Pushing the needle forward on the relationship between autoimmunity and autonomic dysfunction

Immune-mediated diseases (IMDs) impact 4% of the global population, making them of great clinical and economic importance. They are a physical, emotional and economic burden for patients, oftentimes decreasing quality of life in multiple facets. The IMD burden impacts more than just patients: it overflows into the medical community, as the great majority of IMDs are accompanied by numerous comorbidities. Rheumatoid arthritis (RA) falls under the IMD umbrella as a chronic-inflammatory autoimmune disease: it is characterized by systemic inflammation, severe joint pain and an increased risk of serious comorbidities. Of these comorbid conditions, the most alarming is cardiovascular disease (CVD), which accounts for 40–50% of deaths in RA. Patients with RA experience high incidence of myocardial infarction and cerebrovascular stroke. The proposed mechanisms connecting RA and CVD are wide ranging: chronic systemic inflammation, which can wreak havoc on endothelial function; adverse interactions and side effects of disease-altering drugs and biologic therapies; as well as lifestyle and environmental factors that predispose patients to a plethora of CVD risk factors. Over the past five decades, using the technique of microneurography to investigate afferent and efferent nerve impulses has been a staple in autonomic function research. As such, this gold standard assessment of autonomic function, which allows for direct recording of muscle sympathetic nerve activity (MSNA), has been employed to elucidate the ambiguous relationship between RA and CVD. RA is hypothesized to be somewhat unique, as autonomic dysfunction may occur prior to RA development, as found by observational studies (Koopman et al. 2016). Autonomic dysfunction, like that seen in RA, wherein MSNA is elevated in both basal and reactivity measures, is recognized as one of the mechanisms contributing to adverse cardiovascular outcomes in RA. In a disease where early detection can save one from irreparable joint damage, such information is powerful in helping identify risk factors earlier rather than later. Autonomic and haemodynamic reactivity to exercise is complex. The muscle metaboreflex, which responds to an accumulation of metabolites in exercising skeletal muscle when O2 demands are not met, sparks a reflex to increase blood pressure (BP). An increase in MSNA during muscle metaboreflex activation, which can be stimulated via post-exercise ischaemia (PEI), has been shown to contribute to compromised haemodynamic control in various disease states (heart failure, hypertension, etc.). Isolating the metabolic portion of the exercise pressor response provides valuable insight into the neural and metabolic mechanisms contributing to RA. While autonomic dysfunction is clearly a key player in RA, just how much it pervades homeostatic processes has been unclear. This gap in the literature was addressed in a recent article in the Journal of Physiology by Peçanha et al. (2021). The authors recruited (n = 33) post-menopausal females with RA diagnoses and (n = 10) age- and CVD risk-matched controls (CON) for their cross-sectional study. The main findings of this work were that the RA group showed both augmented sympathetic and pressor responses during exercise, which were sustained during PEI. To little surprise, the RA group also had elevated MSNA and compromised baroreflex sensitivity during basal measures. Importantly, CVD risk factors did not differ between the groups. The RA group had a mean ± SD disease duration of 20 ± 12 years with 97% of RA patients taking disease-modifying anti-rheumatic drugs and 48% using biologic agents. Participants underwent three laboratory visits in total: (1) a clinical evaluation consisting of medical history, pain levels via a visual analogue scale (VAS), and disease activity, as well as a 12 h fasted blood sampling (30 ml) for a wide range of biomarkers; (2) a maximal graded exercise test, conducted on a treadmill with incremental increases in speed and grade each minute until voluntary cessation; and (3) a battery of autonomic function tests that consisted of maximal voluntary contraction (MVC) isometric knee extension of the left leg, 15 min of basal measurements, 3 min of isometric knee extension at 30% MVC, directly followed by 2 min of cuff occlusion (PEI), all while remaining supine and recording MSNA from the non-exercising leg in the peroneal nerve at the fibular head. Peçanha et al. found that the RA group presented greater VAS pain (P = 0.02) and inflammatory biomarkers (C-reactive protein, P = 0.01; interferon-γ, P = 0.03; interleukin (IL)-10, P = 0.03; IL-1ra, P = 0.02; IL-8, P = 0.01; and monocyte chemotactic protein 1, P = 0.01) when compared to the CON group. There were no significant differences between groups for resting haemodynamic measures and heart rate variability. However, the RA group had significantly greater basal MSNA burst frequency than the CON group (bursts/min, RA: 33 ± 14 vs. CON: 20 ± 13, P = 0.03) and burst incidence (bursts/100 heart beats, RA: 50 ± 24 vs. CON: 31 ± 20, P = 0.04). Similarly, during exercise there