Rapid and reversible responses to IVIG in autoimmune neuromuscular diseases suggest mechanisms of action involving competition with functionally important autoantibodies

Abstract

Intravenous immunoglobulin (IVIG) is widely used in autoimmune neuromuscular diseases whose pathogenesis is undefined. Many different effects of IVIG have been demonstrated in vitro, but few studies actually identify the mechanism(s) most important in vivo. Doses and treatment intervals are generally chosen empirically. Recent studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy show that some effects of IVIG are readily reversible and highly dependent on the serum IgG level. This suggests that in some autoantibody-mediated neuromuscular diseases, IVIG directly competes with autoantibodies that reversibly interfere with nerve conduction. Mechanisms of action of IVIG which most likely involve direct competition with autoantibodies include: neutralization of autoantibodies by anti-idiotypes, inhibition of complement deposition, and increasing catabolism of pathologic antibodies by saturating FcRn. Indirect immunomodulatory effects are not as likely to involve competition and may not have the same reversibility and dose-dependency. Pharmacodynamic analyses should be informative regarding most relevant mechanism(s) of action of IVIG as well as the role of autoantibodies in the immunopathogenesis of each disease. Better understanding of the role of autoantibodies and of the target(s) of IVIG could lead to more efficient use of this therapy and better patient outcomes.

Keywords: Guillain-Barré syndrome; anti-idiotypes; autoimmune neuromuscular diseases; chronic inflammatory demyelinating polyneuropathy; intravenous immunoglobulin; multifocal motor neuropathy.

Figure 1

Structure of IgG molecule illustrating antigen-binding sites and showing binding of anti-idiotypic antibodies that resemble target antigen of the autoantibody (left) or block its antigen-binding site by “steric hindrance.”

Figure 2

Function of endothelial FcRn in maintaining normal serum IgG concentration (left panel) and mechanism by which FcRn allows intravenous immunoglobulin (IVIG, yellow) to selectively increase degradation of pathogenic IgG (blue) (center panel). From Yu and Lennon (1999); reproduced with permission from the publisher.

Figure 3

Anti-GAD 65 antibodies in patients with “stiff-person syndrome” during treatment with IVIG or placebo. From Dalakas et al. (2001); reproduced with permission from the publisher.

Figure 4

Dose-dependent inhibition by intravenous immunoglobulin (IVIG) of uptake of C3b onto sensitized sheep erythrocytes (left) and also of lysis of the targets (right). Human serum albumin (control) has no effect. Note that a protein concentration in this system of 20 mg/ml is the equivalent of a serum IgG concentration of 2,000 mg/dl, easily achieved during IVIG therapy. From Berger et al. (1985); reproduced with permission from the publisher.

Figure 5

Correlation of clinical outcome with increment in serum IgG after treatment in GBS. Proportion of patients who regained the ability to walk unaided in quartiles based on increase in serum immunoglobulin IgG 2 weeks after treatment with a standard high dose of intravenous immunoglobulin (IVIG). The Kaplan-Meier curves show the cumulative fractions of patients walking unaided along time grouped according to the quartiles (1–4) of increase in serum IgG. Cutoff values of ΔIgG for quartile 1: 3.99 g/l (n = 43); quartile 2: 3.99–7.30 g/l (n = 45); quartile 3: 7.31–10.92 g/l (n = 43); and quartile 4:10.92 g/l (n = 43). p Value is based on the log-rank test for trend. From Kuitwaard et al. (2009); reproduced with permission from the publisher.

Figure 6

(A) Cyclic gain in foot strength, and wear-off effect, in response to monthly intravenous immunoglobulin (IVIG) in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP), and change in baseline after addition of prednisone and azathioprine at day 79. From Pollard and Armati (2011); reproduced with permission from the publisher. (B) Motor excitability recordings pre-IVIg treatment (open), 1-week (filled), and 2-weeks post-IVIG treatment (hatched) in a single representative patient in strength-duration time-constant (SDTC). (C) Changes in threshold electrotonus waveforms pre (open dots), 1 week post (filled dots) and 2 weeks post (grey dots). (D) SDTC changes before and after individual IVIG infusions longitudinally over 22 months in a single patient. Fig. 6B–D from Lin et al. (2011); reproduced with permission from the publisher.