β-endorphin and opioid growth factor as biomarkers of physical ability in multiple sclerosis

Highlights

• OGF levels are elevated in MS patients receiving DMTs.

• OGF levels correlate with serum IL-17A and TNF-α levels.

• Elevated vitamin D levels correlate with improve 25-ft walking tests.

• β-endorphin correlates with better MS-QoL physical composite and social function.

Abstract

Background

Multiple sclerosis (MS) is an autoimmune-mediated degenerative disorder with increased peripheral inflammation disrupting the blood brain barrier. With increasing MS-related healthcare costs, the requirement to validate minimally invasive biomarkers has become imperative.

Methods

Relapsing-remitting MS patients on disease modifying therapies were consented at the Penn State Health MS Clinic to provide blood samples for analyses of serum cytokines and endogenous opioid peptides, as well as to complete the MSQOL-54 survey.

Results

Serum OGF levels in MS patients on glatiramer acetate (mean = 326 pg/ml), dimethyl fumarate (mean = 193.3 pg/ml) and natalizumab (mean = 393.4 pg/ml) were significantly elevated (p < 0.01) compared to healthy controls (mean = 98.46 pg/ml). Individuals with elevated OGF levels also had increased levels of TNFα (r = 0.78) and IL-17A (r = 0.81). Only patients treated with glatiramer acetate had significant (p < 0.01) elevations in serum β-endorphin levels. Analyses of MS-QoL 54 data showed no significant differences in physical or mental composite scores between treatment groups. However, serum levels of β-endorphin had a direct correlation with physical health composite score (r = 0.70) in all treatments. Serum vitamin D levels had an indirect relationship with 25-foot walk test times (r = 0.47).

Conclusion

Both regression and cohort data suggest that serum levels of OGF, β-endorphin, and vitamin D are potential biomarkers for physical disease status in MS.

Introduction

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by periventricular and juxtacortical lesions and white matter demyelinating plaques. Traditionally, MS has been diagnosed in combination with magnetic resonance imaging (MRI) and self-reported symptomatology by patients (Garg and Smith, 2015; McDonald et al., 2001; McNicholas et al., 2018). To establish a diagnosis of MS, individuals must meet criteria for dissemination in space and time through MRI evidence of CNS lesions, self-reported attacks, or cerebral spinal fluid (CSF) oligoclonal bands (OCB) (Aktas et al., 2018; Dobson and Giovannoni, 2019; McNicholas et al., 2018). With the 2017 updates to the McDonald criteria, the utility of oligoclonal bands within the CSF has been reintroduced to solidify dissemination in time (Dobson and Giovannoni, 2019; McNicholas et al., 2018). The prevalence of MS trends upwards in most countries with North American and Europe having the highest prevalence at 140 and 108 per 100,000 people respectively (Belbasis et al., 2015; Eskandarieh et al., 2016). Recently, regions with historically limited cases such as Hong Kong and Iran also have seen a rise towards 0.77 and 85.8 per 100,000 people respectively (Belbasis et al., 2015; Eskandarieh et al., 2016). With increasing prevalence, the emphasis of early diagnosis and treatment has become more important in order to reduce longitudinal disease burden (Axisa and Hafler, 2016; Oh et al., 2018).

Even though OCBs are important to establish a diagnosis of MS, they have limited utility in monitoring progression of disease within serum or CSF (Axisa and Hafler, 2016; Ziemssen et al., 2019). Similar issues have been seen with traditional T2 and FLAIR MRIs. Imaging is often performed only when relapses are suspected to visualize acute changes in the brain and spinal cord. However, traditional imaging does very little in determining the underlying pathology and extent of damage, particularly in normal appearing white matter (Laura et al., 2018; Petracca et al., 2018). To combat these uncertainties, recent studies have focused on deciphering genetic, environmental, and inflammatory contributors to disease progression (Axisa and Hafler, 2016; Baecher-Allan et al., 2018; Bashinskaya et al., 2015; Dendrou et al., 2015; Hollenbach and Oksenberg, 2015; Ziemssen et al., 2019). The role of peripheral inflammation has emerged as a main focus for treatment with strong correlations to HLA class II allele defects and the role of peripheral T and B lymphocytes (Axisa and Hafler, 2016; Baecher-Allan et al., 2018; Dendrou et al., 2015). Current theories suggest CNS-specific antigen autoactivation of peripheral CD4⁺cells propagating T-helper cell differentiation and further cytokine release (Baecher-Allan et al., 2018; Dendrou et al., 2015). As a result, blood brain barrier integrity is compromised, allowing migration of T cells, B cells, monocytes, and macrophages into the CNS. This migration leads to parenchymal inflammation, axonal injury, demyelination, and cerebral atrophy (Baecher-Allan et al., 2018; Lucchinetti et al., 2011).

In response to the growing literature on peripheral inflammation, several potential biomarkers have emerged (Axisa and Hafler, 2016; Ludwig et al., 2017a; Patel et al., 2020; Pul et al., 2019; Ziemssen et al., 2019). Opioid growth factor (OGF), chemically termed [Met⁵]-enkephalin is reduced in MS patients and experimental autoimmune encephalomyelitis (EAE) mice when compared to healthy controls (Ludwig et al., 2017a, 2017b; Patel et al., 2020). OGF is an inhibitory endogenous opioid which binds to the opioid growth factor receptor (OGFr), a non-classical opioid receptor. The receptor is localized to the nuclear envelope and binding to OGF leads to internalization of the receptor and modulation of the cell cycle. OGF-OGFr interaction leads to activation of cyclin dependent inhibitory kinases and delaying the G₁/S phase of the cell cycle. Previous work with the animal model of MS, experimental autoimmune encephalomyelitis (EAE), investigated OGF as a potential biomarker (Hammer et al., 2013; McLaughlin et al., 2015; Zagon et al., 2010) and reported that OGF serum levels declined following administration of myelin oligodendrocytic glycoprotein (MOG).  Moreover, administration of OGF to mice with EAE have reduced peripheral immune responses and less clinical pathology. Furthermore, another endogenous opioid peptide, β-endorphin, has been shown to be decreased in autoimmune disorders. The current study evaluates serum biomarkers of MS patients in correlation with the MS-quality of life (MS-QoL) survey to determine the role of OGF as a biomarker of disease status.