were no differences in heart rate or root mean square of the successive R-R intervals between groups. However, mean arterial pressure (P = 0.003) and MSNA (P = 0.03) during both exercise and PEI were significantly higher in the RA group when compared to CON. Indeed, Peçanha et al. also found that the baroreflex was impaired in the RA group: lower baroreflex effectiveness index (P = 0.002) and trend to lower cardiac baroreflex sensitivity in RA compared to CON (P = 0.06). The authors should be commended for their thorough investigation into this clinical population. They brought forward many powerful points, the most impactful of which, in our novice opinion, is that persons with RA may be experiencing multiple BP dysregulations, or surges, throughout the day, further amplifying the risk of sustaining a severe cardiovascular event. Activities as simple as getting the mail and taking a shower could be a stressor that spikes MSNA, in turn causing harmful and uncontrolled BP fluctuations. Furthermore, this work strengthens our understanding of the relationship between autoimmune disease and autonomic dysfunction. RA is similar to various IMDs, such as Crohn's disease, ulcerative colitis, endometriosis, psoriasis and more, in cytokine storms, inflammatory pathways and adverse cardiovascular outcomes, and this begs the question: how deep rooted is autonomic dysfunction in disease pathogenesis under the IMD umbrella? Along with the limitations listed in the discussion, the authors may have benefitted from utilizing the VAS pain scale during the exercise protocol, given the limits of the clinical population. Chronic pain – chiefly during exercise – certainly may compound with other factors to decrease exercise tolerance. The addition of the VAS pain scale during and after the exercise protocol could have proved valuable in comparing exercise tolerance between RA and CON groups, as well as aiding in the further solidification of the possible role, or lack thereof, of pain in exercise tolerance between groups. One of the most universal strategies for effectively reducing risk of comorbidities common to RA is physical activity. Exercise, when combined with proper drug therapy, is essential in aiding the control of systemic inflammation, and decreasing endocrine-active central adiposity, oxidative stress and CVD risk. However, sufferers of RA have a steep mountain to climb in regards to exercise. Those with sustained and moderate to high disease activity often experience arthrogenic inhibition to the muscles surrounding affected joints, as well as peripheral deafferentation. These changes in sensory feedback could modify proprioception and have an impact on subsequent motor patterns, further decreasing exercise capacity and general physical activity tolerance. Furthermore, there is sufficient evidence that shows correctly designed dynamic strength programmes, consisting of both resistance and aerobic training, are effective in improving physical function and quality of life in RA patients. While dynamic strength training is crucial for post-menopausal women, as loss of bone mineral density and sarcopenia are cause for concern, it is especially relevant in a high disease state like that of RA, where appropriately programmed exercise regimens can decrease CVD risk as well as RA severity and activity (Hakkinen et al. 2001; Stavropoulos-Kalinoglou et al. 2013). Along with the aforementioned suggestion of expanding these findings by investigating the metaboreflex in similar disease states, another avenue that may prove important would be observation of the neurovascular transduction of sympathetic activity into vascular tone. It has been established that as females age, neurovascular transduction of MSNA is increased: high sympathetic activity leads to a higher level of vasoconstriction (Briant et al. 2016). However, for males, this is not the case. Of great interest would be comparing pre- vs. post-menopausal females as well as males vs. females to help elucidate the cardioprotective benefits of oestrogen and its impact on disease pathogenesis. This may be part of the reason for increased prevalence of RA in older females than males. In conclusion, getting RA patients to be physically active early could keep them out of cardiac rehabilitation later. The progressive joint damage and loss of function develops early at disease onset in RA. As such, early diagnosis and appropriate drug therapy are essential for favourable patient outcomes; however, physical activity should be considered an integral aspect to patient care for both prevention and recovery. As previously stated, this work further supports the existence of a relationship between autoimmune disease and autonomic dysfunction. Additional studies are warranted to investigate autonomic (dys)function's role in similar disease states across the sexes: a possible common denominator in an expansive and expensive sea of information. No competing interests declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. We apologize for not citing all relevant works due to reference limitations. We would like to thank Dr. Abigail S. L. Stickford for her encouragement and review of the manuscript.