Treatment of  Toxic Epidermal Necrolysis with  Intravenous Immunoglobulin:  A Retrospective Analysis Suzanne Meyer, MD Aug...
Outline <ul><ul><ul><li>TEN: definition, etiology, clinical features, and treatment. </li></ul></ul></ul><ul><ul><ul><li>S...
Toxic Epidermal Necrolysis (TEN) <ul><ul><li> is a rare, potentially fatal, adverse drug reaction characterized by ten...
Spectrum of Drug Reactions: SJS to TEN <ul><ul><ul><li>Spectrum of adverse cutaneous drug reactions with increasing severi...
Causative Agents <ul><ul><ul><li>More than 100 different drugs have been associated with TEN.  </li></ul></ul></ul><ul><ul...
Clinical Features <ul><ul><ul><li>TEN usually begins 7-21 days after initiation of the culprit drug.  </li></ul></ul></ul>...
Clinical Features Figure 22.4 Cutaneous features of toxic epidermal necrolysis (TEN). A Characteristic dusky-red color of ...
Clinical Features Figure 22.5 Clinical features of toxic epidermal necrolysis (TEN). A Detachment of large sheets of necro...
SCORTEN <ul><li>TEN-specific severity-of-illness score, shown to accurately predict the risk of death in TEN pts. </li></u...
SCORTEN: cont <ul><ul><ul><li>Each parameter is given 1 point if positive.  Computing the sum of the scores for each param...
Treatment <ul><ul><ul><li>Optimal medical management requires early diagnosis, immediate discontinuation of the causative ...
Pathophysiology <ul><ul><ul><li>Exfoliation in TEN is due to extensive keratinocyte cell death via apotosis. </li></ul></u...
IVIG <ul><ul><li>Blood product consisting of Abs obtained from pooled human plasma and contains a high concentration of Ig...
Fas-mediated Keratinocyte Apoptosis in TEN and Potential Mechanism of Inhibition by IVIG <ul><li>In 1998, it was reported ...
Treatment of TEN with IVIG <ul><ul><ul><li>Pilot study in 1998: high-dose IVIG rapidly reversed disease progression in 10 ...
Treatment of TEN with IVIG: Before and After Figure 22.8 Treatment of toxic epidermal necrolysis (TEN). Facial involvement...
<ul><ul><ul><li>Retrospective chart review of 21 pts with biopsy-proven TEN from 1998 through the present treated at WHC. ...
Methods <ul><ul><ul><li>I calculated the SCORTEN for each patient.  For each subgroup of SCORTEN scores, I compared the pr...
Results: Clinical Data <ul><ul><ul><li>21 patients with TEN were treated with IVIG from 1999-2006.  </li></ul></ul></ul><u...
Results: IVIG <ul><ul><ul><li>Infusions of IVIG were initiated on average 3.85 days (range 1-10 days) after the onset of T...
Results: Outcome Data <ul><ul><ul><li>Average length of stay: 25.4 days (range, 7-82 days). </li></ul></ul></ul><ul><ul><u...
Parameters associated with non-response to IVIG <ul><ul><ul><li>Mean age in group that died was younger than group that su...
Mortality Data SMR:  [ ∑  observed deaths/ ∑  expected deaths] x 100 = 51.3% 100 - 51.3 =  48.7% reduction in mortality fo...
Conclusions <ul><li>My results thus far suggest that treatment with IVIG decreases mortality in patients with TEN.  </li><...
References <ul><ul><ul><li>Bachot N, Revuz J, Roujeau JC.  Intraveous immunoglobulin treatment for Stevens-Johnson syndrom...
References: cont <ul><ul><ul><li>Prins C, Kerdel FA, Padilla S, et al.  Treatment of toxic epidermal necrolysis with high-...
Histology Figure 22.1 Histology of toxic epidermal necrolysis (TEN). A Histology of an early-stage lesion of TEN. Arrows: ...
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  • My research project is a retrospective analysis on the treatment of TOXIC EPIDERMAL NECROLYSIS, or TEN, with IVIG.
  • Today I will begin by reviewing TEN…
    I will discuss the SCORTEN, a TEN-specific severity-of-illness score used to predict risk of mortality.
    I will touch on the pathophysiology of TEN and how its understanding provides a rationale for molecular strategies to treat TEN, such as with IVIG.
    I will briefly review the literature on the treatment of TEN with IVIG.
    Finally, I will present the clinical and mortality data I have obtained so far.
  • This exfoliation is due to extensive death of keratinocytes (the main cell type of the epidermis) via apoptosis.
    [TEN has a low incidence of 0.4 to 1.2 cases per million per year.]
