Rheumatoid arthritis (RA) is an autoimmune condition characterized by chronic inflammation occurring locally within the synovial joints and systemically. Accumulating evidence supports an important role of the sympathetic nervous system in the pathophysiology of RA, both as a cause and consequence of inflammation. Acute sympathetic activation results in a shift from a T-helper (Th) 1 to Th2 response to direct the immune response towards the synovial joint thereby limiting systemic inflammation. In contrast, chronic sympathetic activation is pro-inflammatory and has widespread deleterious consequences, which likely contribute to the increased mortality and cardiovascular risk seen in RA. The advent of biologic agents has improved understanding of the pathophysiology of RA, and the complex autonomic nervous system (ANS) interactions. Further work is required to determine whether interventions that target the ANS in RA patients can help ameliorate the deleterious consequences of chronic sympathetic activity, help control inflammation and consequently improve morbidity and mortality.
Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by joint pain, stiffness and swelling. The term rheumatoid is derived from the latin ‘rheuma’ meaning ‘to flow’ and reflects the fleeting pattern of arthritis. Sufferers of RA are typically in one of two states; remission or flare. While it has been long recognized that RA is an autoimmune condition the precise pathophysiology is yet to be fully understood.
There is however accumulating evidence that the autonomic nervous system (ANS) plays an important role in the pathophysiology of RA. Furthermore, a bidirectional relationship exists between the ANS and inflammation. Earlier studies demonstrated ANS dysfunction in patients with RA by way of autonomic neuropathy symptoms and impaired sympathetic/parasympathetic cardiovascular reflexes. However more recent studies have identified the main patterns of ANS dysfunction in RA patients to include reduced parasympathetic activity (as evidenced by low heart rate variability), increased sympathetic activity and reduced baroreflex sensitivity. This pattern of ANS dysfunction may help explain the increased cardiovascular risk seen in patients with RA. The present article will focus on the evidence base for sympathetic nerve dysfunction in RA.
2. Immunological basis of RA
The early pathogenesis of RA is characterized by inflammation within the synovial joints as a result of co-activation of the adaptive and immune systems [1-4]. Complex interactions exist between various structures within the inflamed joint including fibroblasts, synoviocytes, chondrocytes, osteoclasts, macrophages, neutrophils, mast cells, plasma cells and T cells. The key cytokines involved in regulating inflammatory responses in RA include interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1, IL-17, interferon (IFN) and IL-10 . In RA patients, T-helper 1 (Th1) [2, 4] and Th17 cell activity  seems to predominate within the inflamed synovium. Activation of the immune system results in local and systemic inflammatory responses, which in turn activate the sympathetic nervous system. The deleterious effects of chronic system inflammation likely contribute to the increased cardiovascular risk seen in RA, and include: metabolic and endocrine dysfunction, cachexia, fatigue and ANS dysfunction including reduced parasympathetic activity, reduced baroreflex sensitivity and heightened sympathetic outflow (Figure 1).
Figure 1. Schematic figure demonstrating the relationship between inflammation and sympathetic activity in RA. Autoimmune-mediated synovial cell damage within the synovial joint(s) in RA initiates an inflammatory cascade involving local inflammation within the inflamed joint(s) as well as systemic inflammation. Inflammatory cytokines cause acute sympathetic activation which helps direct the immune response to increase Th2 responses (i.e. humoral) and local inflammation within the affected joint(s), whilst inhibiting Th1 responses (i.e. cellular immunity) and systemic inflammation. Chronic inflammation results in sympathetic activation, which further increases local and systemic inflammatory responses in a positive feedback cycle. A number of important modulators exist including the parasympathetic nervous system, pain, the hypothalamus-pituitary-adrenal (HPA) axis, baroreceptors and cardiopulmonary receptors, CNS (e.g. limbic, brainstem), kidneys, renin-angiotensin system, spleen and lymphoid organs. Chronic systemic inflammation has numerous deleterious consequences resulting in increased cardiovascular risk (i.e. heightened sympathetic activity, reduced parasympathetic activity, reduced baroreflex sensitivity, activation of the HPA-axis, cachexia and chronic fatigue). Note: *IL-10 is a major anti-inflammatory cytokine which helps regulate inflammatory responses. CNS central nervous system, HPA hypothalamic-pituitary-adrenal, IFN interferon, IL interleukin, RA rheumatoid arthritis, Th T helper, TNF tumour necrosis factor.
