1. Division of Clinical Pharmacology, 2. Department of Medicine , 3. HOPE Research Centre,
4. Department of Pharmacology, 5. Department of Pharmacy, 6. Division of Dermatology,
University of Toronto, Toronto, ON, Canada

ABSTRACT

Intravenous immunoglobulin (IVIG) has been proposed as a treatment for toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS). A number of retrospective and prospective studies have been conducted, with varying levels of evidence for the efficacy of IVIG. Recent publications provide opposing conclusions. A multi-center, comparative, long-term analysis needs to be conducted to determine the role of IVIG in the management of patients with SJS/TEN.

Key Words:
Intravenous immunoglobulin, IVIG, toxic epidermal necrolysis, TEN, Stevens-Johnson Syndrome, SJS

The terms erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have become entangled and confusing over time. Current concepts support EM as a specific disease that is different from the SJS/TEN spectrum. SJS and TEN represent different degrees of a severe, acute mucocutaneous reaction that often can be caused by drugs.¹ TEN or SJS is diagnosed objectively according to a consensus-derived definition.² The differentiation between SJS and TEN is determined based on the percentage of body surface area (BSA) affected: SJS is characterized by mucous membrane erosions and blisters on less than 10% of the total BSA, whereas TEN involves more than 30% of the total BSA.² Important prognostic factors for SJS/TEN include the percentage loss of BSA, age, heart rate, cancer/hematologic malignancy, urea, bicarbonate, and glucose serum levels.³

Clinical Features

SJS/TEN is most commonly characterized by skin changes (scattered 2-ring target-like lesions with a dark red centre and lighter red halo, red macules with central blistering that can coalesce to larger areas of denuded skin), hemorrhagic mucositis (mouth, eyes, genitals, and respiratory tract), and systemic symptoms (fever, malaise, possible internal organ involvement).¹ In severe TEN cases, fingernails and toenails, eyebrows and cilia may be lost as well. There may be extensive involvement of the gastrointestinal tract and respiratory tract. Sepsis and respiratory distress are the most common complications and ultimately the direct causes of death.

Survivors of SJS/TEN may experience numerous long-term sequelae; the most disabling are those involving the eyes. Cicatrization of conjunctival erosions may lead to inverted eyelashes, photophobia, burning sensation in the eyes, watery eyes, a siccalike syndrome, and corneal and conjunctival neovascularization. As many as 40% of survivors of TEN have residual, potentially disabling lesions on the eye and/or surrounding area, that may cause blindness.

Epidemiology

TEN affects between 0.4–1.2 cases per million people every year.^4-7 SJS is seen more frequently, affecting 1–6 cases per million people every year.^5,7 SJS may prove fatal in approximately 5% of patients. Prognosis is worse in TEN, where there is more epidermal sloughing which increases the severity of the condition with mortality rates ranging from 20%–40% for extensive sloughing.

Pathogenesis

The pathogenesis of drug-induced SJS/TEN is unknown, although several theories have been developed. Reactive metabolites of oxidative drug metabolism have been shown to lead to covalent binding that can stimulate an immune response. For some drugs there have been clear associations with HLA-B haplotypes in specific populations.^8,9 Epidermal death is due in part to apoptosis that is triggered by a death signal (Fas-ligand) and in vitro antibodies to Fas-ligand can block the process.

Drug-related SJS/TEN

Many cases of SJS/TEN are related to drug exposure. The drugs most frequently cited as causes of SJS and TEN are anticonvulsants, antibiotics (especially sulfonamides), allopurinol, and NSAIDs (e.g., piroxicam).⁴ Other causes, especially for SJS, include infections, neoplasia, and autoimmune diseases.

Treatment of SJS/TEN

There is currently no specific treatment for TEN and SJS.10 Discontinuation of the suspected drug is the first step in the management of these patients, with supportive care (e.g., wound care, hydration, and nutritional support) forming the basis of treatment. Immunosuppressives (e.g., cyclosporin, cyclophosphamide) are often recommended,¹⁰ although the use of corticosteroids in SJS and TEN remains controversial. Other therapeutic modalities that have been attempted include hyperbaric oxygen,¹¹ granulocyte colony stimulating factor,^12-14 and plasmapheresis.¹⁵
Intravenous immunoglobulin therapy (IVIG) may improve outcomes and reduce mortality and morbidity in this population. Considered by many clinicians as a treatment option, it is produced from the plasma of thousands of healthy blood donors. The pooled plasma is fractionated and purified to produce a final product containing predominantly IgG (90%–98%) as well as traces of IgA, IgM, CD4, CD8, HLA molecules and cytokines.¹⁶ Albumin also appears in IVIG in quantities ranging from trace amounts to 3000ìg/mL.^17-19