  • Stevens-Johnson syndrome and TEN are considered to be part of a spectrum of adverse cutaneous drug reactions with increasing severity and extent of skin detachment. [STOP]
    The continuum ranges from Stevens-Johnsons with less than 10% of body surface area affected  to Stevens-Johnsons-TEN overlap with 10-30% of body surface area affected  to TEN with greater than 30% skin detachment.
    The severity of epidermal detachment is tightly correlated with the observed rate of mortality: 1-5% in SJS versus 25-35% in TEN.
  • What causes TEN?
    The medications most frequently incriminated as causes of TEN are antibiotics, NSAIDs, antiepileptics, and allopurinol.
  • How does TEN present?
    It often begins with a prodrome of …
    Cutaneous lesions progress from…
    Pts may have a positive Nikolsky’s sign, in which epidermal detachment is reproduced by mechanical pressure on an area of intact skin.
    Extensive cell death results in mucous membrane detachment.
    Sepsis and multiple organ failure are the main causes of death among TEN patients.
  • On the left, you can see the characteristic dusky-red color of the early macular lesions in TEN.
    The image on the right demonstrates a positive Nikolsky sign: epidermal detachment reproduced by mechanical pressure on an area of intact skin.
  • Here you can see detachment of large sheets of necrolytic epidermis, leading to extensive areas of denuded skin.
    You can also appreciate hemorrhagic crusts with mucosal involvement.
    Epidermal detachment of palmar skin.
  • What is the SCORTEN?
    The SCORTEN …
    7 independent risk factors FOR DEATH have been identified:
  • For example:
    a score of 0 or 1 predicts a mortality of 3.2%
    a score of 2 predicts a mortality 12.1%
    a score of 3 predicts a mortality of 35.3%
    a score of 4 predicts a mortality of 58.3%
    a score of 5 or above predicts a mortality of greater than 90% (French, 2006).
  • Supportive care is similar to that performed for severe burns and is aimed at limiting hypovolemia, electrolyte imbalance, renal insufficiency, and sepsis.
    No specific treatments for TEN have met evidence-based medicine standards of acceptance BECAUSE OF THE LOW PREVALENCE OF TEN.
    A few cases have been treated with cyclosporine, cyclophosphamide, plasmapheresis, and N-acetylcysteine and have shown promising results.
    The use of steroids is controversial and SOME REPORTS SUGGEST THAT THEY MAY EVEN increase mortality (secondary to increased risk of septicemia).
  • On to pathophysiology…
    THIS apotosis is mediated by interaction of the death receptor Fas and its ligand, FasLigand (FasL or CD95L).
    IT HAS BEEN SHOWN that there is increased FasLigand expression in TEN.
    IT HAS BEEN SHOWN that FasLigand activity…
  • A little bit about IVIG…
    IVIG is …
    IVIG is an immuno-modulating agent that has multiple activities, including modulation of complement activation and suppression of various inflammatory mediators, including cytokines.
    Side effects from IVIG occur in less than 5% of patients. The most common adverse effects occur soon after infusions and can include…
    If symptoms are anticipated, a patient can be premedicated with antihistamines and IV hydrocortisone.
    The most important, but rare, potential complications of IVIG are thromboembolic events because of the tendency of IVIG to increase blood viscosity.
  • The bottom figure represents the epidermis during TEN. It shows the anti-Fas antibodies in IVIG (represented by red circles) inhibiting apoptosis by blocking the Fas Receptor.
    Fas-mediated keratinocyte apoptosis in TEN and the potential mechanism of inhibition by IVIG: (A) shows normal epidermis. (B) shows TEN with induction of keratinocyte FasLigand expression and interaction with the Fas Receptor at the cell surface, leading to keratinocyte apoptosis. (C) shows the epidermis during TEN treated by IVIG and predicted inhibition of apoptosis by blockade of the Fas Receptor by anti-Fas Ab in IVIG.
  • A pilot study …
    Although these studies were small and non-controlled…
    Furthermore, in the studies using high-dose IVIG (&amp;gt; 2 g/kg), a 59% reduction between expected (SCORTEN) and observed mortality rate is detected, whereas in the low-dose IVIG studies, only a 3% reduction between expected and observed mortality rate was detected.
  • Here is an example from one of the studies of a patient with TEN before and 3 weeks after treatment with IVIG.
  • My study is a…
    I am performing a …
  • THEN, for each subgroup of SCORTEN scores, I have compared the predicted mortality rate with the observed mortality rate.
  • Our study population included…
    Antibiotics and Dilantin were the most common culprit drugs. The culprit drug was unclear in 7 cases.
