**6. References**

320 Rheumatoid Arthritis – Treatment

combined with mechanical stimulation may augment the chondroprotective effects of

Fig. 1. Hypothesized anti-inflammatory and anti-catabolic mechanisms underlying the

Compelling evidence suggests that physiologic exercise exerts beneficial effects in rheumatoid arthritis patients that not only increases quality of life but also suppresses disease activity. The beneficial effects are dependent on the mechanical nature of exercise, including the loading intensity, frequency, and duration. Exercise regimens may have varying effects with age and stage of disease. Furthermore, elucidating mechanisms underlying these beneficial effects of exercise may lead to the development of novel

The authors thank Dr. John Hardin for his critical reading of the manuscript and the

effects of exercise in suppressing cartilage destruction in arthritis.

therapeutic strategies to prevent joint destruction in rheumatoid arthritis.

National Institutes of Health for funding this work (AR52743 and AR47628-04).

**4. Conclusion** 

**5. Acknowledgment** 

exercise. However, these hypotheses still require further investigation.


Molecular Effects of Exercise in Rheumatoid Arthritis 323

Deschner, J., B. Rath-Deschner, & S. Agarwal (2006). Regulation of matrix metalloproteinase

Dossumbekova, A., M. Anghelina, S. Madhavan, L. He, N. Quan, T. Knobloch, & S. Agarwal

Ekblom, B., O. Lovgren, M. Alderin, M. Fridstrom, & G. Satterstrom (1975). Effect of short-

Elsaid, K. A., G. D. Jay, & C. O. Chichester (2007). Reduced expression and proteolytic

Fernandes, J. C., J. Martel-Pelletier, & J. P. Pelletier (2002). The role of cytokines in

Ferretti, M., R. Gassner, Z. Wang, P. Perera, J. Deschner, G. Sowa, R. B. Salter, & S. Agarwal

Forestier, R., J. Andre-Vert, P. Guillez, E. Coudeyre, M. M. Lefevre-Colau, B. Combe, & M.

Gassner, R., M. J. Buckley, H. Georgescu, R. Studer, M. Stefanovich-Racic, N. P. Piesco, C. H.

Ghosh, S., & M. Karin (2002). Missing pieces in the NF-kappaB puzzle. *Cell* Vol.109 Suppl,

(Dec 2006), pp. (8757-66), ISSN 0022-1767 (Print), 0022-1767 (Linking) Ferretti, M., A. Srinivasan, J. Deschner, R. Gassner, F. Baliko, N. Piesco, R. Salter, & S.

2009), pp. (691-8), ISSN 1778-7254 (Electronic), 1297-319X (Linking)

(Aug 1999), pp. (2187-92), ISSN 0022-1767 (Print), 0022-1767 (Linking) Geborek, P., M. Crnkic, I. F. Petersson, & T. Saxne (2002). Etanercept, infliximab, and

(Sep 2002), pp. (793-8), ISSN 0003-4967 (Print), 0003-4967 (Linking)

Apr 2002), pp. (S81-96), ISSN 0092-8674 (Print), 0092-8674 (Linking)

2007), pp. (3284-96), ISSN 0004-3591 (Print), 0004-3591 (Linking)

(Linking)

(Linking)

0300-9742 (Linking)

0006-355X (Print), 0006-355X (Linking)

0736-0266 (Print), 0736-0266 (Linking)

expression by dynamic tensile strain in rat fibrochondrocytes. *Osteoarthritis Cartilage* Vol.14, No.3, (Mar 2006), pp. (264-72), ISSN 1063-4584 (Print), 1063-4584

