VNTR2/VNTR3 genotype in the <i>FCGRT</i> gene is associated with reduced effectiveness of intravenous immunoglobulin in patients with myasthenia gravis

Su, Shengyao; Liu, Qing; Zhang, Xueping; Wen, Xinmei; Lei, Lin; Shen, Faxiu; Fan, Zhirong; Duo, Jianying; Lü, Yan; Di, Li; Wang, Min; Chen, Hai; Zhu, Wenjia; Xu, Min; Wang, Suobin; Da, Yang

doi:10.1177/1756286420986747

Cited by 17 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a limited retrospective analysis however, no relation was found between VNTR3/3 polymorphism and outcome [145]; similar non-significant correlations were also noted in 23 patients with multifocal motor neuropathy [37]. In a recent large study in 334 patients with MG treated with IVIg, the patients with VNTR2/3 genotype had significantly shorter retention of the infused IVIg due to faster IgG catabolism, lesser degree of AChR antibody reduction, and poor response to IVIg compared to VNTR3/3 homozygous patients [43], suggesting that polymorphisms do matter in IVIg efficacy in certain patients by affecting the level and sustainability of the infused IgG (Fig. 3C).…”

Section: Genetic Factors Affecting Ivig Efficacy and Dosing: Fcrn Polymorphisms And Fcγriib Genotypesmentioning

confidence: 82%

“…Because high FcRn expression protects the infused IVIg from degradation, VNTR polymorphisms may affect IVIg efficacy by influencing the sustainability and increased serum IgG level of the infused IVIg. As discussed later, these polymorphisms do matter in certain individuals; VNTR2/3 heterozygous patients with Myasthenia Gravis treated with IVIg had shorter duration of infused IVIg due to fast IgG catabolism, lesser degree of AChR antibody reduction and poor response to IVIg, compared to VNTR3/3 homozygous patients [43] (Fig. 3C).…”

Section: Acceleration Of Igg Catabolism By Saturating the Fcrn Transport Receptors: An Overlooked Factor Individuallymentioning

confidence: 88%

See 1 more Smart Citation

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

Dalakas

2021

Neurotherapeutics

View full text Add to dashboard Cite

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.

show abstract

Section: Genetic Factors Affecting Ivig Efficacy and Dosing: Fcrn Polymorphisms And Fcγriib Genotypesmentioning

confidence: 82%

Section: Acceleration Of Igg Catabolism By Saturating the Fcrn Transport Receptors: An Overlooked Factor Individuallymentioning

confidence: 88%

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

Dalakas

2021

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…In this issue of the journal, Su et al 6 explored whether VNTR3/3 and VNTR2/3 genotypes affected the efficacy of IVIg in 334 patients with myasthenia gravis (MG). They found that those with the VNTR2/3 genotype had significantly lower endogenous IgG levels and poor response to IVIg compared to patients with VNTR3/3 homozygosity.…”

Section: Vntr Polymorphisms and Their Relation To Efficacy Of Ivigmentioning

confidence: 99%

“…It will also be of interest to examine whether efgartigimod as used in MG patients, 23 has a greater reduction in AChR antibody titers and better efficacy in VNTR3 homozygous patients, especially compared to IVIg. 6…”

Section: Effect Of Vntr Polymorphisms On Efficacy Of Therapeutic Mono...mentioning

confidence: 99%

“…Although this concept dates back to more than 50 years ago, 5 it is now gaining major attention. Stimulated by the contribution of Su et al 6 in this issue of Therapeutic Advances in Neurological Disorders , this timely mini-review intends to highlight the role of FcRn in IgG homeostasis, the influence of FcRn genotypes on the efficacy of IVIg and monoclonal antibodies in neurological diseases, and the emerging role of the new neuro-immunotherapeutics that inhibit the capacity of FcRn to affect IgG autoantibodies.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors

Dalakas

Spaeth

2021

Ther Adv Neurol Disord

View full text Add to dashboard Cite

The neonatal Fc receptor (FcRn) binds endogenous IgG and protects it from lysosomal degradation by transporting it back to the cell surface to re-enter the circulation, extending the serum IgG life span. FcRn plays a role in the function of IVIg because the supraphysiological IgG levels derived from IVIg administrations saturate the FcRn allowing the endogenous IgG to be degraded, instead of being recycled, resulting in high levels of infused IgG ensuring IVIg efficiency. New data in myasthenia gravis patients suggest that the that the Variable Number of Tandem 3/2 (VNTR3/2) polymorphisms in FCGRT, the gene that encodes FcRn, may affect the duration of infused IgG in the circulation and IVIg effectiveness. This review addresses these implications in the context of whether the FCGRT genotype, by affecting the half-life of IVIg, may also play a role in up to 30% of patients with autoimmune neurological diseases, such as Guillain–Barré syndrome, CIDP or Multifocal Motor Neuropathy, who did not respond to IVIg in controlled trials. The concern is of practical significance because in such patient subsets super-high IVIg doses may be needed to achieve high IgG levels and ensure efficacy. Whether FCGRT polymorphisms affect the efficacy of other therapeutic monoclonal antibodies by influencing their distribution clearance and pharmacokinetics, explaining their variable effectiveness, is also addressed. Finally, the very promising effect of monoclonal antibodies that inhibit FcRn, such as efgartigimod, rozanolixizumab and nipocalimab, in treating antibody-mediated neurological diseases is discussed along with their efficacy in the IgG4 subclass of pathogenic antibodies and their role in the blood–brain barrier endothelium, that abundantly expresses FcRn.

show abstract

Neonatal Fc Receptor–Targeted Therapies in Neurology

et al. 2022

View full text Add to dashboard Cite

Autoantibodies are increasingly recognized for their pathogenic potential in a growing number of neurological diseases. While myasthenia gravis represents the prototypic antibody (Ab)-mediated neurological disease, many more disorders characterized by Abs targeting neuronal or glial antigens have been identified over the past two decades. Depletion of humoral immune components including immunoglobulin G (IgG) through plasma exchange or immunoadsorption is a successful therapeutic strategy in most of these disease conditions. The neonatal Fc receptor (FcRn), primarily expressed by endothelial and myeloid cells, facilitates IgG recycling and extends the half-life of IgG molecules. FcRn blockade prevents binding of endogenous IgG to FcRn, which forces these antibodies into lysosomal degradation, leading to IgG depletion. Enhancing the degradation of endogenous IgG by FcRn-targeted therapies proved to be a powerful therapeutic approach in patients with generalized MG and is currently being tested in clinical trials for several other neurological diseases including autoimmune encephalopathies, neuromyelitis optica spectrum disorders, and inflammatory neuropathies. This review illustrates mechanisms of FcRn-targeted therapies and appraises their potential to treat neurological diseases.

show abstract

VNTR2/VNTR3 genotype in the FCGRT gene is associated with reduced effectiveness of intravenous immunoglobulin in patients with myasthenia gravis

Cited by 17 publications

References 51 publications

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

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

The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors

Neonatal Fc Receptor–Targeted Therapies in Neurology

Contact Info

Product

Resources

About