    All patients had detachment of the epidermis affecting 30% or more of their TBSA and were thus classified as TEN. (No pts were SJS or SJS-TEN)
  • None of the patients developed severe adverse effects as a consequence of IVIG infusion.
    Approximately half of the patients received steroids. 2 of the 4 patients who died received steroids. We do not believe the use of steroids affected our results.
  • All patients who died had significant underlying disease, such as ALL and AIDS.
  • I wanted to look more closely at the differences between the group that survived vs the group that died.
    UNEXPECTEDLY, the mean age…
    AS EXPECTED
    The total dose of IVIG was essentially the same in both groups – approximately 2.0 g/kg total.
  • 9 pts had a SCORTEN of 2, 5 had a score of 3, 5 had a score of 4, and 2 had a score of 5, both of whom died.
    Based on the SCORTEN, the expected mortality in our study population was 7.82 patients or 37.2%. However, the actual mortality was 4 patients or 19%.
    The SMR analysis indicated a 48.7% reduction in mortality for patients treated with IVIG.
    WE WILL PERFORM A STATISTICAL ANALYSIS TO DETERMINE IF OUR RESULTS ARE SIGNIFICANT
  • (In 4 previous studies using high-dose IVIG (&amp;gt; 2 g/kg), a 59% reduction between expected (SCORTEN) of control group and observed mortality rate is detected.)
  • Key histologic features include necrotic keratinocytes, separation of the epidermis from the dermis, and full-thickness epidermal necrosis
    shows histology of an early-stage lesion of TEN. The arrows point towards apoptotic keratinocytes (in the basal and immediate suprabasal layers of the epidermis – the histologic correlate of the dusky-gray color that is a warning sign of pending full-blown epidermal necrolysis and detachment).
    (B) shows histology of a late-stage lesion of TEN featuring separation of the epidermis from the dermis, and full-thickness necrosis of the epidermis. There is a sparse perivascular infilitrate composed primarily of lymphocytes.
    Histology is useful in distinguishing TEN from Staph Scalded Skin Syndrome (SSSS). TEN results in full-thickness epidermal necrolysis, whereas Staph Scalded Skin Syndrome shows a subcorneal split with a normal underlying epidermis; subcorneal blister with cleavage located in the granular layer of the epidermis.
  • Treatment of Toxic Epidermal Necrolysis with

    1. 1. Treatment of Toxic Epidermal Necrolysis with Intravenous Immunoglobulin: A Retrospective Analysis Suzanne Meyer, MD August 30, 2007
    2. 2. Outline <ul><ul><ul><li>TEN: definition, etiology, clinical features, and treatment. </li></ul></ul></ul><ul><ul><ul><li>SCORTEN, a TEN-specific severity-of-illness score </li></ul></ul></ul><ul><ul><ul><li>Pathophysiology </li></ul></ul></ul><ul><ul><ul><li>Literature Review </li></ul></ul></ul><ul><ul><ul><li>My Study: The Treatment of TEN with IVIG: A Retrospective Analysis </li></ul></ul></ul><ul><ul><ul><ul><li>Methods </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Clincial and Mortality Data </li></ul></ul></ul></ul>
    3. 3. Toxic Epidermal Necrolysis (TEN) <ul><ul><li> is a rare, potentially fatal, adverse drug reaction characterized by tenderness and erythema of the skin and mucosa, and extensive mucocutaneous exfoliation. </li></ul></ul><ul><ul><ul><ul><li>This exfoliation is due to extensive death of keratinocytes via apoptosis. </li></ul></ul></ul></ul><ul><ul><li>Incidence: 0.4 to 1.2 cases per million per year. </li></ul></ul>
    4. 4. Spectrum of Drug Reactions: SJS to TEN <ul><ul><ul><li>Spectrum of adverse cutaneous drug reactions with increasing severity and extent of epidermal detachment associated with increased mortality. </li></ul></ul></ul><ul><ul><ul><ul><li>SJS : < 10% BSA; 1-5% mortality </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SJS-TEN overlap : 10-30% BSA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>TEN : > 30% skin detachment; 25-35% mortality . </li></ul></ul></ul></ul>
    5. 5. Causative Agents <ul><ul><ul><li>More than 100 different drugs have been associated with TEN. </li></ul></ul></ul><ul><ul><ul><li>Most frequently incriminated drugs: </li></ul></ul></ul><ul><ul><ul><ul><li>Antibiotics (quinolones, aminopenicillins, tetracyclines, cephalosporins, imidazole antifungal agents) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>NSAIDS </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Anticonvulsants </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Allopurinol </li></ul></ul></ul></ul>
    6. 6. Clinical Features <ul><ul><ul><li>TEN usually begins 7-21 days after initiation of the culprit drug. </li></ul></ul></ul><ul><ul><ul><li>Prodrome of fever, sore throat, burning eyes, usually 1 to 3 days before cutaneous lesions develop. </li></ul></ul></ul><ul><ul><ul><li>Poorly defined erythematous, dusky, or purpuric macules progress to blister formation and skin soughing. (+) Nikolsky’s sign. </li></ul></ul></ul><ul><ul><ul><li>Mucosal lesions involving the conjunctiva, mouth, and mucosa of the respiratory, GI, and GU tracts. </li></ul></ul></ul><ul><ul><ul><li>Death most commonly due to sepsis and multiple organ failure. </li></ul></ul></ul>
    7. 7. 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.
