Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

Abstract

In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the “common cold”-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients’ sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a “forever necessary therapy” for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed.

Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies

“…In many controlled studies, the total IVIg dose was divided in 2 days; in practice, it is often divided in 3-5 days especially when given as home-infusion to ensure safety and better tolerance. In overweight patients, the idealbody weight is used to calculate the total dose, as described [92]. The duration of efficacy after each monthly IVIg infusion ranges from 4 to 5 weeks, and repeated infusions may be required in several patients with a preferred maintenance dose of 1 g/ kg.…”

“…To ensure the judicious use of IVIg, we advise the patients from the outset that after the first 3 monthly infusions, if there is an objective benefit, we will continue with periodically performing dependency tests by reducing the IVIg dose or prolonging the infusion intervals to objectively assess regression in severity of spasms and stiffness, as recently highlighted [92]. Unfortunately, sometimes IVIg is being used just to reduce pain and improve fatigue or other subjective symptoms; a conditioning effect is also prevalent, as recently highlighted [92], with patients requesting therapy continuation out of fear they may worsen if it is stopped. IVIg still, however, remains the only immunomodulatory therapy with proven benefit in SPS patients, but there is a need to determine long-term benefits beyond the originally tested 3-month period [26].…”

“…We are currently in the process of assessing long-term benefits over a 10-year period. Subcutaneous immunoglobulin may be also an option in patients with poor venous access or when there is a demonstrable early wearing-off effect to ensure sustained benefit [92,93]. b) Rituximab.…”

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

“…IVIg, derived from thousand donors, contains anti-idiotypic IgG1 antibodies forming dimers connected between their F(αβ ′ ) 2 domains (see B in Fig. 1) that bind and neutralize the patients' pathogenic autoantibodies [38][39][40][41][42]. This effect has been shown in demyelinating neuropathies with anti-GM1 or other anti-glycolipid antibodies [43,44] where the IgG1 idiotypes within the IVIg inhibit or neutralize the blocking impulse propagation signals exerted by these patients' sera, resulting in quick clinical benefits [1,[43][44][45].…”

“…iii) Upregulation of the inhibitory FcγRIIB receptors. IgG molecules bind through their Fc region to various FcγR on monocytes, macrophages, dendritic cells, and B cells and exert either activating signaling via the FcγRIA, FcγRIIA, and FcγRIIIA or inhibitory signals via the FcγRIIB, mediating inflammatory and immune effector functions including cellular activation and cytokine production [38][39][40][48][49][50][51]. IVIg selectively upregulates the inhibitory FcγRIIB and inhibits phagocytosis and cytokine production intercepting antibody-dependent cell-mediated cytotoxicity [38][39][40][41][42].…”