A number of retrospective and prospective studies have been conducted to examine the efficacy and safety of IVIG in SJS/TEN patients. A recent review of IVIG use in TEN and SJS examined studies with sample sizes of 10 or more patients.²⁰ Nine studies were included consisting of 134 TEN or SJS/TEN overlap patients and 22 SJS patients. The overall mortality rate of all the studies reviewed was 20.5%, and 22.4% for TEN-specific studies. In a subanalysis of these controlled trials, mortality rate for patients receiving IVIG were 27% compared with 30% for the predicted/control group. Further subanalyses revealed significantly higher average IVIG dose in studies with a positive “effect” conclusion than studies with an “ineffective” conclusion. The authors concluded that there was not strong enough evidence to support IVIG use in TEN or SJS patients. Seven of the nine publications analyzed did not report adverse effects with IVIG treatment. Of the two studies that did report adverse effects, one reported higher complications in the IVIG group. In the other report, there were higher plasma creatinine levels in IVIG patients, especially in elderly patients and in patients with past kidney function impairment.²⁰

An updated review stratified results according to TEN and SJS and examined more studies.²¹ In total, 14 studies in patients with TEN and 3 in patients with SJS were evaluated. The majority of studies reported positive results (11 out of 14),^9,22-31 while three cohort studies did not observe statistically significant improvement with IVIG administration.32-34 For SJS, two of the three studies reported positive results.^23,35 The remaining study showed no significant differences in mortality, progression of detachment or speed of re-epidermalization.³² In the pediatric population there were also positive results for IVIG response and adverse events.^{9,25,28,32,35} Because of the heterogeneity of the studies, a meta-analysis could not be conducted for IVIG in TEN or SJS.

It is important to note that all IVIG studies have examined clinical outcomes based on treatment in adults with doses ranging from 0.2g/kg/day to 2g/kg/day for 1–5 days’ duration. There is no information available on the impact of multiple dosing strategies.

The Toxic Epidermal Necrolysis Website Registry

Recently, a website for TEN and SJS has been launched (www.tenregistry.org) in Canada. At present, this new website is a pilot initiative that was created as an online resource to provide up-to-date information on SJS/TEN to clinicians, patients, and the public. The overall future objective of the website is to create a prospective, longitudinal database or registry of SJS/TEN patients across Canada and globally. At present, cases of suspected TEN or SJS should be reported to the adverse drug reaction monitoring agency. Reports to the adverse drug reaction monitoring centre may provide a signal for drugs that may cause SJS/TEN. Submitted reports of SJS/TEN will aid in determining the epidemiology, prognosis, and the possible causes, and will help plan health policy, especially for newly marketed drugs.

Conclusion

Based on the available data, IVIG may have a positive impact on the treatment of individuals with TEN and SJS. A large, multi-center, long-term analysis needs to be conducted to determine the role of IVIG in the management of these patients.

