Treatment of Toxic Epidermal Necrolysis with

Intravenous Immunoglobulin: A Retrospective Analysis

Suzanne Meyer, MD

August 30, 2007

Outline• TEN: definition, etiology, clinical features, and

treatment.

• SCORTEN, a TEN-specific severity-of-illness score

• Pathophysiology

• Literature Review

• My Study: The Treatment of TEN with IVIG: A Retrospective Analysis

• Methods

• Clincial and Mortality Data

Toxic Epidermal Necrolysis(TEN)

is a rare, potentially fatal, adverse drug reaction characterized by tenderness and erythema of the skin and mucosa, and extensive mucocutaneous exfoliation.

• This exfoliation is due to extensive death of keratinocytes via apoptosis.

Incidence: 0.4 to 1.2 cases per million per year.

Spectrum of Drug Reactions: SJS to TEN

• Spectrum of adverse cutaneous drug reactions with increasing severity and extent of epidermal detachment associated with increased mortality.

• SJS: < 10% BSA; 1-5% mortality• SJS-TEN overlap: 10-30% BSA• TEN: > 30% skin detachment; 25-35%

mortality.

Causative Agents

• More than 100 different drugs have been associated with TEN.

• Most frequently incriminated drugs:

• Antibiotics (quinolones, aminopenicillins, tetracyclines, cephalosporins, imidazole antifungal agents)

• NSAIDS

• Anticonvulsants

• Allopurinol

Clinical Features

• TEN usually begins 7-21 days after initiation of the culprit drug.

• Prodrome of fever, sore throat, burning eyes, usually 1 to 3 days before cutaneous lesions develop.

• Poorly defined erythematous, dusky, or purpuric macules progress to blister formation and skin soughing. (+) Nikolsky’s sign.

• Mucosal lesions involving the conjunctiva, mouth, and mucosa of the respiratory, GI, and GU tracts.

• Death most commonly due to sepsis and multiple organ failure.

Clinical Features

Figure 22.4 Cutaneous features of toxic epidermal necrolysis (TEN). A Characteristic dusky-red color of the early macular eruption in TEN. Lesions with this color often progress to full-blown necrolytic lesions with dermo-

epidermal detachment. B Positive Nikolsky sign: epidermal detachment reproduced by mechanical pressure on an area of erythematous skin.

Clinical Features

Figure 22.5 Clinical features of toxic epidermal necrolysis (TEN). A Detachment of large sheets of necrolytic epidermis (&gt;30% body surface area), leading to extensive areas of denuded skin. B Hemorrhagic crusts with

mucosal involvement. C Epidermal detachment of palmar skin.

SCORTEN• TEN-specific severity-of-illness score, shown to

accurately predict the risk of death in TEN pts.• 7 independent risk factors:

• age > 40 years• malignancy• tachycardia >120/min• initial surface of epidermal detachment >10%• urea > 28 mg/dl• glucose > 252 mg/dL• bicarbonate <20 mmol/L

(Bastuji-Garin, 2000)

SCORTEN: cont

• Each parameter is given 1 point if positive. Computing the sum of the scores for each parameter results in a “SCORTEN” ranging from 0 to 7.

SCORTEN Predicted Mortality (%)

0-1 3.2

2 12.1

3 35.3

4 58.3

5 90

Treatment• Optimal medical management requires early diagnosis,

immediate discontinuation of the causative drug(s), and supportive care.

• Careful daily wound care, hydration, and nutritional support are essential, and preferably, done in an ICU.

• No specific treatments for TEN have met evidence-based medicine standards of acceptance.

• Cyclosporine, cyclophosphamide, plasmapheresis, and N-acetylcysteine have shown promising results.

• The use of corticosteroids is controversial and they may even increase mortality.

Pathophysiology• Exfoliation in TEN is due to extensive keratinocyte cell

death via apotosis.

• Apotosis is mediated by interaction of the death receptor Fas and its ligand, FasL (CD95L).

