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14-06-2018 | Rheumatoid arthritis | Article

Ten weeks of high-intensity interval walk training is associated with reduced disease activity and improved innate immune function in older adults with rheumatoid arthritis: a pilot study

Journal: Arthritis Research & Therapy

Authors: David B. Bartlett, Leslie H. Willis, Cris A. Slentz, Andrew Hoselton, Leslie Kelly, Janet L. Huebner, Virginia B. Kraus, Jennifer Moss, Michael J. Muehlbauer, Guillaume Spielmann, William E. Kraus, Janet M. Lord, Kim M. Huffman

Publisher: BioMed Central

Abstract

Background

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which adults have significant joint issues leading to poor health. Poor health is compounded by many factors, including exercise avoidance and increased risk of opportunistic infection. Exercise training can improve the health of patients with RA and potentially improve immune function; however, information on the effects of high-intensity interval training (HIIT) in RA is limited. We sought to determine whether 10 weeks of a walking-based HIIT program would be associated with health improvements as measured by disease activity and aerobic fitness. Further, we assessed whether HIIT was associated with improved immune function, specifically antimicrobial/bacterial functions of neutrophils and monocytes.

Methods

Twelve physically inactive adults aged 64 ± 7 years with either seropositive or radiographically proven (bone erosions) RA completed 10 weeks of high-intensity interval walking. Training consisted of 3 × 30-minute sessions/week of ten ≥ 60-second intervals of high intensity (80–90% VO2reserve) separated by similar bouts of lower-intensity intervals (50–60% VO2reserve). Pre- and postintervention assessments included aerobic and physical function; disease activity as measured by Disease Activity score in 28 joints (DAS28), self-perceived health, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR); plasma interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand (CXCL)-8, IL-10, and tumor necrosis factor (TNF)-α concentrations; and neutrophil and monocyte phenotypes and functions.

Results

Despite minimal body composition change, cardiorespiratory fitness increased by 9% (change in both relative and absolute aerobic capacity; p < 0.001), and resting blood pressure and heart rate were both reduced (both p < 0.05). Postintervention disease activity was reduced by 38% (DAS28; p = 0.001) with significant reductions in ESR and swollen joints as well as improved self-perceived health. Neutrophil migration toward CXCL-8 (p = 0.003), phagocytosis of Escherichia coli (p = 0.03), and ROS production (p < 0.001) all increased following training. The frequency of cluster of differentiation 14-positive (CD14+)/CD16+ monocytes was reduced (p = 0.002), with both nonclassical (CD14dim/CD16bright) and intermediate (CD14bright/CD16positive) monocytes being reduced (both p < 0.05). Following training, the cell surface expression of intermediate monocyte Toll-like receptor 2 (TLR2), TLR4, and HLA-DR was reduced (all p < 0.05), and monocyte phagocytosis of E. coli increased (p = 0.02). No changes were observed for inflammatory markers IL-1β, IL-6, CXCL-8, IL-10, CRP, or TNF-α.

Conclusions

We report for the first time, to our knowledge, that a high-intensity interval walking protocol in older adults with stable RA is associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, indicative of reduced infection risk and inflammatory potential. Importantly, the exercise program was well tolerated by these patients.