References

1. Fritsch PO, Ruiz-Maldonado R. Stevens-Johnson syndrome – toxic epidermal necrolysis. In: Freedberg IM, Eisen AZ, Wolff K, et al, Eds. Fitzpatrick’s Dermatology in General Medicine. Fifth Ed. Toronto: McGraw-Hill (1999) p.644-50.
2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129(1):92-6 (1993 Jan).
3. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 115(2):149-53 (2000 Aug).
4. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flechet ML, Girre JP. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol 126(1):37-42 (1990 Jan).
5. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 127(6):839-42 (1991 Jun).
6. Naldi L, Locati F, Marchesi L, Cainelli T. Incidence of toxic epidermal necrolysis in Italy. Arch Dermatol 126(8):1103-4 (1990 Aug).
7. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 126(1):43-7 (1990 Jan).
8. Paquet P, Kaveri S, Jacob E, Pirson J, Quatresooz P, Pierard GE. Skin immunoglobulin deposition following intravenous immunoglobulin therapy in toxic epidermal necrolysis. Exp Dermatol 15(5):381-6 (2006 May).
9. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282(5388):490-3 (1998 Oct).
10. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 153(2):241-53 (2005 Aug).
11. Ruocco V, Bimonte D, Luongo C, Florio M. Hyperbaric oxygen treatment of toxic epidermal necrolysis. Cutis 38(4):267-71 (1986 Oct).
12. Bae RJ, Orgill DP, DeBiasse MA, Demling R. Management of a patient with advanced AIDS and toxic epidermal necrolysis using human growth hormone and G-CSF. AIDS Patient Care STDS 11(3):125-9 (1997 Jun).
13. Jarrett P, Rademaker M, Havill J, Pullon H. Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony stimulating factor. Clin Exp Dermatol 22(3):146-7 (1997 May).
14. Goulden V, Goodfield MJ. Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 135(2):305-6 (1996 Aug).
15. Yamada H, Takamori K, Yaguchi H, Ogawa H. A study of the efficacy of plasmapheresis for the treatment of drug induced toxic epidermal necrolysis. Ther Apher 2(2):153-6 (1998 May).
16. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345(10):747-55 (2001 Sep).
17. Talecris Biotherapeutics Inc. Gamunex(R) Product Mono-graph. (2006 Feb).
18. Talecris Biotherapeutics Inc. IVIGnexTM Product Mono-graph, (2006 Mar).
19. Baxter International Inc. Gammagard (R) SD Product Monograph. (2004 Jan).
20. Faye O, Roujeau JC. Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date. Drugs 65(15):2085-90 (2005).
21. Mittmann N, Chan B, Knowles S, Cosentino L, Shear N. Intravenous immunoglobulin use in patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Am J Clin Dermatol 7(6):359-68 (2006).
22. 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 139(1):26-32 (2003 Jan).
23. Stella M, Cassano P, Bollero D, Clemente A, Giorio G. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 203(1):45-9 (2001).
24. Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 47(4):548-52 (2002 Oct).
25. Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report. Br J Plast Surg 58(4):504-10 (2005 Jun).
26. 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 139(1):39-43 (2003 Jan).
27. Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 83(6):430-2 (2003).
28. Al-Mutairi N, Arun J, Osama NE, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol 43(11):847-51 (2004 Nov).
29. Tan A, Tan HH, Lee CC, Ng SK. Treatment of toxic epidermal necrolysis in AIDS with intravenous immunoglobulins. Clin Exp Dermatol 28(3):269-71 (2003 May).
30. Mangla K, Rastogi S, Goyal P, Solanki RB, Rawal RC. Efficacy of low dose intravenous immunoglobulins in children with toxic epidermal necrolysis: an open uncontrolled study. Indian J Dermatol Venereol Leprol 71(6):398-400 (2005 Nov-Dec).
31. Nasser M, Bitterman-Deutsch O, Nassar F. Intravenous immunoglobulin for treatment of toxic epidermal necrolysis. Am J Med Sci 329(2):95-8 (2005 Feb).
32. 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 139(1):33-6 (2003 Jan).
33. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 25(1):81-8 (2004 Jan-Feb).
34. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 25(3):246-55 (2004 May-Jun).
35. Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 207(1):96-9 (2003).

Division of Dermatology¹, Department of Medicine² & Department of Pharmacology³,
University of Toronto, Toronto, ON, Canada

ABSTRACT

A manufactured blood product derived from fractionated human plasma, intravenous immunoglobulin (IVIg) contains supra-physiologic levels of IgG. IVIg is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Uncontrolled clinical studies and anecdotal case reports recommend its use in dermatology, but randomized clinical trials are lacking. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products should be considered. With several measures in place to ensure its safety, IVIg offers new hope for the treatment of many severe dermatologic conditions.