• Increased FasL expression in TEN.

• The molecular mechanism by which culprit drugs up-regulate keratinocyte FasL expression in TEN is currently unknown.

• FasL activity can be blocked with monoclonal Abs that interfere with the interaction of Fas and FasL rationale for molecular strategies to treat TEN.

IVIG Blood product consisting of Abs obtained from pooled

human plasma and contains a high concentration of IgG. Immuno-modulating agent with multiple activities:

modulation of complement activation; suppression of various inflammatory mediators (cytokines).

Adverse effects: less than 5% of patients. • Most common AEs: HA, flushing, chills, myalgia, wheezing,

tachycardia, lower back pain, nausea, and hypotension. Can premedicate with antihistamines and IV hydrocortisone.

• Most important, but rare, potential complication: thromboembolic events.

• Other complications: aseptic meningitis, ARF, postinfusion hyperproteinemia, increased serum viscosity,pseudohyponatremia.

Fas-mediated Keratinocyte Apoptosis in TEN and Potential Mechanism of Inhibition by IVIG

In 1998, it was reported that IVIG contains Abs that are able to block the binding of FasL to Fas, thus inhibiting Fas-mediated keratinocyte apoptosis in vitro.

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

(French et al., 2006)

Treatment of TEN with IVIG• Pilot study in 1998: high-dose IVIG rapidly reversed

disease progression in 10 out of 10 pts (Viard et al).

• 2000-2006: numerous case reports and 8 non-controlled clinical studies containing 9 or more patients have analyzed the therapeutic effect of IVIG in TEN.

• 6 of the 8 studies point towards a benefit of IVIG used at doses greater than 2 g/kg on mortality.

• In the 2 studies that showed no benefit on mortality, the total dose of IVIG used was 2 g/kg or less, whereas in 5 of the 6 studies showing a benefit of IVIG on mortality, the total dose of IVIG used was greater than 2 g/kg.

• IVIG was well-tolerated in all studies.

Treatment of TEN with IVIG: Before and After

Figure 22.8 Treatment of toxic epidermal necrolysis (TEN). Facial involvement of a patient with TEN (50% body surface area involvement) before (A) and 3 weeks after (B) treatment with intravenous immunoglobulin (0.75

g/kg/day for 4 days).

• Retrospective chart review of 21 pts with biopsy-proven TEN from 1998 through the present treated at WHC.

• I hypothesize that IVIG is well tolerated and effective in improving the survival of pts with TEN.  

• For each pt, record and analyze: demographics; co-morbidities; culprit drug(s); time from 1st cutaneous lesion until 1st dose of IVIG; dose of IVIG and length of tx; other txs employed (steroids); type of hospital unit (standard floor, ICU, burn unit); adverse events; number of hospital days; mortality

Treatment of TEN with IVIG: A Retrospective Analysis

Methods• I calculated the SCORTEN for each patient. For each

subgroup of SCORTEN scores, I compared the predicted mortality rate with the observed mortality rate.

• I used the standardized mortality ratio (SMR) to determine whether IVIG treatment could reduce mortality for patients with TEN.

SMR = (∑ observed deaths/∑ expected deaths) x 100

Results: Clinical Data• 21 patients with TEN were treated with IVIG from 1999-2006.

• Mean age: 52.9 years (range, 29-81 years).

• Demographics: 12 men, 9 women. 17 pts were AA, 2 were white, 1 was Hispanic, and 1 was Indian.

• Co-morbidities: 2 pts had malignancy, 4 pts had HIV.

• Culprit Drug: Abx (4), phenytoin (4), allopurinol (2), cold medications, i.e.. Robitussin, Allegra-D (2), HIV drugs (1)case. The culprit drug was unclear in 7 cases.

• Category of TEN: All pts at least 30% of TBSA affected, and thus all pts were classified as TEN.

