Optimizing IgG therapy in chronic autoimmune neuropathies: A hypothesis driven approach

Abstract

Prolonged intravenous immunoglobulin (IVIG) therapy is used for the chronic autoimmune neuropathies chronic idiopathic demyelinating polyneuropathy and multifocal motor neuropathy, but the doses and treatment intervals are usually chosen empirically due to a paucity of data from dose–response studies. Recent studies of the electrophysiology and immunology of these diseases suggest that antibody-induced reversible dysfunction of nodes of Ranvier may play a role in conduction block and disability which responds to immunotherapy more rapidly than would be expected for demyelination or axonal damage per se. Clinical reports suggest that in some cases, the effects of each dose of IVIG may be transient, wearing-off before the next dose is due. These observations lead us to hypothesize that that therapeutic IgG acts by competing with pathologic autoantibodies and that individual patients may require different IgG levels for optimal therapeutic effects. Frequent IVIG dosing and weekly subcutaneous IgG have been tried as ways of continuously maintaining high serum IgG levels, resulting in stabilization of neuromuscular function in small case series. Frequent grip strength and disability measurements, performed by the patient at home and reported electronically, can be used to assess the extent and duration of responses to IgG doses. Individualization of IgG treatment regimens may optimize efficacy, minimize disability, and identify nonresponders. Muscle Nerve 51: 315–326, 2015

Efficacy of Intravenous Immunoglobulin in Neurological Diseases

“…With weekly SCIG, only a few days elapse between the peak serum level from 1 intravenous dose and administration of the next subcutaneous dose; this clearly obviates the low Btrough^serum IgG levels experienced 3-4 weeks after a large bolus of IVIG [100]. Of interest, pooled data have shown that serum IgG levels are higher by 10-20 % (mean 13 %) with weekly SCIG compared with monthly IVIG [96]. After 6-12 weekly infusions, SCIG results in near steady-state IgG levels, with peak trough differences only about 5 % of the overall mean.…”

“…The infused IVIG is distributed in the extracellular space, which is about double the intravascular space [96]; it is then catabolized slowly compared with other plasma proteins via FcRn, which recycles IgG and protects it from lysosomal degradation [97]. As a result, the half-life of IgG is maintained at approximately 21 days, and repeated infusions are needed after 1 month.…”

“…The saturation of the FcRn with high concentrations of normal IgG from the infused exogenous IVIG keeps the endogenous pathologic IgG from this pathway and increases its degradation [98]. In contrast, SCIG is first transported through the lymphatic systems and enters the bloodstream via the thoracic duct, with equilibration of IgG derived from SCIG into the intravascular space requiring up to 72 h [96]. The peak serum IgG concentration achieved with SCIG is, on average, 61 % of the peak achieved with intravenous infusions of the same dose [99].…”

Subcutaneous immunoglobulins in the treatment of chronic immune-mediated neuropathies

“…They suggest subcutaneous IgG as a tool for continuously maintaining high serum IgG levels, resulting in clinical stabilization [Berger and Allen, 2015].…”

Considerations for dosing immunoglobulin in obese patients

“…Optimum dosing of immunoglobulin remains a hotly debated topic in general for both replacement and autoimmune indications , so tackling this topic in a subset of patients who are not well represented in research is challenging. Zuckerman et al .…”