Key Words:
Intravenous immunoglobulin, IVIg, immunodeficiency syndromes, inflammatory disorders, autoimmune disease, infectious disease

Intravenous immunoglobulin (IVIg) is currently used in the treatment of primary and secondary immunodeficiency diseases, autoimmune disorders and certain infectious states. Off-label (non-approved) uses for high-dose IVIg are becoming increasingly common in dermatology.^1,2 As a blood product derivative, IVIg is manufactured from the sterilized, purified human plasma of between 10,000 to 20,000 donors per batch.³ The final IVIg preparation is primarily composed of IgG, with trace amounts of IgA, IgM and albumin.³ For the treatment of autoimmune diseases such as dermatomyositis and pemphigus, the precise mechanism of action is unknown. The immunomodulatory effects may be exerted through one or more of the following: 1) functional blockade of the Fc receptors; 2) inhibition of complement-mediated damage; 3) alteration of cytokine and cytokine antagonist profiles; 4) reduction of circulating antibodies via anti-idiotype antibodies; and 5) neutralization of toxins which trigger autoantibody production.⁴ In toxic epidermal necrolysis, IVIg blocks Fas (CD95) mediated keratinocyte death by inhibiting Fas – Fas ligand interactions.⁵

Use in Dermatology

The efficacy of IVIg is best documented in patients with graft-versus-host disease, Kawasaki’s disease and dermatomyositis; however, its utility in dermatology continues to grow.^6-8 A number of case series have found IVIg effective in the treatment of patients with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, herpes gestationis and epidermolysis bullosa acquisita (EBA).^9-16 A consensus statement was recently published on the use of IVIg in patients with autoimmune mucocutaneous blistering diseases.¹⁷ For autoimmune bullous disease the recommended guidelines for IVIg are as follows: 1) failure of conventional therapy; 2) significant adverse effects from conventional therapy; 3) contraindications, relative or absolute, to the use of high-dose long-term systemic therapy; 4) progressive disease despite conventional therapy; 5) uncontrolled, rapid debilitating disease; and 6) rapidly progressive EBA with generalized cutaneous involvement.¹⁷

The evidence for the use of IVIg in toxic epidermal necrolysis has been recently the subject of debate.^5,18-20 No consensus has been reached due to the lack of randomized clinical trials. The anecdotal results differ from one center to another. Yet, IVIg remains commonly used as initial therapy for toxic epidermal necrolysis. Current data are insufficient to recommend the routine administration of IVIg in patients with pyoderma gangrenosum, atopic dermatitis, chronic urticaria and Steven-Johnson syndrome.^21-25 For a review of the major clinical trials and larger case series, refer to Tables 1 and 2.

Table 1. A review of the major clinical trials and case series of IVIg in dermatology.

Table 2. Guidelines for use of IVIg in dermatology. Adapted from Bloody Easy.

Prior to starting IVIg therapy, complete blood cell counts, liver function and renal function studies are preformed. Immunoglobulin levels are measured to exclude IgA deficiency. In the absence IgA, or in the presence of low IgA, anti-IgA titers are ordered to minimize the risk of anaphylaxis. Screening for rheumatoid factor and cryoglobulins is recommended as these patients are at an increased risk of acute renal failure. In patients with compromised cardiac or renal function, IVIg must be carefully administered in order to prevent fluid overload. For medicolegal reasons, baseline testing for hepatitis B, C and the human immunodeficiency virus is advisable. Lastly, a small sample of serum should be stored for future analysis in the event of infectious disease transmission.^17,26

Premedications may be administered to minimize the risk of infusion-related side effects, such as headaches, myalgias and rigors. Analgesics (i.e., acetaminophen), nonsteroidal antiinflammatory agents (i.e., celecoxib), antihistamines (i.e., diphenhydramine) and even low-dose intravenous corticosteroids may be of benefit to a subset of individuals.¹⁷

In Kawasaki’s disease, IVIg is administered as a single 2g/kg infusion over 6-12 hours.⁷ For toxic epidermal necrolysis, a dose of 1g/kg for 3 consecutive days (i.e., total dose 3g/kg) appears most effective.¹⁹ In autoimmune disease, the published experience would suggest that the dose of 2g/kg per cycle is most valuable; however, clinical improvement has been noted with lower doses.¹⁷ A typical cycle consists of the total dose divided equally over 2-5 consecutive days (i.e., 1g/kg daily for 2 days, or 0.4g/kg daily for 5 days). As the half-life of IVIg ranges from 3-5 weeks, the infusions are given monthly until there is effective disease control. While the maintenance schedule for its use has not been adequately established, tapering the frequency of IVIg infusions may be useful in maintaining a disease-free state. Ahmed and Dahl have suggested that the intervals between infusions be increased from 4 to 6, 8, 10, 12, 14 and 16 weeks before discontinuing the IVIg therapy.¹⁷ The rate of IVIg infusion is dependent upon the product recommendations (Table 3).