3. Sympathetic-immune interactions
3.1. Effect of inflammatory cytokines on sympathetic activity
Bi-directional links between sympathetic activity and inflammation have been identified. The intravenous administration of recombinant IL-1b has been shown to increase splenic, adrenal and renal sympathetic nerve activity in anaesthetized rats . Infusion of recombinant IL-1b in humans with malignant melanoma resulted in an increased heart rate, increased systolic blood pressure and reduced hand vein compliance . The authors demonstrated that the IL-1b induced vasoconstriction was sympathetically mediated as it was reversed with local administration of an a-antagonist. A number of animal studies have consistently shown that cytokines increase sympathetic activity [7-16]. Peripheral administration of TNF-α [13, 16] and IL-1β [5, 9, 10] and central administration of TNF-α [14, 17], IL-1β [8, 14, 15] and IL-6  have been shown to increase sympathetic activity.
These results suggest that circulating inflammatory cytokines in RA increase sympathetic nerve activity via centrally mediated mechanisms however, it is unclear how these effects are exerted particularly as pro-inflammatory cytokines are lipophobic and too large to pass the blood-brain barrier. A possible explanation is that circulating cytokines exert central effects via circumventricular organs (e.g. subfornical organ, area postrema, vascular organ of lamina terminalis, median eminence, pituitary neural lobe and the pineal gland) . This is supported by a study from Wei et al (2013) whereby intra-carotid administration of TNF-α and IL-1β resulted in diminished heart rate, mean blood pressure and renal sympathetic nerve responses in rats with subfornical organ lesions . Additionally, the authors demonstrated a high density of TNF-α and IL-1 receptors within the subfornical organ. Recent studies have demonstrated elevated concentrations of IL-1β within the cerebrospinal fluid of RA patients, raising the suspicion that cytokines may also enter the brain via the blood-cerebrospinal fluid barrier [19, 20].
3.2. Effect of sympathetic activity on the immune system
The presence of sympathetic nerves in immune organs (e.g. spleen, bone marrow) [21-23] and α- and β-adrenergic receptors on the surface of immune cells allows the potential for sympathetic nerve modulation of the immune system. Catecholamines have been shown to affect the release of cytokines from immune cells by increasing Th2 responses (i.e. humoral immunity) and inhibiting Th1 responses (i.e. cellular immunity). Catecholamines have been shown to specifically inhibit IL-1 [24, 25], IL-2 , IL-12 , IFN-γ [28, 29], TNF-α [28, 30-33]; and specifically increase the release of IL-10 [27, 32, 34-36], IL-6 [30, 37], transforming growth factor-β  and IL-8 [25, 39].
Acute sympathetic activation shifts immune responses from Th1 to Th2 activity, which may protect the host from the deleterious effects of systemic inflammation by limiting inflammatory responses to local and specific targets . This is further supported by an animal study of rats demonstrating that lipopolysaccharide-induced inflammatory responses, as measured by plasma TNF-α concentrations, were increased five-fold following splanchnic nerve dissection .
Chronic sympathetic activation, in contrast to acute sympathetic activation appears to have pro-inflammatory effects. Animal studies have shown that chronic β-adrenergic stimulation with isoproterenol (non-selective b-adrenergic agonist): increases plasma concentrations of IL-1β and IL-6; increases tissue IL-1β within the pituitary, hypothalamus and hippocampus ; and increases tissue IL-1β, IL-6 and TNF-α within the myocardium . In one human study of patients with chronic inflammatory bowel disease, sympathetic blockade with clonidine reduced muscle sympathetic nerve activity (MSNA) and reduced disease activity .
