Sympathetic Nervous System & Rheumatoid Arthritis
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.
1. Introduction
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 [3]. In RA patients, T-helper 1 (Th1) [2, 4] and Th17 cell activity [1] 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 [5]. 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 [6]. 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 [7] 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) [18]. 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 [13]. 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 [26], IL-12 [27], 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 [38] 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 [21]. 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 [40].
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 [41]; and increases tissue IL-1β, IL-6 and TNF-α within the myocardium [42]. 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 [43].
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 [44]. 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) [45]. 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 [46]. 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 [47].
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) [46]. 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 [47].
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 [48], 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 [49]. 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 [50].
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 [58].
In RA patients, over three quarters of studies have demonstrated parasympathetic dysfunction including impaired cardiovascular reflexes and low heart rate variability [45]. 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) [59]. Koopman et al. provided the most direct evidence for a causal relationship between parasympathetic nerve dysfunction and inflammation in RA [60]. 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).
Hypothalamus-pituitary-adrenal axis
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 [61] 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 [62] 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 [61].
Pain
Inflammation and pain are characteristic features of RA, with joint swelling and tenderness comprising key components of the disease activity score-28 [67]. Chronic pain has been shown to increase sympathetic outflow in experimental models [68]. Amongst RA patients and controls, self-reported pain was independently positively associated with MSNA burst frequency [47]. Animal [69, 70] and human experiments [71] 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 [71]. In an animal model of chronic arthritis, TNF-α inhibition attenuated thermal and mechanical hyperalgesia via effects on the dorsal root ganglia [70]. 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 [70].
In a recent study, RA patients were found to have higher pain rating in response to the cold pressor test, compared to normotensive controls [59]. 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 [72]. 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.
Author’s Affiliation
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: adlan.ahmed@gmail.com Tel: 0 (+44) 7921 999 927; Fax: 0 (+44) 151 600 1696; Twitter: @ahmed_adlan
Non-standard Abbreviations
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.
References
1 Church LD, Filer AD, Hidalgo E, et al. Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression. Arthritis Res Ther 2010; 12: R184.
2 Kusaba M, Honda J, Fukuda T, Oizumi K. Analysis of type 1 and type 2 T cells in synovial fluid and peripheral blood of patients with rheumatoid arthritis. J Rheumatol 1998; 25: 1466-71.
3 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-19.
4 Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A 1994; 91: 8562-6.
5 Niijima A, Hori T, Aou S, Oomura Y. The effects of interleukin-1 beta on the activity of adrenal, splenic and renal sympathetic nerves in the rat. J Auton Nerv Syst 1991; 36: 183-92.
6 Haefeli WE, Bargetzi MJ, Starnes HF, Blaschke TF, Hoffman BB. Evidence for activation of the sympathetic nervous system by recombinant human interleukin-1 beta in humans. J Immunother Emphasis Tumor Immunol 1993; 13: 136-40.
7 Helwig BG, Craig RA, Fels RJ, Blecha F, Kenney MJ. Central nervous system administration of interleukin-6 produces splenic sympathoexcitation. Auton Neurosci 2008; 141: 104-11.
8 Ichijo T, Katafuchi T, Hori T. Central interleukin-1 beta enhances splenic sympathetic nerve activity in rats. Brain Res Bull 1994; 34: 547-53.
9 Kannan H, Tanaka Y, Kunitake T, Ueta Y, Hayashida Y, Yamashita H. Activation of sympathetic outflow by recombinant human interleukin-1 beta in conscious rats. Am J Physiol 1996; 270: R479-85.
10 Takahashi H, Nishimura M, Sakamoto M, Ikegaki I, Nakanishi T, Yoshimura M. Effects of interleukin-1 beta on blood pressure, sympathetic nerve activity, and pituitary endocrine functions in anesthetized rats. Am J Hypertens 1992; 5: 224-9.
11 Vriend CY, Zuo L, Dyck DG, Nance DM, Greenberg AH. Central administration of interleukin-1 beta increases norepinephrine turnover in the spleen. Brain Res Bull 1993; 31: 39-42.
12 Wei SG, Yu Y, Zhang ZH, Felder RB. Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension 2015; 65: 1126-33.
13 Wei SG, Zhang ZH, Beltz TG, Yu Y, Johnson AK, Felder RB. Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines. Hypertension 2013; 62: 118-25.
14 Wei SG, Zhang ZH, Yu Y, Felder RB. Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-alpha, and MAP kinase signaling. Am J Physiol Heart Circ Physiol 2014; 307: H1643-54.
15 Yokotani K, Okuma Y, Osumi Y. Recombinant interleukin-1 beta inhibits gastric acid secretion by activation of central sympatho-adrenomedullary outflow in rats. Eur J Pharmacol 1995; 279: 233-9.
