By Mary L. Vo, MD, PharmD
Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: Nearly 25% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) have a poor response to intravenous immunoglobulin treatment. Variations in the PRF1 and FCGR2B genes in CIDP patients offer insights into the heterogenous treatment response.
SOURCE: Kuitwaard K, van Doorn PA, Bengrine T, et al. Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2021;28:1677-1683.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy resulting in progressive weakness, sensory loss, and gait instability evolving over at least eight weeks. In the absence of a biomarker, diagnosis relies on clinical evaluation with confirmation of unequivocal demyelination on electrodiagnostic studies. Intravenous immunoglobulin (IVIg) is preferred over other treatments because of its rapid onset, accessibility, and favorable side effect profile. However, unpredictable treatment responses pose a significant clinical challenge, since one-quarter of CIDP patients either have a suboptimal response or are refractory to immunosuppressive treatment altogether.
Poor clinical response to IVIg may be the result of misdiagnosis, severe axonal loss, and disease course. Diagnostic pitfalls contribute to observations that nearly 40% patients diagnosed initially with CIDP had an alternate cause of their neuropathy.1 The presence of severe axonal loss and the relapsing remitting course of CIDP can further complicate assessment of treatment response.
Moreover, pharmacodynamic and pharmacogenetic features may influence IVIg efficacy and account for differences in treatment response between patients. The mechanism of IVIg in CIDP is unknown, although studies suggest the predominant mechanisms include neutralizing pathogenic autoantibodies, inhibiting complement binding, and directly enhancing remyelination.2 Recent studies have identified potential molecular biomarkers involved in FcγRIIb receptor modulation and axonal injury that may affect IVIg responsiveness in CIDP patients.3
The authors conducted a retrospective genetic association analysis focusing on six candidate genes previously associated with IVIg responsiveness in CIDP patients. Blood samples were taken from 172 patients with CIDP treated at Erasmus MC University Medical Centre in Rotterdam, Netherlands, between 1980 and 2018. Patients met clinical criteria for CIDP defined by the European Federation of Peripheral Neuropathies/Peripheral Nerve Society (EFNS/PNS) and were treated with at least one course of IVIg (2 g/kg). Treatment response was defined as > one-point improvement in the Modified Rankin Scale determined by a neuromuscular specialist.
Genetic variations in GJB1, CNTN2, PRF1, SH2D2A, FCGRT, and FCGR2B were analyzed. Chi-squared tests and Fisher exact tests were used to compare IVIg response among patients with different genotypes. A two-tailed P value < 0.05 was deemed significant. A multivariate logistic regression model was used to assess IVIg responsiveness.
Overall, 79% of the 172 CIDP subjects responded to IVIg. There were no significant differences in age, gender, or acute onset CIDP between the responder and non-responder groups. Genetic association studies for all six candidate genes were determined in 163 patients. Multivariate analysis showed that the PRF1 p.Ala91Val variant was negatively associated with IVIg response (odds ratio [OR] = 0.57) and FCGR2B promoter 2B.4/2B.1 was positively associated with IVIg response (OR = 2.56). PRF1 encodes for perforin, an essential component for the function of cytotoxic T-cells and NK-T cells. The PRF1 p.Ala91Val variant causes a reduction in cytotoxic perforin activity. Patients harboring the p.Ala91Val variant of the PRF1 gene were more likely to have a poor response to IVIg. PRF1 variants are more prevalent in CIDP patients with axonal damage, a feature that predicts poor IVIg response.
CIDP patients with the 2B.4/2B.1 promoter genotype for FCGR2B were more likely to respond to IVIg. FCGR2B encodes for the FcγRIIb receptor expressed by monocytes, macrophages, dendritic cells, and B-cells. It has been suggested that the 2B.4 variant induces FcγRIIb receptor expression and may facilitate IVIg response by reducing cell activation, proliferation, and cytokine production. Variations in CNTN2, FCGRT, and SH2D2A were not associated with IVIg response. No disease-associated changes were observed in the GJB1 gene.
This genetic association study is among the first to explore pharmacogenetic relationships affecting IVIG response in CIDP. PRF1 and FCGR2B variants can influence IVIg responsiveness by identifying patients with axonal injury who would be less amenable to treatment and also offers insights into the predominant mechanisms influencing IVIg activity in CIDP.
COMMENTARY
The identification of molecular biomarkers influencing axonal injury and IVIg response sheds light on the complex pharmacogenetic mechanisms affecting IVIg response. Innovations in pharmacogenetic analysis to predict IVIg response would allow individualized treatment approaches early in the disease course and optimize clinical outcomes. Further prospective study is needed to corroborate these findings and elucidate the immunoregulatory mechanisms of IVIg.
REFERENCES
- Broers MC, Bunschoten C, Drenthen J, et al. Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2021;28:2065-2073.
- Khoo A, Frasca J, Schultz D. Measuring disease activity and predicting response to intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy. Biomark Res 2019; Feb 12. doi: 10.1186/s40364-019-0154-2. [eCollection 2019].
- Dalakas MC. Potential biomarkers for monitoring therapeutic response in patients with CIDP. J Peripher Nerv Syst 2011;16(Suppl1):63-67.