3.3. Sympathetic nerve dysfunction in RA
Early observations from a study of RA patients in the 1960s demonstrated autonomic dysfunction in approximately half of patients tested, as determined from abnormal sweat responses . A systematic literature review of 40 studies performed some 40 years later corroborated these early findings with more than half of studies reporting sympathetic dysfunction; most studies demonstrated impaired sympathetic cardiovascular reflexes (blood pressure responses to orthostasis, hand grip, cold pressor test and mental stress) . Plasma catecholamines and biomarkers of sympathetic activity (neuropeptide-Y, chromogranin) have been shown to be increased in RA patients compared to controls although there are also studies showing no difference.
There is evidence from one study that sympathetic nerve dysfunction occurs early in the pathogenesis of RA . The authors assessed the pre-ejection period (a marker of sympathetic activity) which was found to be increased in patients with early RA (within 2 years of diagnosis), compared to matched healthy controls. In a more recent study MSNA (burst frequency) determined from direct peroneal nerve recordings, was found to be elevated in patients with RA compared to controls .
3.4. Inflammation and sympathetic nerve dysfunction in RA
Few studies in RA patients have formally assessed the relationship between inflammation and sympathetic dysfunction [45-47]. Dekkers et al demonstrated that higher sympathetic activity (pre-ejection period) was positively associated with higher disease activity (as assessed by erythrocyte sedimentation rate and Thompson joint score) . In a recent study MSNA was positively associated with inflammation, as assessed by high sensitivity C-reactive protein (hs-CRP), although this relationship appeared to be driven by heart rate .
Further, no significant relationship between MSNA and serum inflammatory cytokine concentrations (IL-6, TNF-α, IL-10) were found. Igari et al reported that 24 hour urinary adrenaline and noradrenaline concentrations were significantly reduced 2 weeks following synovectomy in 6 patients with RA , suggesting that heightened sympathetic activity was a consequence of inflammation within the joint. In a case study, parasympathetic reflexes were improved following 12 weeks of disease modifying anti-rheumatoid drugs, while sympathetic reflexes were unaffected . In a subsequent study including 25 RA patients and 25 controls, Syngle et al found a significant inverse relationship between serum TNF-α concentrations and blood pressure responses to standing .
3.5 Modulation of the sympathetic nervous system in RA
The sympathetic nervous system is complex and influenced by numerous systems including the parasympathetic nervous system, pain, hypothalamic-pituitary-adrenal (HPA) axis, central nervous system (e.g. limbic, brainstem), baroreflex, cardiopulmonary receptors, kidneys, renin-angiotensin system, the spleen and other lymphoid organs (Figure 1). A detailed review of these is outside the scope of the present article, however the influence of the parasympathetic nervous system, the HPA-axis and pain in RA patients is briefly discussed.
Parasympathetic nervous system
The cholinergic anti-inflammatory pathway as described by Tracey and colleagues refers to the presence of neural reflex circuits that can mediate an inflammatory response via nicotine acetylcholine (Ach) receptors [51-53]. In animal experiments, stimulation of Ach receptors either directly using vagal nerve stimulation or pharmacologically with cholinergic agonists attenuated the release of inflammatory cytokines (TNF, IL-1β, IL-6 and IL-18) and reduced local and systemic inflammatory responses [54-57]. The efferent arc of the reflex is thought to involve splenic sympathetic neurons, given the absence of vagal fibres within the spleen .
In RA patients, over three quarters of studies have demonstrated parasympathetic dysfunction including impaired cardiovascular reflexes and low heart rate variability . In a recent study, RA patients had reduced heart rate variability compared to controls which was independently inversely associated with inflammation (as measured by serum hs-CRP) . Koopman et al. provided the most direct evidence for a causal relationship between parasympathetic nerve dysfunction and inflammation in RA . Vagal nerve stimulation devices were implanted in 18 RA patients with active disease despite methotrexate therapy. Serum TNF was significantly reduced after 42 days of vagal nerve stimulation, and rose 14 days after switching the device off, and again reduced after a further 2 weeks of vagal nerve stimulation. The authors reported a similar pattern with disease activity (DAS28-CRP).