(2007). Biomechanical signals inhibit IKK activity to attenuate NF-kappaB transcription activity in inflamed chondrocytes. *Arthritis Rheum* Vol.56, No.10, (Oct

term physical training on patients with rheumatoid arthritis. a six-month follow-up study. *Scand J Rheumatol* Vol.4, No.2, (1975), pp. (87-91), ISSN 0300-9742 (Print),

susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen-induced arthritis. *Arthritis Rheum* Vol.56, No.1, (Jan 2007), pp. (108-16), ISSN 0004-3591 (Print), 0004-3591

osteoarthritis pathophysiology. *Biorheology* Vol.39, No.1-2, (2002), pp. (237-46), ISSN

(2006). Biomechanical signals suppress proinflammatory responses in cartilage: early events in experimental antigen-induced arthritis. *J Immunol* Vol.177, No.12,

Agarwal (2005). Anti-inflammatory effects of continuous passive motion on meniscal fibrocartilage. *J Orthop Res* Vol.23, No.5, (Sep 2005), pp. (1165-71), ISSN

A. Mayoux-Benhamou (2009). Non-drug treatment (excluding surgery) in rheumatoid arthritis: clinical practice guidelines. *Joint Bone Spine* Vol.76, No.6, (Dec

Evans, & S. Agarwal (1999). Cyclic tensile stress exerts antiinflammatory actions on chondrocytes by inhibiting inducible nitric oxide synthase. *J Immunol* Vol.163, No.4,

leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden. *Ann Rheum Dis* Vol.61, No.9,

Vol.172, No.11, (Jun 2004), pp. (6744-50), ISSN 0022-1767 (Print), 0022-1767 (Linking)


Chowdhury, T. T., D. L. Bader, & D. A. Lee (2003). Dynamic compression counteracts IL-1

Chowdhury, T. T., D. L. Bader, & D. A. Lee (2006). Anti-inflammatory effects of IL-4 and

Darnell, J. E., Jr. (1997). STATs and gene regulation. *Science* Vol.277, No.5332, (Sep 1997), pp.

de Jong, Z., M. Munneke, L. M. Jansen, K. Ronday, D. J. van Schaardenburg, R. Brand, C. H.

de Jong, Z., M. Munneke, H. M. Kroon, D. van Schaardenburg, B. A. Dijkmans, J. M. Hazes,

de Jong, Z., M. Munneke, V. Vilim, A. H. Zwinderman, H. M. Kroon, H. K. Ronday, W. F.

de Jong, Z., M. Munneke, A. H. Zwinderman, H. M. Kroon, A. Jansen, K. H. Ronday, D. van

de Jong, Z., & T. P. Vliet Vlieland (2005). Safety of exercise in patients with rheumatoid

Deighton, C., R. O'Mahony, J. Tosh, C. Turner, & M. Rudolf (2009). Management of

Dekker, M. J., S. Lee, R. Hudson, K. Kilpatrick, T. E. Graham, R. Ross, & L. E. Robinson

2009), pp. (663-71), ISSN 1434-9949 (Electronic), 0770-3198 (Linking)

(688-96), ISSN 1063-4584 (Print), 1063-4584 (Linking)

(1630-5), ISSN 0036-8075 (Print), 0036-8075 (Linking)

ISSN 0004-3591 (Print), 0004-3591 (Linking)

(Electronic), 1462-0324 (Linking)

3591 (Print), 0004-3591 (Linking)

ISSN 1468-5833 (Electronic), 0959-535X (Linking)

(Print), 1040-8711 (Linking)

(Linking)

(Linking)

(Linking)

Vol.172, No.11, (Jun 2004), pp. (6744-50), ISSN 0022-1767 (Print), 0022-1767

beta-induced release of nitric oxide and PGE2 by superficial zone chondrocytes cultured in agarose constructs. *Osteoarthritis Cartilage* Vol.11, No.9, (Sep 2003), pp.

dynamic compression in IL-1beta stimulated chondrocytes. *Biochem Biophys Res Commun* Vol.339, No.1, (Jan 2006), pp. (241-7), ISSN 0006-291X (Print), 0006-291X

van den Ende, T. P. Vliet Vlieland, W. M. Zuijderduin, & J. M. Hazes (2004). Differences between participants and nonparticipants in an exercise trial for adults with rheumatoid arthritis. *Arthritis Rheum* Vol.51, No.4, (Aug 2004), pp. (593-600),

