Just Ask the Expert: Is human IgG a viable treatment for IMHA?

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Please review the use of human IgG in the treatment of immune-mediated hemolytic anemia (IMHA) in veterinary patients.

Fred L. Metzger Jr., DVM, DABVP

Metzger Animal Hospital

State College, Pa.

Intravenous immunoglobulin (IVIg) therapy has been used in a variety of autoimmune disorders in people for more than two decades. Comparatively, the use of IVIg in veterinary species is rare.

Christopher G. Byers, DVM, DACVECC, DACVIM

IVIg is a preparation of fractionated immunoglobulins, mostly intact IgG, harvested from pooled human plasma; it also contains trace amounts of IgA; soluble CD4, CD8, and human leukocyte antigen molecules; as well as certain cytokines. After infusion, the half-life of IVIg in dogs is reportedly seven to nine days, but no definitive pharmacokinetic or pharmacodynamic research is available to my knowledge.

The mechanisms of action of IVIG are complex and not entirely understood. They include1,2

1. Inhibiting pathologic autoantibodies via anti-idiotypic antibodies

2. Transiently blocking the function of Fc gamma receptors on phagocytes

3. Modulating complement activation to divert complement away from target tissues to reduce damage

4. Interfering with superantigen activation of cytotoxic T cells.

IVIg has been used to treat several disorders in dogs and cats, but the most experience involves the treatment of idiopathic IMHA in dogs. Specific findings from studies include

• In eight dogs with IMHA in which a response to IVIg treatment could be evaluated, five dogs had a clinically meaningful response, as determined by a significant increase in the hematocrit and hemoglobin concentration from day 0 to day 28. There were no controls, and all animals in this study were receiving concurrent immunosuppressive therapy, so the effect of IVIg on survival could not be determined.3

• In 13 of 37 dogs with IMHA, the response rate in the IVIg group was 85%, compared with 75% in the control group. As this was a nonrandomized study, this difference may have been a result of bias. The time to response after IVIg therapy ranged from 0.6 to 6 days.4

• A prospective, randomized, double-blinded, controlled trial evaluated 28 dogs receiving glucocorticoid therapy and either IVIg or placebo for the initial management of IMHA. Of the 14 dogs treated with IVIg, 13 were discharged from the hospital and were alive two weeks later. Six dogs died or were euthanized within 40 days, but five were in remission five months later. However, there were no statistically significant differences in survival, length of hospitalization, lag time to hematocrit stabilization, or transfusion requirements between the two groups.5

IVIg has been used in dogs with nonregenerative anemia and myelofibrosis, thought to be immune-mediated in nature.6 IVIg has also been used in dogs with immune-mediated thrombocytopenia (ITP) and sudden acquired retinal degeneration.7-9 Additional case reports document the use of IVIg in the successful treatment of erythema multiforme in a cat,10 a drug-induced dermatologic reaction in a dog,11 pemphigus foliaceus in a dog,12 and epidermolysis bullosa acquisita in a dog.13

Adverse effects of IVIg in people and dogs are relatively uncommon, and documented incidents include

• Volume overload and dyspnea5

• Increases in blood pressure5

• Thromboembolic events.14

The production costs and high demand for IVIg in human medicine make this drug extremely expensive. As the diseases in which IVIg may be used are traditionally serious, the lack of authoritative indication that IVIg is helpful in treating immunologic disorders makes justification difficult. Recommendations that IVIg be used when dogs with IMHA fail to respond to conventional therapy must be weighed against the considerable additional cost after clients have already spent a substantial amount of money during initial treatment.

Christopher G. Byers, DVM, DACVECC, DACVIM

VCA, Veterinary Referral Associates

500 Perry Parkway

Gaithersburg, MD 20877

REFERENCES

1. Bayry J, Thirion M, Misra N, et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Neurol Sci 2003;24(Suppl 4):S217-S221.

2. Simon HU, Späth PJ. IVIG—mechanisms of action. Allergy 2003;58(7):543-552.

3. Scott-Moncrieff JCR, R agan WJ, Snyder PW, et al. Intravenous administration of human immune globulin in dogs with immune-mediated hemolytic anemia. J Am Vet Med Assoc 1997;210(11):1623-1627.

4. Kellerman DL, Bruyette DS. Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med 1997;11(6):327-332.

5. Whelan MF, O'Toole TE, Chan DL, et al. Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia. J Vet Emerg Crit Care 2009;19(2):158-164.

6. Scott-Montcrieff JCR, Reagan WJ, Glickman LT, et al. Treatment of nonregenerative anemia with human gamma-globulin in dogs. J Am Vet Med Assoc 1995;206(12):1895-1900.

7. Bianco D, Armstrong PJ, Washabau RJ. Treatment of severe immune-mediated thrombocytopenia with human IV immunoglobulin in 5 dogs. J Vet Intern Med 2007;21(4):694-699.

8. Bianco D, Armstrong PJ, Washabau RJ. A prospective, randomized, double-blinded, placebo-controlled study of human intravenous immunoglobulin for the acute management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med 2009;23(5):1071-1078.

9. Grozdanic SD, Kecova H, Harper MM, et al. Antibody mediated retinopathy: new mechanisms and treatment strategies, in Proceedings. Am Coll Vet Ophthalmol Conf, 2008.

10. Byrne KP, Giger U. Use of human immunoglobulin for treatment of severe erythema multiforme in a cat. J Am Vet Med Assoc 2002;220(2):197-201.

11. Nuttall TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson syndrome in a dog. J Small Anim Pract 2004;45(7):357-361.

12.. Rahilly LJ, Keating JH, O'Toole TE. The use of intravenous human immunoglobulin in treatment of severe pemphigus foliaceus in a dog. J Vet Intern Med 2006;20(6):1483-1486.

13. Hill PB, Boyer P, Lau P, et al. Epidermolysis bullosa acquisita in a Great Dane. J Small Anim Pract 2008;49(2):89-94.

14. Zaidan R, Al Moallem M, Wani BA, et al. Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurol 2003;10(4):367-372.