    8. 8. 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.
    9. 9. SCORTEN <ul><li>TEN-specific severity-of-illness score, shown to accurately predict the risk of death in TEN pts. </li></ul><ul><li>7 independent risk factors: </li></ul><ul><ul><ul><ul><li>age > 40 years </li></ul></ul></ul></ul><ul><ul><ul><ul><li>malignancy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>tachycardia >120/min </li></ul></ul></ul></ul><ul><ul><ul><ul><li>initial surface of epidermal detachment >10% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>urea > 28 mg/dl </li></ul></ul></ul></ul><ul><ul><ul><ul><li>glucose > 252 mg/dL </li></ul></ul></ul></ul><ul><ul><ul><ul><li>bicarbonate <20 mmol/L </li></ul></ul></ul></ul><ul><li>(Bastuji-Garin, 2000) </li></ul>
    10. 10. SCORTEN: cont <ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>SCORTEN Predicted Mortality (%) </li></ul></ul></ul><ul><ul><ul><li> 0-1 3.2 </li></ul></ul></ul><ul><ul><ul><li> 2 12.1 </li></ul></ul></ul><ul><ul><ul><li> 3 35.3 </li></ul></ul></ul><ul><ul><ul><li> 4 58.3 </li></ul></ul></ul><ul><ul><ul><li> 5 90 </li></ul></ul></ul>
    11. 11. Treatment <ul><ul><ul><li>Optimal medical management requires early diagnosis, immediate discontinuation of the causative drug(s), and supportive care. </li></ul></ul></ul><ul><ul><ul><li>Careful daily wound care, hydration, and nutritional support are essential, and preferably, done in an ICU. </li></ul></ul></ul><ul><ul><ul><li>No specific treatments for TEN have met evidence-based medicine standards of acceptance. </li></ul></ul></ul><ul><ul><ul><li>Cyclosporine, cyclophosphamide, plasmapheresis, and N-acetylcysteine have shown promising results. </li></ul></ul></ul><ul><ul><ul><li>The use of corticosteroids is controversial and they may even increase mortality. </li></ul></ul></ul>
    12. 12. Pathophysiology <ul><ul><ul><li>Exfoliation in TEN is due to extensive keratinocyte cell death via apotosis. </li></ul></ul></ul><ul><ul><ul><li>Apotosis is mediated by interaction of the death receptor Fas and its ligand, FasL (CD95L). </li></ul></ul></ul><ul><ul><ul><ul><li>Increased FasL expression in TEN. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>The molecular mechanism by which culprit drugs up-regulate keratinocyte FasL expression in TEN is currently unknown. </li></ul></ul></ul></ul><ul><ul><ul><li>FasL activity can be blocked with monoclonal Abs that interfere with the interaction of Fas and FasL  rationale for molecular strategies to treat TEN. </li></ul></ul></ul>
    13. 13. IVIG <ul><ul><li>Blood product consisting of Abs obtained from pooled human plasma and contains a high concentration of IgG. </li></ul></ul><ul><ul><li>Immuno-modulating agent with multiple activities: modulation of complement activation; suppression of various inflammatory mediators (cytokines). </li></ul></ul><ul><ul><li>Adverse effects: less than 5% of patients. </li></ul></ul><ul><ul><ul><li>Most common AEs: HA, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension. Can premedicate with antihistamines and IV hydrocortisone. </li></ul></ul></ul><ul><ul><ul><li>Most important, but rare, potential complication: thromboembolic events. </li></ul></ul></ul><ul><ul><ul><li>Other complications: aseptic meningitis, ARF, postinfusion hyperproteinemia, increased serum viscosity,pseudohyponatremia. </li></ul></ul></ul>
    14. 14. Fas-mediated Keratinocyte Apoptosis in TEN and Potential Mechanism of Inhibition by IVIG <ul><li>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. </li></ul>(French et al., 2006)
    15. 15. Treatment of TEN with IVIG <ul><ul><ul><li>Pilot study in 1998: high-dose IVIG rapidly reversed disease progression in 10 out of 10 pts (Viard et al). </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><ul><li>6 of the 8 studies point towards a benefit of IVIG used at doses greater than 2 g/kg on mortality. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>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. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>IVIG was well-tolerated in all studies. </li></ul></ul></ul></ul>
    16. 16. 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).