& T. P. Vliet Vlieland (2009). Long-term follow-up of a high-intensity exercise program in patients with rheumatoid arthritis. *Clin Rheumatol* Vol.28, No.6, (Jun

Lems, B. A. Dijkmans, F. C. Breedveld, T. P. Vliet Vlieland, J. M. Hazes, & J. Degroot (2008). Value of serum cartilage oligomeric matrix protein as a prognostic marker of large-joint damage in rheumatoid arthritis--data from the RAPIT study. *Rheumatology (Oxford)* Vol.47, No.6, (Jun 2008), pp. (868-71), ISSN 1462-0332

Schaardenburg, B. A. Dijkmans, C. H. Van den Ende, F. C. Breedveld, T. P. Vliet Vlieland, & J. M. Hazes (2003). Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. *Arthritis Rheum* Vol.48, No.9, (Sep 2003), pp. (2415-24), ISSN 0004-

arthritis. *Curr Opin Rheumatol* Vol.17, No.2, (Mar 2005), pp. (177-82), ISSN 1040-8711

rheumatoid arthritis: summary of NICE guidance. *BMJ* Vol.338, 2009), pp. (b702),

(2007). An exercise intervention without weight loss decreases circulating interleukin-6 in lean and obese men with and without type 2 diabetes mellitus. *Metabolism* Vol.56, No.3, (Mar 2007), pp. (332-8), ISSN 0026-0495 (Print), 0026-0495


Molecular Effects of Exercise in Rheumatoid Arthritis 325

Jay, G. D., U. Tantravahi, D. E. Britt, H. J. Barrach, & C. J. Cha (2001). Homology of lubricin

Johansson, A. C., A. S. Hansson, K. S. Nandakumar, J. Backlund, & R. Holmdahl (2001). IL-

King, D. E., P. Carek, A. G. Mainous, 3rd, & W. S. Pearson (2003). Inflammatory markers and

Knudsen, L. S., I. J. Christensen, T. Lottenburger, M. N. Svendsen, H. J. Nielsen, L. Nielsen,

Kowh, C., L. Anderson, J. Greene, D. Johnson, J. O'Dell, M. Robbins, W. Roberts Jr, R.

Lavie, C. J., R. J. Thomas, R. W. Squires, T. G. Allison, & R. V. Milani (2009). Exercise

Lemmey, A. B., S. M. Marcora, K. Chester, S. Wilson, F. Casanova, & P. J. Maddison (2009).

Leong, D. J., X. I. Gu, Y. Li, J. Y. Lee, D. M. Laudier, R. J. Majeska, M. B. Schaffler, L.

Leong, D. J., Y. H. Li, X. I. Gu, L. Sun, Z. Zhou, P. Nasser, D. M. Laudier, J. Iqbal, R. J.

Liacini, A., J. Sylvester, W. Q. Li, W. Huang, F. Dehnade, M. Ahmad, & M. Zafarullah (2003).

2003), pp. (575-81), ISSN 0195-9131 (Print), 0195-9131 (Linking)

ISSN 0736-0266 (Print), 0736-0266 (Linking)

ISSN 1354-750X (Print), 1354-750X (Linking)

1942-5546 (Electronic), 0025-6196 (Linking)

34), ISSN 0004-3591 (Print), 0004-3591 (Linking)

(Print), 0004-3591 (Linking)

053X (Linking)

6638 (Linking)

(Print), 0014-4827 (Linking)

and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. *J Orthop Res* Vol.19, No.4, (Jul 2001), pp. (677-87),