The HPA axis is activated during acute inflammation resulting in increased production and release of cortisol from the adrenal glands. Cortisol exerts anti-inflammatory effects  as well as metabolic effects to equip the host with glucose and energy. A negative feedback loop exists, to inhibit the release of corticotrophin releasing hormone and adrenocorticotrophin hormone from the hypothalamus and anterior pituitary gland, respectively. Endogenous as well as exogenous glucocorticoids up-regulate cardiac β1-adrenergic receptor sensitivity  thereby potentiating the effects of circulating adrenaline and noradrenaline. A few studies suggest that RA patients have higher mental and pain stress responses compared to controls, which were associated with higher serum inflammatory cytokines (IL-6, TNF-α) [63-66]. Abnormalities in the HPA axis have been identified in RA patients. Serum cortisol levels were lower in RA patients, compared to controls and were lowered further following epinephrine infusion .
Inflammation and pain are characteristic features of RA, with joint swelling and tenderness comprising key components of the disease activity score-28 . Chronic pain has been shown to increase sympathetic outflow in experimental models . Amongst RA patients and controls, self-reported pain was independently positively associated with MSNA burst frequency . Animal [69, 70] and human experiments  have shown that inflammatory cytokines have a direct role in modulation of pain perception. TNF-α inhibition acutely blocked both central nociceptive activity and activation of the limbic system in RA patients . In an animal model of chronic arthritis, TNF-α inhibition attenuated thermal and mechanical hyperalgesia via effects on the dorsal root ganglia . Expression of TNF receptor-1 was identified in the dorsal root ganglia following inflammation induction, whilst TNF receptor-2 was absent in dorsal root ganglia and present within macrophages and monocytes .
In a recent study, RA patients were found to have higher pain rating in response to the cold pressor test, compared to normotensive controls . Heart rate responses to the cold pressor test were independently associated with serum inflammatory cytokines (TNF-α and IL-10). Cannabinoid receptors have also been implicated in the modulation of arthritis disease. Peripheral norepinephrine release from sympathetic terminals in controlled by cannabinoid receptor type 1 (CB1) which in turn is activated by endocannabinoids . Transient receptor potentials (TRPs) induce sensation of pain and also support inflammation by secretion of pro-inflammatory neuropeptides. Both CB1 and TRPs are expressed on the surface of synovial tissue in patients with RA [73, 74].
4. Conclusions and clinical implications
In RA, auto-antibodies directed at synovial cells cause cell damage thereby initiating a cascade of inflammatory responses resulting in local inflammation within the inflamed joint(s) as well as systemic inflammation (Figure 1). Inflammatory cytokines cause acute sympathetic activation which helps direct the immune response to increase local inflammation within the affected joint(s), whilst inhibiting systemic inflammation. Chronic sympathetic activation occurs as a consequence of chronic inflammation and pain, which further increases local and systemic inflammatory responses. A number of important modulators exist including the HPA axis, pain, parasympathetic nervous system, baroreceptors and cardiopulmonary receptors, kidneys, renin-angiotensin system as well as spleen and lymphoid organs. Chronic inflammation has numerous deleterious consequences including heightened sympathetic activity which likely contributes to the increased cardiovascular risk in RA. The advent of biologic agents that target cytokine/inflammatory cell receptors (e.g. IL-6, TNF-α, B cell, IL-1) provides an opportunity to greatly improve understanding of RA pathophysiology, however far more studies are warranted to fully understand the role of the ANS. Interventions to target the ANS may help control inflammation in patients with RA, thereby improving morbidity and mortality.
Ahmed M Adlan MBBS, PhD, MRCP – Department of Cardiology, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool, UK, L14 3PE; Cardiology Registrar Electrophysiology & Devices; Department of Cardiology, Liverpool Heart and Chest Hospital; Thomas Drive, Liverpool, UK, L14 3PE; Email: firstname.lastname@example.org Tel: 0 (+44) 7921 999 927; Fax: 0 (+44) 151 600 1696; Twitter: @ahmed_adlan
Ach, acetylcholine; ANS, autonomic nervous system; CB1, cannabinoid receptor type 1; CNS, central nervous system; DAS, disease activity score; HPA, hypothalamic-pituitary-adrenal; hs-CRP, high sensitivity C-reactive protein; IFN, interferon; IL, interleukin, MSNA, muscle sympathetic nerve activity; RA, rheumatoid arthritis; Th, T helper cell; TNF, tumor necrosis factor; TRP, transient receptor potential.
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