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Intravenous Immunoglobulin: Use in Dermatology


P. R. Mydlarski, MD1,2 N. Mittmann, Ph.D3, N. H. Shear, MD1-3

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

ABSTRACT

AA 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.

Disease Trial Design Demographics Treatment

Additional
Therapy
 

Outcome Response
Time

Dermatomyositis8

Double-blind, placebo controlled crossover study(n=15)

10F, 5M
Av. age 36 yrs

1g/kg/day x 2 days per month vs. placebo

Prednisolone (azathioprine, methotrexate, cyclophsphamide in some but not all)

IVIg: 11/12 improved; 1 unchanged
Placebo: 3/11 minimal improvement; 3 no change, 5 worse

1-2 month to response; maximal response at 3 months

Pemphigus Vulgaris15

Case series of patients with recalcitrant PV (n=21)

11F, 10M
Av. age 56 yrs

2g/kg over 3 days, monthly infusions until clear, followed by a maintenance schedule

Prednisone (azathioprine, cyclosporine, cyclophosphamide, tacrolimus, dapsone, gold, methotrexate in some but not all)

IVIg produced a sustained remission in all 21 patients, had a steroid sparing effect and improved quality of life

Mean effective clinical response 4.5 months

Pemphigus Foliaceus12

Case series of patients with recalcitrant PF (n=11)

8F, 3M
Av. age 55 yrs

2g/kg over 3 days, monthly infusions until clear, followed by a maintenance schedule

Prednisone (azathioprine, dapsone, gold cyclosporine, cyclophosphamide, tetracycline, nicotinamide, methotrexate in some but not all)

IVIg produced a sustained remission in all 11 patients, had a steroidsparing effect and improved quality of life

Mean effective clinical response 5.3 months

Mucous Membrane Pemphigoid16

Case series of patients with recalcitrant, ocular MMP (n=10)

5F, 5M
Av. age 74.6 yrs

2-3g/kg over 3 days, repeated every 2 to 6 weeks

Prednisone (dapsone, tacrolimus, cytosine arabinoside, azathioprine, methotrexate, cyclophosphamide in some but not all)

Visual acuity stabilized or improved, subjective complaints decreased in all 10 patients

Maximum response between 4 and 12 cycles

Bullous Pemphigoid14

Case series of patients with recalcitrant BP (n=15)

5F, 10M
Av. age 76 yrs

2g/kg over 3 days, monthly infusions until clear, followed by a maintenance schedule

Prednisone (azathioprine, dapsone, gold, cyclosporine, cyclophosphamide, tetracycline, nicotinamide, methotrexate in some but not all)

IVIg produced a sustained remission in all 15 patients, had a steroid-sparing effect and improved quality of life

Mean effective clinical response 2.9 months

Toxic Epidermal Necrolysis5

Case series (n=10)

4F, 6M
Av. age 39.4 yrs

0.2 - 0.75g/kg/day for 4 days

None

IVIg rapidly halted disease progression and produced a favorable outcome in all patients

Mean time to response: 1.5 days
Mean time to skin healing: 6.9 days
Survival rate: 100%

Toxic Epidermal Necrolysis18

Retrospective analysis (n=16)

8F, 8M
Av. age 42.8 yrs

1g/kg/d for 4 days (n=15); 0.4g/kg/day for 4 days (n=1)

None

IVIg significantly decreased mortality (observed vs. SCORTEN predicted mortality rate)

Mean time to response: 3.75 days
Mean time to skin healing: 8.50 days
Survival rate: 93.75%

Toxic Epidermal Necrolysis19

Multicenter retrospective analysis (n=48)

24F, 24M
Av. age 43 yrs

0.65-5.8g/kg (average 2.7g/kg) over 1-5 days

None

IVIg rapidly halted disease progression and produced a favorable outcome in the majority of patients

Mean time to response: 2.3 days
Mean time to skin healing: 15 days
Objective response rate: 90%
Survival rate: 88%

Steven Johnson Syndrome, Toxic Epidermal Necrolysis & SJS-TEN Overlap20

Prospective, non-comparative study (SJS, n=9; SJS-TEN, n=5; TEN, n=20)

22F, 12M
Av. age 47 yrs

1g/kg in 3 patients; 2g/kg in 31 patients; over 2 days in 27 cases and 3-5 days in 7 cases

None

No arrest in progression; no improvement in skin healing; no improvement in mortality rate

Mean time to skin healing: 18 days
Survival rate: 68%

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

Indication Summary of Evidence Dosing Comments

Dermatomyositis

Benefit established

2g/kg (over 2 days)
Initially given every month, maintenance schedule individualized

Resistant or intolerant to prednisone or immunosuppressives

Kawasaki’s disease

Benefit established

2g/kg (over 6-12 hours)

Toxic epidermal necrolysis

Case series, anecdotal evidence

1g/kg/day for 3 days

Pemphigus variants

Case series, anecdotal evidence

2g/kg (over 2-3 days)
Initially given every month, maintenance schedule individualized

Adjunctive or second line therapy

Bullous pemphigoid

Case series, anecdotal evidence

2g/kg (over 2-3 days)
Initially given every month, maintenance schedule individualized

Adjunctive or second line therapy

Mucous membrane pemphigoid

Case series, anecdotal evidence

2-3 g/kg (over 3 days)
Initially given every 2-6 weeks, maintenance schedule individualized

Adjunctive or second line therapy

Epidermolysis bullosa acquisita

Anecdotal evidence

2g/kg (over 2-3 days)
Initially given every month, maintenance schedule individualized

Adjunctive or second line therapy

Necrotizing fasciitis

Uncertain benefit

2g/kg (over 6-12 hours); repeat 1-2g/kg in 2-5 days if disease progresses

Adjunctive for progressive disease

Pyoderma gangrenosum

Uncertain benefit

2g/kg (over 2 days)
Initially given every month, maintenance schedule individualized

May be considered

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

Gammagard

Iveegam

Gamimune

Gamunex

Manufacturer

Baxter

Baxter

Bayer

Bayer

Form

Lyophilized

Lyophilized

Liquid

Liquid

Concentration

5%

10%

10%

10%

Infusion rate

4.0ml/kg/hr

2.0ml/kg/hr

3.6ml/kg/hr

8.4ml/kg/hr

Time to infuse 70g

5.3 hr

12 hr

2.3 hr

<2 hr

Viral Inactivation

Solvent/Detergent

Solvent/Detergent
Polyethylene glycol
Trypsin

Solvent/Detergent
pH 4.25

Caprylate
pH 4.25

Storage

Room Temperature

2-8oC

2-8oC

2-8oC, Room Temp.

Shelf-Life

24 months

24 months

36 months

36 months

pH

6.8

6.4-7.2

4.25

4.25

Osmolarity (mOsm/L)

636 at 5%

>240

278 260

Sugar Content

2% glucose

5% glucose

No sugar (Glycine)

No sugar (Glycine)

Sodium Content

0.85%

0.3%

Traces

Traces

IgA (mg/mL)

<3.7

<10

210 46
 

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. Intravenous Immunoglobulin: Use in Dermatology
  2. New Approaches to Surgery of Lentigo Maligna