Table 3. Comparison of the various IVIg preparations available in Canada.

Product Differences

IVIg is distributed by the Canadian Blood Services with the exception of Québec, where Hema Québec is the main distributor. There are four licensed IVIg preparations available in Canada (Table 3). While there are no studies which compare the safety and efficacy of the four products, there are some differences that may be clinically important.

Variability of the manufacturing processes may lead to differences in the marketed IVIg products. The use of additional production steps (i.e., stabilization, purification and/or pathogen safety) has the potential to impact negatively the biological activity and integrity of the IgG molecule, tolerability and yield. As shown in Table 3, IVIg preparations are available in both liquid and lyophilized formulations. While the lyophilized formulations require reconstitution, the liquid formulations are ready-to-use. If the lyophilized form is reconstituted to a higher than recommended concentration, the final osmolarity will be significantly increased above physiologic  levels. Moreover, the higher the concentration of the IVIg product, the less volume required for infusion. For example, a 70-kg individual receiving 1g/kg would require either 700ml of a 10% solution, or 1400ml of a 5% solution. In high-risk patients, such as those with cardiac or renal failure, these factors must be taken into consideration. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products must be considered.

Safety

Adverse effects with IVIg are usually rare and self-limiting. Infusion-related side effects include: headache, flushing, chills, myalgias, low back pain, nausea, wheezing, chest pain, tachycardia and blood pressure changes.^1,26 These symptoms are generally mild and begin within 30-60 minutes of the infusion. If encountered, the symptoms are easily managed by slowing or temporarily discontinuing the infusion. If symptoms are anticipated, the patient may be premedicated with antihistamines or intravenous steroids.

Anaphylaxis has been reported in IgA-deficient patients with anti-IgA antibodies. As most IVIg preparations contain trace amounts of IgA, administration of IVIg may result in antigen-antibody complex formation.¹⁷ Aseptic meningitis, often presenting with headache and photophobia, occurs in up to 11% of patients treated with IVIg.^29,30 More common in patients with a history of migraines, aseptic meningitis may last several days. Both hematological and dermatological reactions (i.e., eczema, erythema multiforme, urticaria) have also been described.²⁶

Patients with cardiac or kidney disease must be closely followed to prevent fluid overload. Those receiving lyophilized formulations or sucrose containing products (US and Europe only) are at increased risk of renal failure as a result of osmotic injury to the proximal renal tubules.^17,26

An association between IVIg and thromboembolic events has been reported in the literature. Sugar-stabilized and hyperosmolar products may increase serum viscosity.³¹ The risk appears to be greater in the patients receiving high doses or rapid infusion rates. By lowering the dose and slowing the rate of infusion, the risk of thrombotic events may be minimized.³¹

While donors are carefully selected and screened to ensure pathogen safety, a number of viral inactivation methods are used as part of the IVIg manufacturing process. These include: physical inactivation steps (i.e., heat and pasteurization) and chemical inactivation steps (i.e., solvent/detergent, low pH, trypsin, pepsin and caprylate). Pathogens are removed by precipitation, chromatography and filtration techniques. In the Gamunex process, the combination of caprylate precipitation, cloth filtration and chromatography has further been shown to significantly reduce prion transmission.^3,32,33

Pharmacoeconomics

Over the years, there has been an increase in both the cost and utilization of IVIg in Canada. At an average cost of $70 CDN per gram, the pharmacoeconomic impact of IVIg is significant.²⁸ For a 70-kg pemphigus patient receiving IVIg at a dose of 2g/kg, the cost for one cycle amounts to $9,800 CDN. As the average number of cycles required is 18, the total drug bill approaches $176,400 CDN.¹⁵ With an incidence of 1 per 100,000 population, the overall cost for the Canadian health care system exceeds $52 million CDN.

In toxic epidermal necrolysis, a 70-kg patient would receive 1g/kg for three consecutive days, amounting to an overall drug cost of $14,700 CDN. At an estimated annual incidence of 1 per million population, an aggregate cost for Canada is projected at over $400,000 CDN. Laboratory expenses, nursing costs and hospital expenditures must also be considered when determining the economic impact of IVIg. These costs must be balanced against improvement of symptoms and quality of life, reduced costs of conventional therapy, decreased complications, fewer hospital admissions and time off work.