    17. 17. <ul><ul><ul><li>Retrospective chart review of 21 pts with biopsy-proven TEN from 1998 through the present treated at WHC. </li></ul></ul></ul><ul><ul><ul><li>I hypothesize that IVIG is well tolerated and effective in improving the survival of pts with TEN.   </li></ul></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul>Treatment of TEN with IVIG: A Retrospective Analysis
    18. 18. Methods <ul><ul><ul><li>I calculated the SCORTEN for each patient. For each subgroup of SCORTEN scores, I compared the predicted mortality rate with the observed mortality rate. </li></ul></ul></ul><ul><ul><ul><li>I used the standardized mortality ratio (SMR) to determine whether IVIG treatment could reduce mortality for patients with TEN. </li></ul></ul></ul><ul><ul><ul><li>SMR = ( ∑ observed deaths/ ∑ expected deaths) x 100 </li></ul></ul></ul>
    19. 19. Results: Clinical Data <ul><ul><ul><li>21 patients with TEN were treated with IVIG from 1999-2006. </li></ul></ul></ul><ul><ul><ul><li>Mean age: 52.9 years (range, 29-81 years). </li></ul></ul></ul><ul><ul><ul><li>Demographics: 12 men, 9 women. 17 pts were AA, 2 were white, 1 was Hispanic, and 1 was Indian. </li></ul></ul></ul><ul><ul><ul><li>Co-morbidities: 2 pts had malignancy, 4 pts had HIV. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>Category of TEN: All pts at least 30% of TBSA affected, and thus all pts were classified as TEN. </li></ul></ul></ul>
    20. 20. Results: IVIG <ul><ul><ul><li>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). </li></ul></ul></ul><ul><ul><ul><li>No severe adverse effects as a consequence of IVIG infusion. IVIG therapy was well tolerated in all cases. </li></ul></ul></ul>
    21. 21. Results: Outcome Data <ul><ul><ul><li>Average length of stay: 25.4 days (range, 7-82 days). </li></ul></ul></ul><ul><ul><ul><li>17 pts survived, for a survival rate of 81.0% . </li></ul></ul></ul><ul><ul><ul><li>4 pts died, for a mortality rate of 19.0% </li></ul></ul></ul><ul><ul><ul><ul><li>Pt 2 died from multi-organ hemorrhage, sepsis, and TEN in the setting of advanced leukemia. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pt 5 died from multi-organ system failure and sepsis in the setting of injuries secondary to a motor vehicle accident. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pt 16 died from septic shock in the setting of a permacath infection. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pt 18 died from TEN, sepsis, and ARF in the setting of AIDS. </li></ul></ul></ul></ul>
    22. 22. Parameters associated with non-response to IVIG <ul><ul><ul><li>Mean age in group that died was younger than group that survived: 48.5 (range, 31-60) vs 53.9 (range, 29-81). </li></ul></ul></ul><ul><ul><ul><li>G reater surface of epidermal detachment was associated with a worse prognosis. 2/4 pts that died had 90% TBSA affected. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul>
    23. 23. Mortality Data SMR: [ ∑ observed deaths/ ∑ expected deaths] x 100 = 51.3% 100 - 51.3 = 48.7% reduction in mortality for pts txed with IVIG 4 19 7.82 37.2 4 21 1 50 1.8 90.0 1 2 > 5 1 20 2.92 58.3 1 5 4 2 40 1.77 35.3 2 5 3 0 0 1.33 12.1 0 9 2 0 0 0 3.2 0 0 0-1 Rate % Rate % No. of Pts who Died Total No. of Pts SCORTEN Observed Mortality Expected Mortality
    24. 24. Conclusions <ul><li>My results thus far suggest that treatment with IVIG decreases mortality in patients with TEN. </li></ul><ul><ul><ul><li>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). </li></ul></ul></ul><ul><ul><ul><li>This suggests that total doses of 3-4 g/kg are most likely to be effective in decreasing mortality. </li></ul></ul></ul><ul><ul><li>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. </li></ul></ul>
    25. 25. References <ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>Herbert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol . 2004;50:286-8. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul>
    26. 26. References: cont <ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul>
    27. 27. 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.

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