Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis

Abstract

High Mobility Group Box-1 (HMGB1) is a cytokine implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. The cholinergic anti-inflammatory pathway, a vagus nerve-dependent mechanism, inhibits HMGB1 release in experimental disease models. Here, we examine the relationship between vagus nerve activity and HMGB1 in patients with RA. We compared RR interval variability, an index of cardiac vagal modulation, HMGB1 and hsCRP serum levels, and disease activity scores in thirteen RA patients and eleven age- and sex-matched controls. In RA patients, serum levels of HMGB1 and hsCRP were elevated as compared with controls (HMGB1=71 ng/mL [45-99] vs. 18 ng/mL [0-40], P<0.0001; hsCRP=14.5 mg/L [0.7-59] vs. 1 mg/L [0.4-2.9], P<0.001). RR interval variability in RA patients was significantly decreased as compared with controls (HF=38 msec2 [14-80] vs. 288 msec2 [38-364], P<0.0001; rMSSD=20.9+/-9.79 msec, 52.6+/-35.3 msec, P<0.01). HMGB1 levels and RR interval variability were significantly related (rho=-0.49, P<0.01). HMGB1 serum levels significantly correlated with disease activity scores (DAS-28) in patients with RA (P=0.004). The study design does not enable a determination of causality, but the results are consistent with the hypothesis that decreased cholinergic anti-inflammatory pathway activity is associated with increased HMGB1 levels in patients with RA.

Figures

Figure 1

Detection of HMGB1 in patients with Rheumatoid Arthritis. Rheumatoid arthritis serum HMGB1 = 71 ng/mL (45–99), control serum HMGB1 = 18 ng/mL (0–40); P < 0.0001.

Figure 2

A) Decreased vagus nerve activity in Rheumatoid Arthritis patients. HF power, a measurement of vagus nerve activity, was measured in patients with RA and healthy control subjects. RA patients had significantly decreased vagus nerve activity as compared with control subjects (RA; HF = 38 msec2 [14–80], controls; HF = 288 msec2 [38–364], P < 0.0001); B) Elevated heart rate in Rheumatoid Arthritis patients. Heart rates were measured from electrocardiograms in RA patients and control subjects (RA; Heart Rate = 77 beats/min [60–115], Controls; Heart Rate = 68 beats/min [44–83], P = 0.09); C) Elevated respiratory rates in Rheumatoid Arthritis patients. Respiratory rates were measured using an abdominal sensor. RA patients; Respiratory Rate = 15 breaths/min (–17), controls; Respiratory Rate = 12 breaths/min (–15), (P < 0.001).

Figure 3

A) Disease activity and vagus nerve activity. Disease activity was measured using DAS-28. Note that disease activity is independent of HF power. Kruskal-Wallis ANOVA = 16.72, P = 0.0008; B) Relationship between HMGB1 serum levels and disease activity. HMGB1 serum levels were compared with disease activity scores (DAS-28). Below 3.2 represents low activity, a score of 3.2–5.1 represents intermediate activity, and > 5.1 represents high disease activity. Kruskal-Wallis ANOVA = 13.14 P = 0.004.