Trial registration

ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.
Literature
1.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.CrossRefPubMed
2.
Weyand CM, Goronzy JJ. Aging of the immune system: mechanisms and therapeutic targets. Ann Am Thorac Soc. 2016;13(Suppl 5):S422–8.CrossRefPubMedPubMedCentral
3.
Mazzone A, et al. Immunomodulation of neutrophil chemotaxis in rheumatoid arthritis using levamisole and methisoprinol. Clin Ther. 1986;8(2):232–7.PubMed
4.
Sapey E, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: towards targeted treatments for immunosenescence. Blood. 2014;123(2):239–48.CrossRefPubMedPubMedCentral
5.
Cedergren J, et al. Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients. J Rheumatol. 2007;34(11):2162–70.PubMed
6.
Khandpur R, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178):178ra40.CrossRefPubMedPubMedCentral
7.
Fairhurst AM, et al. Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species. Arthritis Res Ther. 2007;9(2):R29.CrossRefPubMedPubMedCentral
8.
Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 2016;12(8):472–85.CrossRefPubMed
9.
Shaw AC, et al. Aging of the innate immune system. Curr Opin Immunol. 2010;22(4):507–13.CrossRefPubMedPubMedCentral
10.
Rossol M, et al. The CD14brightCD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 2012;64(3):671–7.CrossRefPubMed
11.
Iwahashi M, et al. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 2004;50(5):1457–67.CrossRefPubMed
12.
Gierut A, Perlman H, Pope RM. Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am. 2010;36(2):271–96.CrossRefPubMedPubMedCentral
13.
Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11(3):234–50.CrossRefPubMed
14.
Arleevskaya MI, et al. Mononuclear phagocytes in rheumatoid arthritis patients and their relatives – family similarity. Open Rheumatol J. 2011;5:36–44.CrossRefPubMedPubMedCentral
15.
Bongartz T, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275–85.CrossRefPubMed
16.
Veldhuijzen van Zanten JJ, et al. Perceived barriers, facilitators and benefits for regular physical activity and exercise in patients with rheumatoid arthritis: a review of the literature. Sports Med. 2015;45(10):1401–12.CrossRefPubMedPubMedCentral
17.
Swardh E, Brodin N. Effects of aerobic and muscle strengthening exercise in adults with rheumatoid arthritis: a narrative review summarising a chapter in physical activity in the prevention and treatment of disease (FYSS 2016). Br J Sports Med. 2016;50(6):362–7.CrossRefPubMed
18.
Gleeson M, et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11(9):607–15.CrossRefPubMed
19.
Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol. 2005;98:1154–62.CrossRefPubMed
20.
Bartlett DB, et al. Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults. Brain Behav Immun. 2016;56:12–20.CrossRefPubMedPubMedCentral
21.
Slentz CA, et al. Effects of exercise training alone vs a combined exercise and nutritional lifestyle intervention on glucose homeostasis in prediabetic individuals: a randomised trial. Diabetologia. 2016;59(10):2088–98.CrossRefPubMedPubMedCentral
22.
Bartlett DB, et al. Association of the composite inflammatory biomarker GlycA, with exercise-induced changes in body habitus in men and women with prediabetes. Oxid Med Cell Longev. 2017;2017:5608287.PubMedPubMedCentral
23.
Kraus WE, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med. 2002;347(19):1483–92.CrossRefPubMed
24.
Stewart LK, et al. Influence of exercise training and age on CD14+ cell-surface expression of Toll-like receptor 2 and 4. Brain Behav Immun. 2005;19(5):389–97.CrossRefPubMed
25.
Bartlett DB, et al. Neutrophil and monocyte bactericidal responses to 10 weeks of low-volume high-intensity interval or moderate-intensity continuous training in sedentary adults. Oxid Med Cell Longev. 2017;2017:8148742.PubMedPubMedCentral
26.
McFarlin BK, et al. TLR4 is lower in resistance-trained older women and related to inflammatory cytokines. Med Sci Sports Exerc. 2004;36(11):1876–83.CrossRefPubMed
27.
Gibala MJ, et al. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J Physiol. 2012;590(5):1077–84.CrossRefPubMedPubMedCentral
