Skeletal muscle fatigue and post-exertional malaise are key symptoms of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (ME/CFS). We have previously shown that AMP-activated protein kinase (AMPK) activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells in vitro. The aim of the present study was to assess if AMPK could be activated pharmacologically in ME/CFS. Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or compound 991. AMPK activation was assessed by Western blot and glucose uptake measured. Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared with controls. Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of EPS to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

Metabolic disorders including obesity, diabetes and non-alcoholic steatohepatitis are a group of conditions characterised by chronic low-grade inflammation of metabolic tissues. There is now a growing appreciation that various metabolites released from adipose tissue serve as key signalling mediators, influencing this interaction with inflammation. G protein-coupled receptors (GPCRs) are the largest family of signal transduction proteins and most historically successful drug targets. The signalling pathways for several key adipose metabolites are mediated through GPCRs expressed both on the adipocytes themselves and on infiltrating macrophages. These include three main groups of GPCRs: the FFA4 receptor, which is activated by long chain free fatty acids; the HCA2 and HCA3 receptors, activated by hydroxy carboxylic acids; and the succinate receptor. Understanding the roles these metabolites and their receptors play in metabolic-immune interactions is critical to establishing how these GPCRs may be exploited for the treatment of metabolic disorders.

Objectives To estimate the cost-effectiveness of a Cognitive Behavioural Approach (CBA) or a Personalised Exercise Programme (PEP), alongside usual care (UC), in patients with Inflammatory Rheumatic Diseases who report chronic, moderate to severe, fatigue. Methods A within-trial cost-utility analysis, was conducted using individual patient data collected within a multicentre, three-arm randomised controlled trial over a 56-week period. The primary economic analysis was conducted from the UK National Health Service (NHS) perspective. Uncertainty was explored using cost-effectiveness acceptability curves and sensitivity analysis. Results Complete-case analysis showed that, compared with UC, both PEP and CBA were more expensive [adjusted mean cost difference: PEP £569 (95%CI £464 to £665), CBA £845 (95%CI £717 to £993)] and, in the case of PEP, significantly more effective [adjusted mean QALY difference: PEP 0.043 (95% CI 0.019–0.068), CBA 0.001 (95% CI -0.022–0.022)]. These led to an incremental cost-effectiveness ratio (ICER) of £13 159 for PEP vs. UC, and £793 777 for CBA vs. UC). Non-parametric bootstrapping showed that, at a threshold value of £20 000 per QALY gained, PEP had a probability of 88% of being cost-effective. In multiple imputation analysis, PEP was associated with significant incremental costs of £428 (95% CI £324 to £511) and a non-significant QALY gain of 0.016 (95% CI -0.003–0.035), leading to an ICER of £26 822 vs. UC. The estimates from sensitivity analyses were consistent with these results. Conclusion The addition of a PEP alongside UC is likely to provide a cost-effective use of health care resources.