10-deficient B10.Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies. *J Immunol* Vol.167, No.6, (Sep 2001), pp. (3505-12), ISSN 0022-1767 (Print), 0022-1767 (Linking)

exercise: differences related to exercise type. *Med Sci Sports Exerc* Vol.35, No.4, (Apr

K. Horslev-Petersen, J. E. Jensen, G. Kollerup, & J. S. Johansen (2008). Pre-analytical and biological variability in circulating interleukin 6 in healthy subjects and patients with rheumatoid arthritis. *Biomarkers* Vol.13, No.1, (Feb 2008), pp. (59-78),

Simms, & R. Yood (2002). Guidelines for the management of rheumatoid arthritis: 2002 Update. *Arthritis Rheum* Vol.46, No.2, (Feb 2002), pp. (328-46), ISSN 0004-3591

training and cardiac rehabilitation in primary and secondary prevention of coronary heart disease. *Mayo Clin Proc* Vol.84, No.4, (Apr 2009), pp. (373-83), ISSN

Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial. *Arthritis Rheum* Vol.61, No.12, (Dec 15 2009), pp. (1726-

Cardoso, & H. B. Sun (2010). Matrix metalloproteinase-3 in articular cartilage is upregulated by joint immobilization and suppressed by passive joint motion. *Matrix Biol* Vol.29, No.5, (Jun 2010), pp. (420-6), ISSN 1569-1802 (Electronic), 0945-

Majeska, M. B. Schaffler, M. B. Goldring, L. Cardoso, M. Zaidi, & H. B. Sun (2011). Physiological loading of joints prevents cartilage degradation through CITED2. *FASEB J* Vol.25, No.1, (Jan 2011), pp. (182-91), ISSN 1530-6860(Electronic), 0892-

Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. *Exp Cell Res* Vol.288, No.1, (Aug 2003), pp. (208-17), ISSN 0014-4827


Hakkinen, A. (2004). Effectiveness and safety of strength training in rheumatoid arthritis.

Hakkinen, A., A. Pakarinen, P. Hannonen, H. Kautiainen, K. Nyman, W. J. Kraemer, & K.

Hall, J., S. M. Skevington, P. J. Maddison, & K. Chapman (1996). A randomized and

No.3, (Jun 1996), pp. (206-15), ISSN 0893-7524 (Print), 0893-7524 (Linking) Handschin, C., & B. M. Spiegelman (2008). The role of exercise and PGC1alpha in

Haskell, W. L., I. M. Lee, R. R. Pate, K. E. Powell, S. N. Blair, B. A. Franklin, C. A. Macera, G.

Hoffmann, A., A. Levchenko, M. L. Scott, & D. Baltimore (2002). The IkappaB-NF-kappaB

Hurkmans, E., F. J. van der Giesen, T. P. Vliet Vlieland, J. Schoones, & E. C. Van den Ende

(2009), pp. (CD006853), ISSN 1469-493X (Electronic), 1361-6137 (Linking) Isenberg, D., A. Bull, A. Unsworth, & A. Amis (2004). Biomechanics of articulations and

Jay, G. D., K. A. Elsaid, J. Zack, K. Robinson, F. Trespalacios, C. J. Cha, & C. O. Chichester

(Aug 2007), pp. (1423-34), ISSN 0195-9131 (Print), 0195-9131 (Linking) Helmark, I. C., U. R. Mikkelsen, J. Borglum, A. Rothe, M. C. Petersen, O. Andersen, H.

ISSN 1476-4687 (Electronic), 0028-0836 (Linking)

1478-6362 (Electronic), 1478-6354 (Linking)

ISSN 0315-162X (Print), 0315-162X (Linking)

Aug 2005), pp. (505-12), ISSN 0392-856X (Print), 0392-856X (Linking) Hakkinen, A., T. Sokka, A. Kotaniemi, & P. Hannonen (2001). A randomized two-year study

1040-8711 (Linking)

3591 (Linking)

Press, Oxford.