28.
Robinson E, et al. Short-term high-intensity interval and moderate-intensity continuous training reduce leukocyte TLR4 in inactive adults at elevated risk of type 2 diabetes. J Appl Physiol (1985). 2015;119(5):508–16.CrossRef
29.
Durrer C, et al. Acute high-intensity interval exercise reduces human monocyte Toll-like receptor 2 expression in type 2 diabetes. Am J Physiol Regul Integr Comp Physiol. 2017;312(4):R529–38.CrossRefPubMedPubMedCentral
30.
Sandstad J, et al. The effects of high intensity interval training in women with rheumatic disease: a pilot study. Eur J Appl Physiol. 2015;115(10):2081–9.CrossRefPubMed
31.
Baslund B, et al. Effect of 8 wk of bicycle training on the immune system of patients with rheumatoid arthritis. J Appl Physiol (1985). 1993;75(4):1691–5.CrossRef
32.
van den Ende CH, et al. Comparison of high and low intensity training in well controlled rheumatoid arthritis: results of a randomised clinical trial. Ann Rheum Dis. 1996;55(11):798–805.CrossRefPubMedPubMedCentral
33.
Arnett FC, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.CrossRefPubMed
34.
Howley ET. Type of activity: resistance, aerobic and leisure versus occupational physical activity. Med Sci Sports Exerc. 2001;33(6 Suppl):S364–9. discussion S419-20.CrossRefPubMed
35.
AbouAssi H, et al. Adipose depots, not disease-related factors, account for skeletal muscle insulin sensitivity in established and treated rheumatoid arthritis. J Rheumatol. 2014;41(10):1974–9.CrossRefPubMedPubMedCentral
36.
Siri WE. Body composition from fluid spaces and density: analysis of methods. 1961. Nutrition. 1993;9(5):480–91. discussion 480, 492PubMed
37.
Dempster P, Aitkens S. A new air displacement method for the determination of human body composition. Med Sci Sports Exerc. 1995;27(12):1692–7.CrossRefPubMed
38.
Nordin E, et al. Prognostic validity of the Timed Up-and-Go test, a modified Get-Up-and-Go test, staff's global judgement and fall history in evaluating fall risk in residential care facilities. Age Ageing. 2008;37(4):442–8.CrossRefPubMed
39.
Muir SW, et al. Balance impairment as a risk factor for falls in community-dwelling older adults who are high functioning: a prospective study. Phys Ther. 2010;90(3):338–47.CrossRefPubMed
40.
Muir SW, et al. Use of the Berg Balance Scale for predicting multiple falls in community-dwelling elderly people: a prospective study. Phys Ther. 2008;88(4):449–59.CrossRefPubMed
41.
Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford. HOMA calculator. https://​www.​dtu.​ox.​ac.​uk/​homacalculator/​. Accessed June 2014.
42.
Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487–95.CrossRefPubMed
43.
Muinonen-Martin AJ, et al. An improved chamber for direct visualisation of chemotaxis. PLoS One. 2010;5(12):e15309.CrossRefPubMedPubMedCentral
44.
Zhu X, et al. A surrogate method for assessment of β2-integrin-dependent adhesion of human eosinophils to ICAM-1. J Immunol Methods. 2000;240(1-2):157–64.CrossRefPubMed
45.
Hazeldine J, et al. Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell. 2014;13(4):690–8.CrossRefPubMedPubMedCentral
46.
Smith BD, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1–32.PubMed
47.
Cooney JK, et al. Benefits of exercise in rheumatoid arthritis. J Aging Res. 2011;2011:681640.CrossRefPubMedPubMedCentral
48.
Stenstrom CH, Minor MA. Evidence for the benefit of aerobic and strengthening exercise in rheumatoid arthritis. Arthritis Rheum. 2003;49(3):428–34.CrossRefPubMed
49.
Plasqui G. The role of physical activity in rheumatoid arthritis. Physiol Behav. 2008;94(2):270–5.CrossRefPubMed
50.
Fenton SAM, et al. Sedentary behaviour in rheumatoid arthritis: definition, measurement and implications for health. Rheumatology (Oxford). 2018;57(2):213–26.CrossRef
51.
Hakkinen A, et al. A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. Arthritis Rheum. 2001;44(3):515–22.CrossRefPubMed
52.
Hakkinen A, et al. Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up. Ann Rheum Dis. 2004;63(8):910–6.CrossRefPubMedPubMedCentral
53.