16 Zhang ZH, Wei SG, Francis J, Felder RB. Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol 2003; 284: R916-27.
17 Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 2001; 86: 1154-9.
18 Ferguson AV. Circumventricular Organs: Integrators of Circulating Signals Controlling Hydration, Energy Balance, and Immune Function. In: De Luca LA, Menani JV, Johnson AK, eds, Neurobiology of Body Fluid Homeostasis: Transduction and Integration. Boca Raton (FL). 2014.
19 Kosek E, Altawil R, Kadetoff D, et al. Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain–interleukin-8 in fibromyalgia and interleukin-1 beta in rheumatoid arthritis. J Neuroimmunol 2015; 280: 49-55.
20 Lampa J, Westman M, Kadetoff D, et al. Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice. Proc Natl Acad Sci U S A 2012; 109: 12728-33.
21 Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacological reviews 2000; 52: 595-638.
22 Felten DL, Ackerman KD, Wiegand SJ, Felten SY. Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. Journal of neuroscience research 1987; 18: 28-36, 118-21.
23 Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S. Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 1985; 135: 755s-65s.
24 Koff WC, Fann AV, Dunegan MA, Lachman LB. Catecholamine-induced suppression of interleukin-1 production. Lymphokine Res 1986; 5: 239-47.
25 Van der Poll T, Lowry SF. Epinephrine inhibits endotoxin-induced IL-1 beta production: roles of tumor necrosis factor-alpha and IL-10. Am J Physiol 1997; 273: R1885-90.
26 Chouaib S, Welte K, Mertelsmann R, Dupont B. Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression. J Immunol 1985; 135: 1172-9.
27 Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians 1996; 108: 374-81.
28 Elenkov IJ, Hasko G, Kovacs KJ, Vizi ES. Modulation of lipopolysaccharide-induced tumor necrosis factor-alpha production by selective alpha- and beta-adrenergic drugs in mice. J Neuroimmunol 1995; 61: 123-31.
29 Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol 1997; 158: 4200-10.
30 Hasko G, Nemeth ZH, Szabo C, Zsilla G, Salzman AL, Vizi ES. Isoproterenol inhibits Il-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages. Brain Res Bull 1998; 45: 183-7.
31 Severn A, Rapson NT, Hunter CA, Liew FY.Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. J Immunol 1992; 148: 3441-5.
32 van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest 1996; 97: 713-9.
33 van der Poll T, Jansen J, Endert E, Sauerwein HP, van Deventer SJ. Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood. Infect Immun 1994; 62: 2046-50.
34 Kox M, van Eijk LT, Zwaag J, van den Wildenberg J, Sweep FC, van der Hoeven JG, Pickkers P. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proc Natl Acad Sci U S A 2014; 111: 7379-84.
35 Siegmund B, Eigler A, Hartmann G, Hacker U, Endres S. Adrenaline enhances LPS-induced IL-10 synthesis: evidence for protein kinase A-mediated pathway. Int J Immunopharmacol 1998; 20: 57-69.
36 Suberville S, Bellocq A, Fouqueray B, Philippe C, Lantz O, Perez J, Baud L. Regulation of interleukin-10 production by beta-adrenergic agonists. Eur J Immunol 1996; 26: 2601-5.
37 DeRijk RH, Boelen A, Tilders FJ, Berkenbosch F. Induction of plasma interleukin-6 by circulating adrenaline in the rat. Psychoneuroendocrinology 1994; 19: 155-63.
38 Fisher SA, Absher M. Norepinephrine and ANG II stimulate secretion of TGF-beta by neonatal rat cardiac fibroblasts in vitro. Am J Physiol 1995; 268: C910-7.
39 Linden A. Increased interleukin-8 release by beta-adrenoceptor activation in human transformed bronchial epithelial cells. Br J Pharmacol 1996; 119: 402-6.
40 Martelli D, Yao ST, McKinley MJ, McAllen RM. Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol 2014; 592: 1677-86.
41 Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN, Fleshner M. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 2005; 135: 1295-307.
42 Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 2000; 101: 2338-41.
43 Furlan R, Ardizzone S, Palazzolo L, et al. Sympathetic overactivity in active ulcerative colitis: effects of clonidine. Am J Physiol Regul Integr Comp Physiol 2006; 290: R224-32.
44 Bennett PH, Scott JT. Autonomic Neuropathy in Rheumatoid Arthritis. Annals of the rheumatic diseases 1965; 24: 161-8.
45 Adlan AM, Lip GY, Paton JF, Kitas GD, Fisher JP. Autonomic function and rheumatoid arthritis–a systematic review. Seminars in arthritis and rheumatism 2014; 44: 283-304.