*Curr Opin Rheumatol* Vol.16, No.2, (Mar 2004), pp. (132-7), ISSN 1040-8711 (Print),

Hakkinen (2005). Effects of prolonged combined strength and endurance training on physical fitness, body composition and serum hormones in women with rheumatoid arthritis and in healthy controls. *Clin Exp Rheumatol* Vol.23, No.4, (Jul-

of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. *Arthritis Rheum* Vol.44, No.3, (Mar 2001), pp. (515-22), ISSN 0004-3591 (Print), 0004-

controlled trial of hydrotherapy in rheumatoid arthritis. *Arthritis Care Res* Vol.9,

inflammation and chronic disease. *Nature* Vol.454, No.7203, (Jul 2008), pp. (463-9),

W. Heath, P. D. Thompson, & A. Bauman (2007). Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. *Med Sci Sports Exerc* Vol.39, No.8,

Langberg, & M. Kjaer (2010). Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial. *Arthritis Res Ther* Vol.12, No.4, (2010), pp. (R126), ISSN

signaling module: temporal control and selective gene activation. *Science* Vol.298, No.5596, (Nov 2002), pp. (1241-5), ISSN 1095-9203 (Electronic), 0036-8075 (Linking)

(2009). Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. *Cochrane Database Syst Rev* Vol.No.4,

derangements in disease, In: *Oxford Textbook of Rheumatology,* D. Isenberg, P. J. Maddison, P. Woo, D. Glass and F. Breedveld, pp. (379-386), Oxford University

(2004). Lubricating ability of aspirated synovial fluid from emergency department patients with knee joint synovitis. *J Rheumatol* Vol.31, No.3, (Mar 2004), pp. (557-64),


Molecular Effects of Exercise in Rheumatoid Arthritis 327

Milner, C. E. (2008). *Functional Anatomy for Sport and Exercise; Quick Reference* Routledge,

Minor, M. A., J. E. Hewett, R. R. Webel, S. K. Anderson, & D. R. Kay (1989). Efficacy of

Moffet, H., L. Noreau, E. Parent, & M. Drolet (2000). Feasibility of an eight-week dance-

Morse, C. I., J. M. Thom, O. S. Mian, K. M. Birch, & M. V. Narici (2007). Gastrocnemius

Muller-Riemenschneider, F., C. Meinhard, K. Damm, C. Vauth, A. Bockelbrink, W. Greiner,

Muller, R. D., T. John, B. Kohl, A. Oberholzer, T. Gust, A. Hostmann, M. Hellmuth, D.

Murphy, M., A. Nevill, C. Neville, S. Biddle, & A. Hardman (2002). Accumulating brisk

Neill, J., I. Belan, & K. Ried (2006). Effectiveness of non-pharmacological interventions for

Neuberger, G. B., L. S. Aaronson, B. Gajewski, S. E. Embretson, P. E. Cagle, J. K. Loudon, &

Nieman, D. (2000). Exercise Soothes Arthritis Joint Effects. *ACSM's Health and Fitness Journal*

Olson, T. P., D. R. Dengel, A. S. Leon, & K. H. Schmitz (2007). Changes in inflammatory

pp. (100-11), ISSN 0893-7524 (Print), 0893-7524 (Linking)

(688-700), ISSN 1741-8275 (Electronic), 1741-8267 (Linking)

35), ISSN 0309-2402 (Print), 0309-2402 (Linking)

Vol.4, No.3, (2000), pp. (20-27), ISSN 1091-5397 (Print)

physical conditioning exercise in patients with rheumatoid arthritis and osteoarthritis. *Arthritis Rheum* Vol.32, No.11, (Nov 1989), pp. (1396-405), ISSN 0004-

based exercise program and its effects on locomotor ability of persons with functional class III rheumatoid arthritis. *Arthritis Care Res* Vol.13, No.2, (Apr 2000),

specific force is increased in elderly males following a 12-month physical training programme. *Eur J Appl Physiol* Vol.100, No.5, (Jul 2007), pp. (563-70), ISSN 1439-

& S. N. Willich (2011). Effectiveness of nonpharmacological secondary prevention of coronary heart disease. *Eur J Cardiovasc Prev Rehabil* Vol.17, No.6, (Dec 2011), pp.

