Cholinergic Anti-Inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis

Richard S Goldstein,Peter K Gregersen,Nirav B Patel,Annette Bruchfeld,Sangeeta Chavan,Abdul R Qureshi,Lihong Yang,Mauricio Rosas-Ballina,Margot Gallowitsch-Puerta,Brett J Huston,Kevin J Tracey,Andrew E Sama,Christopher J Czura,Richard P Sloan

doi:10.2119/2006-00108.goldstein

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.

Highlights

Rheumatoid arthritis (RA), a chronic autoimmune destructive polyarthropathy, has a worldwide prevalence of 0.5-1%, and an incidence of three cases per 10,000 persons annually [1,2,3]
High mobility group box-1 (HMGB1) levels were significantly increased in RA patients as compared with the healthy control group
We observed that the absolute value of HF power was significantly lower in RA patients as compared with controls (38 msec2 [14-80] vs. 288 [38-364], P < 0.0001) indicating that vagus nerve activity is decreased in RA (Figure 2a). rMSSD, another parameter to measure vagus nerve activity, was attenuated in RA subjects as compared with healthy volunteers (20.9 ± 9.79 msec vs. 52.6 ± 35.3 msec, P < 0.01)

Summary

Introduction

Rheumatoid arthritis (RA), a chronic autoimmune destructive polyarthropathy, has a worldwide prevalence of 0.5-1%, and an incidence of three cases per 10,000 persons annually [1,2,3]. Affected individuals have significantly diminished quality of life and a three to ten year decrease in life expectancy [4]. Over-expression of cytokines mediates tissue injury and drugs that decrease the activity of TNF or IL-1 have improved the lives of RA patients significantly. High mobility group box-1 (HMGB1), a recently identified proinflammatory cytokine, has been implicated in the pathogenesis of arthritis [510]. HMGB1 expression is increased in the synovium of patients with RA and in experimental animal models of collagen and adjuvant-induced arthritis [6]. AntiHMGB1 antibodies confer significant protection against the development of experimental arthritis in animals, but little is known about mechanisms that regulate HMGB1 release in this disease [5,6,7]

Methods

Results

Conclusion