van den Ende CH, et al. Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 2000;59(8):615–21.CrossRefPubMedPubMedCentral
54.
Komatireddy GR, et al. Efficacy of low load resistive muscle training in patients with rheumatoid arthritis functional class II and III. J Rheumatol. 1997;24(8):1531–9.PubMed
55.
Stavropoulos-Kalinoglou A, et al. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72(11):1819–25.CrossRefPubMed
56.
Walsh NP, et al. Position statement part one: immune function and exercise. Exerc Immunol Rev. 2011;17:6–63.PubMed
57.
Nieman DC, et al. Physical activity and immune function in elderly women. Med Sci Sports Exerc. 1993;25(7):823–31.CrossRefPubMed
58.
Rall LC, et al. Effects of progressive resistance training on immune response in aging and chronic inflammation. Med Sci Sports Exerc. 1996;28(11):1356–65.CrossRefPubMed
59.
den Broeder AA, et al. Neutrophil migration and production of reactive oxygen species during treatment with a fully human anti-tumor necrosis factor-α monoclonal antibody in patients with rheumatoid arthritis. J Rheumatol. 2003;30(2):232–7.PubMed
60.
Miesel R, Murphy MP, Kroger H. Enhanced mitochondrial radical production in patients which rheumatoid arthritis correlates with elevated levels of tumor necrosis factor α in plasma. Free Radic Res. 1996;25(2):161–9.CrossRefPubMed
61.
Talbot J, et al. CCR2 expression in neutrophils plays a critical role in their migration into the joints in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(7):1751–9.CrossRefPubMed
62.
Fuente MDL, Hernanz A, Vallejo M. The immune system in the oxidative stress conditions of aging and hypertension: favorable effects of antioxidants and physical exercise. Antioxid Redox Signal. 2005;7(9-10):1356–66.CrossRefPubMed
63.
Syu GD, Chen HI, Jen CJ. Differential effects of acute and chronic exercise on human neutrophil functions. Med Sci Sports Exerc. 2012;44(6):1021–7.CrossRefPubMed
64.
Babior BM. Phagocytes and oxidative stress. Am J Med. 2000;109(1):33–44.CrossRefPubMed
65.
Hazeldine J, Lord J. Innate immunesenescence: underlying mechanisms and clinical relevance. Biogerontology. 2015;16(2):187–201.CrossRefPubMed
66.
de Siqueira MB, et al. Enhanced neutrophil phagocytic capacity in rheumatoid arthritis related to the autoantibodies rheumatoid factor and anti-cyclic citrullinated peptides. BMC Musculoskelet Disord. 2015;16:159.CrossRefPubMedPubMedCentral
67.
Paino IM, et al. Phagocytosis and nitric oxide levels in rheumatic inflammatory states in elderly women. J Clin Lab Anal. 2011;25(1):47–51.CrossRefPubMed
68.
Turner RA, Schumacher R, Myers AR. Phagocytic function of polymorphonuclear leukocytes in rheumatic diseases. J Clin Invest. 1973;52(7):1632–5.CrossRefPubMedPubMedCentral
69.
Wynne KM, et al. Cellular phagocytic studies in rheumatoid arthritis patients treated with levamisole. Ann Rheum Dis. 1981;40(4):382–7.CrossRefPubMedPubMedCentral
70.
Okuda K, et al. An investigation of leukocyte function and phagocytosis of immune complexes in patients with rheumatoid arthritis. Jpn J Exp Med. 1975;45(1):1–10.PubMed
71.
Wong KL, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 2011;118(5):e16–31.CrossRefPubMed
72.
Ziegler-Heitbrock L, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74–80.CrossRefPubMed
73.
Cros J, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010;33(3):375–86.CrossRefPubMedPubMedCentral
74.
Huang QQ, Pope RM. Role of Toll like receptors in rheumatoid arthritis. Curr Rheumatol Rep. 2009;11(5):357–64.CrossRefPubMedPubMedCentral
75.
Bartlett DB, et al. A novel inflammatory biomarker, GlycA, associates with disease activity in rheumatoid arthritis and cardio-metabolic risk in BMI-matched controls. Arthritis Res Ther. 2016;18(86)
76.
Huffman KM, et al. Response of high-sensitivity C-reactive protein to exercise training in an at-risk population. Am Heart J. 2006;152(4):793–800.CrossRefPubMed
77.
Krüger K, et al. Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms. Brain Behav Immun. 2008;22(3):324–38.CrossRefPubMed
78.
Kruger K, Mooren FC. T cell homing and exercise. Exerc Immunol Rev. 2007;13:37–54.PubMed