46 Dekkers JC, Geenen R, Godaert GL, Bijlsma JW, van Doornen LJ. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clinical and experimental rheumatology 2004; 22: 63-70.
47 Adlan AM, Paton JF, Lip GY, Kitas GD, Fisher JP. Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in rheumatoid arthritis. J Physiol 2017; 595: 967-81.
48 Igari T, Takeda M, Obara K, Ono S. Catecholamine metabolism in the patients with rheumatoid arthritis. The Tohoku journal of experimental medicine 1977; 122: 9-20.
49 Syngle A, Verma I, Krishan P. Interleukin-6 blockade improves autonomic dysfunction in rheumatoid arthritis. Acta Reumatol Port 2015; 40: 85-8.
50 Syngle V, Syngle A, Garg N, Krishan P, Verma I. Predictors of autonomic neuropathy in rheumatoid arthritis. Auton Neurosci 2016; 201: 54-9.
51 Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405: 458-62.
52 Tracey KJ. The inflammatory reflex. Nature 2002; 420: 853-9.
53 Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003; 421: 384-8.
54 Hu Y, Liu R, Li J, Yue Y, Cheng W, Zhang P. Attenuation of Collagen-Induced Arthritis in rat by nicotinic alpha7 receptor partial agonist GTS-21. BioMed research international 2014; 2014: 325875.
55 Levine YA, Koopman FA, Faltys M, et al. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PloS one 2014; 9: e104530.
56 Li T, Zuo X, Zhou Y, et al. The vagus nerve and nicotinic receptors involve inhibition of HMGB1 release and early pro-inflammatory cytokines function in collagen-induced arthritis. Journal of clinical immunology 2010; 30: 213-20.
57 van Maanen MA, Lebre MC, van der Poll T, LaRosa GJ, Elbaum D, Vervoordeldonk MJ, Tak PP. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis and rheumatism 2009; 60: 114-22.
58 Tracey KJ. Reflex control of immunity. Nature reviews Immunology 2009; 9: 418-28.
59 Adlan AM, Veldhuijzen van Zanten J, Lip GYH, Paton JFR, Kitas GD, Fisher JP. Cardiovascular autonomic regulation, inflammation and pain in rheumatoid arthritis. Auton Neurosci 2017; 208: 137-45.
60 Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 2016; 113: 8284-9.
61 Straub RH, Gunzler C, Miller LE, Cutolo M, Scholmerich J, Schill S. Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro. FASEB J 2002; 16: 993-1000.
62 Nishimura H, Yoshikawa T, Kobayashi N, Anzai T, Nagami K, Handa S, Ogawa S. Effects of methylprednisolone on hemodynamics and beta-adrenergic receptor signaling in rabbits with acute left ventricular failure. Heart and vessels 1997; 12: 84-91.
63 Edwards RR, Wasan AD, Bingham CO, 3rd, Bathon J, Haythornthwaite JA, Smith MT, Page GG. Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res Ther 2009; 11: R61.
64 Hirano D, Nagashima M, Ogawa R, Yoshino S. Serum levels of interleukin 6 and stress related substances indicate mental stress condition in patients with rheumatoid arthritis. J Rheumatol 2001; 28: 490-5.
65 Lechin F, van der Dijs B, Lechin A, et al. Plasma neurotransmitters and cortisol in chronic illness: role of stress. J Med 1994; 25: 181-92.
66 Yoshino S, Mukai E. Neuroendocrine-immune system in patients with rheumatoid arthritis. Mod Rheumatol 2003; 13: 193-8.
67 Dougados M, Aletaha D, van Riel P. Disease activity measures for rheumatoid arthritis. Clinical and experimental rheumatology 2007; 25: S22-9.
68 Fazalbhoy A, Birznieks I, Macefield VG. Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure and heart rate. Exp Physiol 2012; 97: 1084-92.
69 Boettger MK, Hensellek S, Richter F, et al. Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis and rheumatism 2008; 58: 2368-78.
70 Inglis JJ, Nissim A, Lees DM, Hunt SP, Chernajovsky Y, Kidd BL. The differential contribution of tumour necrosis factor to thermal and mechanical hyperalgesia during chronic inflammation. Arthritis Res Ther 2005; 7: R807-16.
71 Hess A, Axmann R, Rech J, et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A 2011; 108: 3731-6.
72 Lowin T, Straub RH. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Arthritis Res Ther 2015; 17: 226.
73 Carey MR, Myoga MH, McDaniels KR, Marsicano G, Lutz B, Mackie K, Regehr WG. Presynaptic CB1 receptors regulate synaptic plasticity at cerebellar parallel fiber synapses. J Neurophysiol 2011; 105: 958-63.
74 Engler A, Aeschlimann A, Simmen BR, Michel BA, Gay RE, Gay S, Sprott H. Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 2007; 359: 884-8.