Conclusion

IVIg has become increasingly recognized as a safe, effective therapy for a number of dermatological conditions. The cost impact of this medication is potentially large if the list of indications continues to expand. Formal pharmacoeconomic, burden of illness studies and collaborative clinical trials are required to further explore the role of IVIg in dermatology.

References

1. Jolles S, Hughes J, Whittaker S. Dermatological uses of highdose intravenous immunoglobulin. Arch Dermatol 134:80-6 (1998)
2. Rutter A, Luger TA. Intravenous immunoglobulin: an emerging treatment for immune-mediated skin diseases. Curr Opin Investig Drugs 3:713-9 (2002).
3. Bussel JB, Eldor A, Kelton JG, et al. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life. Thromb Haemost 91:771-8 (2004).
4. Ibanez C, Montoro-Ronsano JB. Intravenous immunoglobulin preparations and autoimmune disorders: mechanisms of action. Curr Pharm Biotechnol 4:239-47 (2003).
5. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-3 (1998).
6. Winston DJ, Antin JH, Wolff SN, et al. A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versushost disease and infection after allogeneic bone marrow transplantation. Bone Marrow Transplant 28:187-96 (2001).
7. Oates-Whitehead R, Baumer J, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 4:CD004000 (2003).
8. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatmentfor dermatomyositis. N Engl J Med 329:1993-2000 (1993).
9. Jolles S. High-dose intravenous immunoglobulin (hdIVIg) in the treatment of autoimmune blistering disorders. Clin Exp Immunol 129:385-9 (2002).
10. Gourgiotou K, Exadaktylou D, Aroni K, et al. Epidermolysis bullosa acquisita: treatment with intravenous immunoglobulins. J Eur Acad Dermatol Venereol 16:77-80 (2002).
11. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol 47:358-63 (2002).
12. Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol 46:42-9 (2002).
13. Jolles S. A review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin Exp Dermatol 26:127-31 (2001).
14. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 45:825- 35 (2001).
15. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 45:679-90 (2001).
16. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmology 106:2136-43 (1999).
17. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 139:1051-9 (2003).
18. Trent JT, Kirsner RS, Romanelli P, et al. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 139:39-43 (2003).
19. 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 139:26-32 (2003).
20. 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 139:33-6 (2003).
21. Asero R. Are IVIG for chronic unremitting urticaria effective? Allergy 55:1099-101 (2000).
22. Kroiss M, Vogt T, Landthaler M, et al. The effectiveness of low-dose intravenous immunoglobulin in chronic urticaria. Acta Derm Venereol 80:225 (2000).
23. Hagman JH, Carrozzo AM, Campione E, et al. The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum. J Dermatolog Treat 12:19-22 (2001).
24. Paul C, Lahfa M, Bachelez H, et al. A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 147:518- 22 (2002).
25. Dawn G, Urcelay M, Ah-Weng A, et al. Effect of high-dose intravenous immunoglobulin in delayed pressure urticaria. Br J Dermatol 149:836-40 (2003).
26. Wittstock M, Benecke R, Zettl UK. Therapy with intravenous immunoglobulins: complications and side-effects. Eur Neurol 50:172-5 (2003).
27. Callum JL, Pinkerton PH. Bloody Easy: Blood transfusions, blood alternatives and transfusion reactions. A guide to transfusion medicine. Toronto (ON): Sunnybrook and Women’s College Health Sciences Centre (2003).
28. Provincial Blood Coordination Office (Canada), IVIG Utilization Management Handbook. Vancouver (BC): Provincial Blood Coordination Office, Ministry of Health Services (2002).
29. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf 22:215-26 (2000).
30. Nettis E, Calogiuri G, Colanardi MC, et al. Drug-induced aseptic meningitis. Curr Drug Targets Immune Endocr Metabol Disord 3:143-9 (2003).
31. Katz KA, Hivnor CM, Geist DE, et al. Stroke and deep venous thrombosis complicating intravenous immunoglobulin infusions. Arch Dermatol 139:991-3 (2003).
32. Stenland C, Terry J, Cai K, et al. Evaluation of TSE clearance by the filtration process of a new intravenous immunoglobulin product (GamunexTM, 10%). J Allergy Clin Immunol 111:a611 (2003).
33. Lebing W, Remington KM, Schreiner C, et al. Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang 84:193-201 (2003).