No evidence of abnormal metabolic or inflammatory activity in the brains of patients with rheumatoid arthritis: results from a preliminary study using whole-brain magnetic resonance spectroscopic imaging (MRSI)

Altamish Daredia,Thomas S Denney,Christina Mueller,Joanne C Lin,Ronald Beyers,Jarred W Younger,Halle H Thannickal

doi:10.1007/s10067-019-04923-5

Abstract

Introduction/objectivesMany individuals with rheumatoid arthritis (RA) report persistent fatigue even after management of peripheral disease activity. This study used whole-brain magnetic resonance spectroscopic imaging (MRSI) to investigate whether abnormal inflammatory activity in the central nervous system may be associated with such symptoms. We hypothesized that RA patients would show higher brain choline (CHO), myo-inositol (MI), and lactate (LAC), and higher brain temperature than healthy controls. We further hypothesized that the metabolite levels would be positively correlated with self-reported fatigue.MethodThirteen women with RA provided fatigue severity ratings and underwent whole-brain MRSI and a joint examination. Thirteen healthy controls (HC) provided comparison imaging and fatigue data. CHO, MI, LAC, and brain temperature in 47 brain regions were contrasted between groups using independent-samples t tests. Significant differences were determined using a false discovery rate (FDR)-adjusted p value threshold of ≤ 0.0023. Secondary analyses obtained correlations between imaging and clinical outcomes in the RA group.ResultsNo brain metabolic differences were identified between the groups. In the RA group, fatigue severity was positively correlated with CHO in several brain regions—most strongly the right frontal lobe (rs = 0.823, p < 0.001). MI was similarly correlated with fatigue, particularly in the right calcarine fissure (rs = 0.829, p < 0.001). CHO in several regions was positively correlated with joint swelling and tenderness.ConclusionsWe conclude that abnormal brain metabolites are not a common feature of RA, but may been seen in patients with persistent fatigue or disease activity after conventional treatment.Key Points• Whole-brain magnetic resonance spectroscopy revealed no metabolic abnormalities in the brain in patients with rheumatoid arthritis.• Brain choline levels were correlated with fatigue severity reported by RA patients and with peripheral joint swelling and tenderness.• Brain myo-inositol levels were similarly correlated with fatigue severity in RA patients.

Highlights

Rheumatoid arthritis (RA) is a peripheral autoimmune inflammatory disorder affecting the joints. It is characterized by synovial inflammation leading to joint damage, production of peripheral inflammatory cytokines such as tumor necrosis factor α (TNF-α), and chronic immune system activation [1, 2]
It is possible that the ongoing fatigue in RA is due to inflammatory activity in the brain that cannot be addressed by conventional RA medications not designed to cross the blood-brain barrier (BBB)
This pro-inflammatory activity in the brain can manifest behaviorally as fatigue, cognitive problems, and mood abnormalities [12]. Supporting this idea, Bodnar and colleagues demonstrated that inducing synovial inflammation in an animal model of RA is followed by increases in pro-inflammatory cytokine levels in the brain [13]

Summary

Introduction

Rheumatoid arthritis (RA) is a peripheral autoimmune inflammatory disorder affecting the joints. High levels of several peripheral pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, and TNF-α, are present in the blood of RA patients [5,6,7] These cytokines may enter the brain via a compromised BBB and activate microglia [8,9,10]. Microglia increase the production of the same pro-inflammatory factors (e.g., IL1, IL-6, and TNF-α) as those seen in systemic circulation [11] When active chronically, this pro-inflammatory activity in the brain can manifest behaviorally as fatigue, cognitive problems, and mood abnormalities [12]. This pro-inflammatory activity in the brain can manifest behaviorally as fatigue, cognitive problems, and mood abnormalities [12] Supporting this idea, Bodnar and colleagues demonstrated that inducing synovial inflammation in an animal model of RA is followed by increases in pro-inflammatory cytokine levels in the brain [13]

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