mortality (high dose vs. low dose: OR 0.494; 95% CI 0.106 to 2.300; p= 0.369). [2]

A 2021 systematic review and network meta-analysis investigated the effects of systemic immunomodulator therapies on mortality for SJS and TEN. A total of 67 studies were included (2,079 patients). Based on standardized mortality ratio (SMR), a network meta-analysis revealed that corticosteroids and IVIg combination therapy was the only treatment with significant survival benefits (SMR 0.53; 95% CI 0.31 to 0.93). IVIg is typically administered at a dosage of 3 g/kg, divided over 3 days, while corticosteroid treatment is reported at dosages of prednisone 0.5-1 mg/kg/day or pulse methylprednisolone 1 mg/kg/d for 3 days. [3], [4], [5]

In a 2022 Cochrane review assessing interventions for SJS and TEN, their findings were uncertain whether IVIg plus corticosteroid versus corticosteroid alone improved outcomes, based on a single study of 36 patients. IVIg was dose between 0.2 to 0.5 g/kg cumulative doses divided over 3 days, whilst IV dexamethasone 0.1 to 0.3 mg/kg/day was rapidly tapered within one to two weeks according to response. Compared to corticosteroids alone, there were 11.2% fewer deaths with IVIg plus corticosteroids and a 67% lower mortality risk. Because of the limited quality of data and very-low certainty of evidence, it is uncertain whether there is a benefit for time to complete re-epithelialization and reducing hospital length of stay. Whether effects are possibly dose-related was not discussed. Another cohort study comparing cyclosporine versus IVIg (continuous infusion 0.75 g/kg/day for 4 days [total dose 3 g/kg] in participants with normal renal function) suggests lower risk of disease-specific mortality with cyclosporine, but only 22 patients were involved, and the certainty of evidence was very-low. [6]

A 2009 review article discusses the potential benefits of IVIg in SJS/TEN patients. Prospective RCTs have not been performed due to the rarity of the disease. Analysis of retrospective studies and case series mentioned in the review show similar outcomes with the use of IVIg, with common results being quickened wound healing and better overall mortality compared to those not treated with IVIg. However, some contrasting evidence has not found a significant benefit of use. Based on the data, it is difficult to propose an optimized dosing regimen that should be individualized based on patient population and disease severity. The authors recommend a dose of 2 g/kg per cycle (3 to 4 g/kg in patients with TEN) with a cycle slowly infused over 4 to 4.5 hours. Although the study referenced the utilization of systemic corticosteroids in the trials, the precise dosage was not specified. [7], [8], [9]

A 2018 review article aimed to comprehensively address management strategies for SJS/TEN within the context of the Indian guidelines. Notably, the importance of early intervention with steroids in achieving improved outcomes was underscored. The utilization of systemic corticosteroids and IVIg remains a subject of debate. Optimal results have been observed when oral steroid therapy is initiated within 24 to 48 hours of disease onset, followed by a gradual tapering over 7 to 10 days. While the recommended dose of dexamethasone is 8 to 16 mg/day, adjustments to a higher dosage can be considered if deemed necessary. In instances of inadequate recovery, an incremental increase of 4 mg dexamethasone on successive days, accompanied by subsequent evaluation, is advised. Methylprednisolone pulse therapy has exhibited efficacy in reducing pro-inflammatory cytokine levels. A prospective study conducted in India involving 18 TEN patients treated with intramuscular dexamethasone (1 mg/kg/day) demonstrated a 100% survival rate. Additionally, in a retrospective analysis involving 85 patients, early initiation (within 4 days of onset) of pulse corticosteroids displayed potential in diminishing severe ocular complications. Another retrospective study encompassing 70 SJS/TEN patients revealed favorable outcomes with corticosteroid use, regardless of dosage regimen—whether low-dose (≤ 2 mg/kg/day) or high-dose (> 2 mg/kg/day). However, further research is essential to elucidate the role of pulse therapy in SJS/TEN. [10], [11]

Conversely, multiple sources of data have indicated a correlation between steroid administration and prolonged hospitalization duration, coupled with an elevated incidence of infectious complications associated with SJS/TEN. Consequently, the role of systemic corticosteroids in managing SJS/TEN remains contentious. [10], [11]

IVIg emerged as the predominant immunomodulatory treatment globally for SJS/TEN, typically administered at a dose of 2 g/kg. Encouragingly, low-dose IVIg has demonstrated safety and efficacy in treating TEN among pediatric patients. The synergy achieved through combining low-dose IVIg with steroids has proven more efficacious, leading to reduced mortality rates and expedited resolution of symptoms compared to steroid monotherapy. [10], [11]

References:

[1] Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016;174(6):1194-1227. doi:10.1111/bjd.14530
[2] Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012;167(2):424-432. doi:10.1111/j.1365-2133.2012.10965.x
[3] Frantz R, Huang S, Are A, Motaparthi K. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Review of Diagnosis and Management. Medicina (Kaunas). 2021;57(9):895. Published 2021 Aug 28. doi:10.3390/medicina57090895
[4] Tsai TY, Huang IH, Chao YC, et al. Treating toxic epidermal necrolysis with systemic immunomodulating therapies: A systematic review and network meta-analysis. J Am Acad Dermatol. 2021;84(2):390-397. doi:10.1016/j.jaad.2020.08.122
[5] Coulombe J, Belzile E, Duhamel A, et al. Pediatric SJS/TEN Subdued by a Combination of Dexamethasone, Cyclosporine, and Etanercept. J Cutan Med Surg. 2019;23(5):547-550. doi:10.1177/1203475419861078
[6] Jacobsen A, Olabi B, Langley A, et al. Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome. Cochrane Database Syst Rev. 2022;3(3):CD013130. Published 2022 Mar 11. doi:10.1002/14651858.CD013130.pub2
[7] Momin SB. Review of intravenous immunoglobulin in the treatment of stevens-johnson syndrome and toxic epidermal necrolysis. J Clin Aesthet Dermatol. 2009;2(2):51-58.
[8] Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139(1):26.
[9] Morici MV, Galen WK, Shetty AK, et al. Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol. 2000;27(10):2494-2497.
[10] Kumar R, Das A, Das S. Management of Stevens-Johnson Syndrome-Toxic Epidermal Necrolysis: Looking Beyond Guidelines!. Indian J Dermatol. 2018;63(2):117-124. doi:10.4103/ijd.IJD_583_17
[11] Chang HC, Wang TJ, Lin MH, Chen TJ. A Review of the Systemic Treatment of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Biomedicines. 2022;10(9):2105. Published 2022 Aug 28. doi:10.3390/biomedicines10092105