Results: IVIG

• Infusions of IVIG were initiated on average 3.85 days (range 1-10 days) after the onset of TEN and given over a period of 5 days at a mean total dose of 1.96 g/kg (range, 1.5-2.0g/kg).

• No severe adverse effects as a consequence of IVIG infusion. IVIG therapy was well tolerated in all cases.

Results: Outcome Data• Average length of stay: 25.4 days (range, 7-82 days).

• 17 pts survived, for a survival rate of 81.0%.

• 4 pts died, for a mortality rate of 19.0%

• Pt 2 died from multi-organ hemorrhage, sepsis, and TEN in the setting of advanced leukemia.

• Pt 5 died from multi-organ system failure and sepsis in the setting of injuries secondary to a motor vehicle accident.

• Pt 16 died from septic shock in the setting of a permacath infection.

• Pt 18 died from TEN, sepsis, and ARF in the setting of AIDS.

Parameters associated with non-response to IVIG

• Mean age in group that died was younger than group that survived: 48.5 (range, 31-60) vs 53.9 (range, 29-81).

• Greater surface of epidermal detachment was associated with a worse prognosis. 2/4 pts that died had 90% TBSA affected.

• IVIG infusions were initiated on ave 1.56 days earlier in those that responded to tx. IVIG was initiated on ave on day 3.69 (range, 1-10) in those who responded to tx vs day 5.25 (range, 3-10) in those who died.

• The ave. total dose of IVIG infused was 1.97 g/kg (range, 1.5-2.0 g/kg) in those who survived and 1.95 g/kg (range, 1.8-2.0 g/kg) in those who died despite IVIG infusion.

Mortality DataExpected Mortality Observed Mortality

SCORTEN Total No. of

Pts

No. of Pts who

Died

% Rate % Rate

0-1 0 0 3.2 0 0 0

2 9 0 12.1 1.33 0 0

3 5 2 35.3 1.77 40 2

4 5 1 58.3 2.92 20 1

>5 2 1 90.0 1.8 50 1

21 4 37.2 7.82 19 4

SMR: [∑ observed deaths/∑ expected deaths] x 100 = 51.3%100 - 51.3 = 48.7% reduction in mortality for pts txed with IVIG

Conclusions My results thus far suggest that treatment with IVIG

decreases mortality in patients with TEN. • However, the decrease in mortality observed in our study

population is less than that reported in other studies using IVIG at higher doses (>2 g/kg).

• This suggests that total doses of 3-4 g/kg are most likely to be effective in decreasing mortality.

I hope that this study will serve as a basis for designing a prospective controlled trial to definitively determine the therapeutic benefit of IVIG in TEN.

References• Bachot N, Revuz J, Roujeau JC. Intraveous immunoglobulin treatment for

Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33-6.

• Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz P, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115:149-53.

• Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil. 2004;25:81-8.

• French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. International Immunopharmacology. 2006;6:543-549.

• Herbert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol. 2004;50:286-8.

• Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics. 2003;112:1430-1436.

References: cont• Prins C, Kerdel FA, Padilla S, et al. Treatment of toxic epidermal necrolysis with

high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139:26-32.

• Prins C, Vittorio C, Padilla S, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology. 2003;207:96-99.

• Shortt R, Gomez M, Mittman N, Cartotto R. Intraveous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil. 2004;25:246-55.

• Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami experience. Arch Dermatol. 2003;139:39-43.

• Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol. Jul 2004;140(7):890-2.

• Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998;282:490-3.

• Yeung CK, Lam LK, Chan HH. The timing of intravenous immunoglobulin therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis. Clinical Experimental Dermatology. 2005;30:578-602.

Histology

Figure 22.1 Histology of toxic epidermal necrolysis (TEN). A Histology of an early-stage lesion of TEN. Arrows: apoptotic keratinocytes. B Histology of a late-stage lesion of TEN featuring separation of the epidermis from the dermis, and full-thickness necrosis of the epidermis.