Gene Variation Linked to Immunotherapy Response

Patients with myasthenia gravis (MG) who have one copy of an FCGRT gene variant have lower levels of circulating antibodies called immunoglobulin G (IgG) and are more likely to be resistant to intravenous immunoglobulin (IVIg) treatment, a small study found.

The results suggest that both the gene variant and the lower levels of antibodies may be predictive markers for poor responses to IVIG in people with MG, investigators said.

The study, “VNTR2/VNTR3 genotype in the FCGRT gene is associated with reduced effectiveness of intravenous immunoglobulin in patients with myasthenia gravis,” was published in the journal Therapeutic Advances in Neurological Disorders. 

In about 10–20% of MG cases, exacerbations characterized by extreme weakness in the respiratory, throat, and mouth muscles may develop over a short period of time. If untreated, the exacerbation, which may be triggered by infection, stress, or lack of medication, will progress rapidly to life-threatening myasthenic crisis requiring the use of a ventilator.

IVIg is used to treat myasthenic crisis in patients experiencing rapid disease exacerbations. However, many patients are unresponsive to the therapy. The identification of MG patients who are resistant to IVIg will help ensure they receive appropriate and timely treatment, particularly during an impending myasthenic crisis.

The neonatal Fc receptor (FcRn) prevents the degradation of IgG, thereby extending the time that immunoglobulin treatments remain in the body. A polymorphism or variation called VNTR in the FCGRT gene that provides instructions to make FcRn is associated with the effectiveness of immunoglobulin treatments.

VNTR2 and VNTR3 are the most common of these variations, and individuals with one copy of each (VNTR2/3, meaning two or three repeats) have decreased FcRn levels and reduced responsiveness to IVIg treatment compared to patients with two copies of VNTR3 (VNTR3/3).

Here, researchers in China investigated whether the presence of VNTR2/3 would similarly affect MG patient response to IVIg treatment. Patient records or follow-up phone calls were used to assess treatment outcomes.

Of the 334 adult MG patients included in the study, 11 (3.3%) had the VNTR2/3 combination while 323 (96.7%) had VNTR3 in both gene copies. At baseline, 26 patients (15 with VNTR3/3 and 11 with VNTR2/3) were evaluated for IgG levels. These were significantly higher in VNTR3/3 patients than in those with VNTR2/3 (12.41 g/L vs. 9.81 g/L).

A total of 61 patients received IVIg therapy and 48 (78.7%) responded to the treatment. All of the responders and nine of the IVIg-resistant patients were VNTR3/3. The remaining four IVIg-resistant patients were VNTR2/3. Notably, none of the IVIg responders had VNTR2 in one copy and VNRT3 in the other.

Among the 12 IVIg responders (all with VNTR3/3) and five IVIg-resistant patients (four with VNTR2/3 and one with VNTR3/3) who had not received prior immunotherapy, IgG levels were higher in responders (12.93 g/L vs. 8.85 g/L) compared to IVIg-resistant patients. Also, IgG levels were significantly lower in IVIg-resistant patients with VNTR2/3 (7.86 g/L) than in responders with VNTR3/3 (12.93 g/L).

“To our knowledge, this is the first study investigating the association between the VNTR polymorphism and the efficacy of IVIG therapy in MG patients,” the research team wrote, adding that “a well-designed prospective study is needed to further investigate the relationship between VNTR genotypes and IVIG efficacy.” 

According to the scientists, the study was limited by the small sample size, the inability to obtain complete IgG data for comparison or to track disease-causing autoantibodies levels before and after treatment, and the lack of analysis of FcRn function based on FCGRT variant and of objective evaluation of IVIg outcomes.