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the data regarding optimal steroid and IVIG dosing for SJS/TENS?

Please see Tables 1-2 for your response.


The Role of Intravenous Immunoglobulin in Toxic Epidermal Necrolysis: A Retrospective Analysis of 64 Patients Managed in A Specialized Centre

Design

Retrospective analysis

N=64

Objective

To evaluate whether the use of IVIg improved mortality in patients with Stevens–Johnson syndrome (SJS)/TEN overlap and TEN

Study Groups

Patient data (N=64)

Inclusion Criteria

Patients with SJS/TEN overlap and TEN

Criteria for TEN: Epidermal detachment > 30%, involvement of at least one mucous membrane, and histological features of full-thickness epidermal apoptosis

Criteria for SJS/TEN overlap: Epidermal detachment of 10–30% with at least one mucous membrane involved and consistent histopathological findings

Exclusion Criteria

Patients without SJS/TEN overlap or TEN

Methods

Patient data of those who fit the inclusion criteria were collected and analyzed. Predicted mortality was calculated based on severity-of-illness score for TEN (SCORTEN) values.

SCORTEN is a severity-of-illness score predictive model based on French patients from a specialized center. It has demonstrated accurate predictive disease outcomes which has been validated in other countries.

Duration

January 2003 to December 2010

Outcome Measures

Risk of in-hospital mortality

Baseline Characteristics

 

Patients data (n=64)

   

Age, years

57 ± 19     

Male

41%    

Ethnicity

Chinese

Malaysian

Indian

 

66%

28%

6%

   

SCORTEN Overall

2.6 ± 1.2    

Cumulative Dosage of IVIg, g kg-1

2.4 ± 0.8    

Daily Dosage of IVIg, g kg-1

0.6 ± 0.2    

Duration of administration, days

4.0 ± 1.3    

Delay to administration, days

3.2 ± 2.8    

Results

SCORTEN Score

Predicted Mortality

Observed Mortality

Standardized Mortality Rate (95% CI)

All patients: 

     0-1 (9 patients)

     2 (24 patients)

     3 (16 patients)

     4 (13 patients)

     ≥5 (2 patients)

 

0.29

2.9

5.65

7.58

1.80

 

0

4

7

7

2

1.10 (0.62-1.58)

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

This study shows that the use of IVIg does not yield survival benefits in SJS/TEN overlap and TEN, even when corrected for IVIg dosages.

InpharmD Researcher Critique

Although all patients who were admitted to the unit received the same supportive treatment protocol, it is possible that variations in treatment and care prior to transfer may have influenced the outcome.

References:

Lee HY, Lim YL, Thirumoorthy T, Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. Br J Dermatol. 2013;169(6):1304-1309. doi:10.1111/bjd.12607

 

Intravenous Immuniglobulin Treatment for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Design

Prospective Open Trial

N=34

Objective

To study the effects of IVIG on Stephens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Study Groups

SJS (n=9)

SJS-TEN (n=5)

TEN (n=20)

Inclusion Criteria

Detachment of epidermis on more than 1% of their TBSA, disease progression within 24 hours preceding admission, no contraindication of IVIG, h/o of anaphylaxis, diagnosis of SJS/TEN confirmed via skin biopsy.

Exclusion Criteria

N/A

Methods

Patients hospitalized into the ICU with SJS/TEN were treated with 2 g/kg of IVIG continuous infusion immediately after admission. Dose rates were extended based on renal function (e.g. 2 g/kg/day if patients had normal renal function).

Duration

January 1999 to December 2000

Outcome Measures

Detached plus detachable proportions of the total body surface area measured before and after treatment

Predicted death rate estimate on admission with validated prognostic score

Baseline Characteristics

 

 

Patient data (N=34)

Age, years

47 ± 21

Diagnosis of SJS

Diagnosis of TEN

SJS-TEN overlap

26%

59%

15%

Acquired immunodeficiency syndrome (AIDS)

35%

Length of admittance, days

4.1 ± 2

Results

Endpoint

Overall Cohort (n=34)

Detached and detachable TBSA

Admission

After IVIG treatment

 

32% ± 26%

12.4% ± 15.7%

Predicted death rate

Actual Death rate

95% Confidence interval (CI)

8.2 (21%)

11 (32%)

17% to 51%

Death occurred mostly in elderly patients with initially impaired renal function

Study Author Conclusions

The confidence interval of the observed death rate excludes a dramatic decrease in mortality. No measurable effect was observed on the progression of detachment or on the speed of reepidermalization. These results do not support the routine use of IVIG treatment for patients with SJS or TEN, especially in cases of impaired renal function.

InpharmD Researcher Critique

Aside from a small sample size, the study was not randomized. There may have been underlying diseases beyond the SJS/TEN that have caused a reaction or worsen the death rate as noticed by the elderly with renal impairment who were most susceptible.

References:

Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139(1):33-36. doi:10.1001/archderm.139.1.33