Background:Fatigue is reported as a common symptom among autoimmune and other chronic diseases such as fibromyalgia (FM), a long-term condition with uncertain pathophysiology. Previous studies from our group suggest that non-invasive vagus nerve stimulation (nVNS) may contribute to the improvement of patient reported outcome measures (PROMs) of fatigue in patients with primary Sjögren’s Syndrome (1).Objectives:This follow-up study uses the gammaCore device (electroCore) to assess the effect of nVNS on PROMs of fatigue and immune responses in chronic fatigue syndrome (CFS), FM and rheumatoid arthritis (RA).Methods:The study included thirteen CFS, fourteen FM and fifteen RA patients who used the gammaCore nVNS device twice daily over a 26-day period. Pre- and post- nVNS bloods were drawn at baseline and final visits. Whole blood samples were stimulated with 2 ng/mL lipopolysaccharide (LPS) and the IL-6 and TNF-α cytokine concentrations were quantified at 24 hours. In addition, the epidermal growth factor (EGF), IFN-γ, IL-6, IP-10, MIP-1α, and TNF-α levels were measured in ‘pre-nVNS’ serum and flow cytometric profiles of whole blood immune cells were analysed. The patient reported outcome measures (PROMs) recorded at each visit were the Visual Analogue Scale (VAS) (0-100 cm) of abnormal fatigue, Hospital Anxiety and Depression (HAD) Scale, Orthostatic Grading Scale, Epworth Sleepiness Scale (daytime sleepiness), and Profile of fatigue (PRO-F) for Physical and Mental fatigue. Paired t-tests were performed to assess for changes in PROMs, cytokine levels, and cell subset distribution and associations of cytokine response with PROMs were investigated by correlation analyses.Results:Eleven CFS, twelve FM and fourteen RA patients completed the study. There was a significant reduction in daytime sleepiness in CFS (p =0.0321) and FM (p =0.0294) patients between the final and baseline visits and a significant reduction in HAD depression (p =0.0413) in FM (Fig.1). Improvement in VAS for abnormal fatigue, HAD-Anxiety, HAD-Depression, PRO-F Physical and Mental fatigue was observed in all three groups over the study period with a reduction in VAS fatigue in 64% of CFS, 67% of FM and 62% of RA patients. There were no significant changes in the immune cell subsets or in cytokine response. Finally, higher baseline pre-nVNS supernatant IL-6 levels were predictive of an improvement in VAS fatigue (p =0.0006), Daytime Sleepiness (p =0.0466) and PRO-F Physical fatigue (p =0.0196) in RA, while higher baseline TNF-α levels were predictive of an improvement in VAS fatigue (p =0.0003), Daytime Sleepiness (p =0.0380), Orthostatic (p =0.0281) and PRO-F Physical fatigue (p =0.0007) in FM.Conclusion:Our findings suggest that nVNS may contribute to the improvement of PROMs of fatigue in CFS, FM and RA. NVNS led to significant reductions in daytime sleepiness in CFS and FM, and depression in FM. Further studies and a larger sample size are needed to investigate the potential effects of nVNS on diseases characterised by persistent fatigue.References:[1]Tarn J, Legg S, Mitchell S, Simon B, Ng WF. The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjögren’s Syndrome. Neuromodulation Technol Neural Interface. 2018;22(5):580–5.Figure 1.VAS for abnormal fatigue and PROMs recorded at baseline and final visits in patients with chronic fatigue syndrome (CFS), fibromyalgia (FM) and rheumatoid arthritis (RA). Boxplots show the median, upper, and lower quartiles for PROMs at visit 1 and visit 3 in each disease group. Paired-t tests revealed a significant reduction in daytime sleepiness in CFS and FM (B), and a significant reduction in HAD depression in FM (E). Improvement trends were observed in VAS for abnormal fatigue, HAD-Anxiety, HAD-Depression, PRO-F Physical fatigue and PRO-F Mental fatigue in all three groups over the 26-day study period.Acknowledgements:This study received infrastructural support from the National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University.Disclosure of Interests:Emmanuella Traianos: None declared, Bethany Dibnah: None declared, Dennis Lendrem: None declared, Yasmin Clark: None declared, Victoria Macrae: None declared, Victoria Slater: None declared, Karl Wood: None declared, David Storey: None declared, Bruce Simon Shareholder of: Bruce Simon is an employee and shareholder of electroCore., Employee of: electroCore, Inc., Justyna Blake Shareholder of: Justyna Blake is an employee of electroCore, and receives stock ownership., Employee of: electroCore, Inc., Jessica Tarn: None declared, Wan Fai Ng: None declared

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by abnormal synovial hyperplasia, inflammatory cell infiltration, and destruction of cartilage or bone. Early use of disease-modifying anti-rheumatic drugs (DMARDs) can significantly improve the patient's condition. However, many patients had no response after treatment or gradually decreased after treatment for some time. DMARDs Multidrug resistance(MDR) is an important cause of the above phenomenon 1 . How to reverse MDR in RA patients, and then control the disease is a major problem in RA treatment. The mechanism of MDR is complex. ATP binding cassette transporter super family consists of 48 transporters, ABCB1/P-glycoprotein (P-gp) is one of the major proteins associated with MDR 2 . The expression of P-gp is induced not only by genotoxic mechanisms, but also by inflammatory cytokines such as IL-2, IL-4, IL-6, and TNF-α in some inflammatory diseases 3,4 . Objectives: The multiple drug resistance(MDR) to disease modifying anti-rheumatic drugs(DMARDs) is the key factor in Rheumatoid arthritis(RA) treatment field. P-glycoprotein (P-gp) encoded by multidrug resistance gene 1 (MDR1) is involved in the excretion of numerous DMARDs. We investigated the effects of methotrexate(MTX) alone and combined with interleukin 6 (IL-6) on P-gp expression and examined the signaling pathway involved in Peripheral blood mononuclear cells of RA patients. Methods: The Peripheral blood mononuclear cells were extracted from Fifteen RA patients who were without any DMARDs and biological agents treatment. These cells were treated with IL-6, IL-6+MTX(0.01ug/m), IL-6+MTX (0.1ug/m), IL-6+MTX (1ug/m) for 72h. P-gp expression was measured by flow cytometry and real-time polymerase chain reaction (RT-PCR); JAK2 and STAT3 were measured by RT-PCR. Results: Methotrexate produce a dose-responsive reduction of both P-gp, JAK2 and STAT3 expression induced by IL-6. Conclusion: Methotrexate downregulates p-glycoprotein expression and inhibits the activation of JAK2/STAT3 pathway in rheumatoid arthritis peripheral blood mononuclear cells.