Laface, B. Hutchins, G. Laube, R. W. Veh, S. K. Tschoeke, W. Ertel, & G. Schulze-Tanzil (2008). IL-10 overexpression differentially affects cartilage matrix gene expression in response to TNF-alpha in human articular chondrocytes in vitro. *Cytokine* Vol.44, No.3, (Dec 2008), pp. (377-85), ISSN 1096-0023 (Electronic), 1043-

walking for fitness, cardiovascular risk, and psychological health. *Med Sci Sports Exerc* Vol.34, No.9, (Sep 2002), pp. (1468-74), ISSN 0195-9131 (Print), 0195-9131

fatigue in adults with multiple sclerosis, rheumatoid arthritis, or systemic lupus erythematosus: a systematic review. *J Adv Nurs* Vol.56, No.6, (Dec 2006), pp. (617-

P. A. Miller (2007). Predictors of exercise and effects of exercise on symptoms, function, aerobic fitness, and disease outcomes of rheumatoid arthritis. *Arthritis Rheum* Vol.57, No.6, (Aug 2007), pp. (943-52), ISSN 0004-3591 (Print), 0004-3591

biomarkers following one-year of moderate resistance training in overweight women. *Int J Obes (Lond)* Vol.31, No.6, (Jun 2007), pp. (996-1003), ISSN 0307-0565

Oxfordshire.

4666 (Linking)

(Linking)

(Linking)

(Print), 0307-0565 (Linking)

3591 (Print), 0004-3591 (Linking)

6319 (Print), 1439-6319 (Linking)


Lubberts, E., L. A. Joosten, M. M. Helsen, & W. B. van den Berg (1998). Regulatory role of

Lundberg, I. E., & G. A. Nader (2008). Molecular effects of exercise in patients with

Madhavan, S., M. Anghelina, B. Rath-Deschner, E. Wypasek, A. John, J. Deschner, N. Piesco,

Madhavan, S., M. Anghelina, D. Sjostrom, A. Dossumbekova, D. C. Guttridge, & S. Agarwal

Maini, R., & M. Feldmann (2004). Rheumatoid arthritis: immunopathgenesis of rheumatoid

Marcora, S. M., A. B. Lemmey, & P. J. Maddison (2005). Can progressive resistance training

Matschke, V., P. Murphy, A. B. Lemmey, P. Maddison, & J. M. Thom (2010). Skeletal muscle

No.2, (Mar 2001), pp. (320-32), ISSN 0730-2312 (Print), 0730-2312 (Linking) Medicine, A. C. o. S., L. Durstine, G. Moore, P. Painter, & S. Roberts (2009). *ACSM's Exercise* 

Melikoglu, M. A., S. Karatay, K. Senel, & F. Akcay (2006). Association between dynamic

Metsios, G. S., A. Stavropoulos-Kalinoglou, A. Sandoo, J. J. van Zanten, T. E. Toms, H. John,

Millward-Sadler, S. J., & D. M. Salter (2004). Integrin-dependent signal cascades in

2010), pp. (2149-55), ISSN 1530-0315 (Electronic), 0195-9131 (Linking) McHugh, K. P., S. Kitazawa, S. L. Teitelbaum, & F. P. Ross (2001). Cloning and

1998), pp. (361-9), ISSN 1043-4666 (Print), 1043-4666 (Linking)

pp. (597-604), 1745-8390 (Electronic), ISSN 1745-8390 (Linking)

2007), pp. (6246-54), ISSN 0022-1767 (Print), 0022-1767 (Linking)

Glass and F. Breedveld, pp. Oxford University Press, Oxford.

(Linking)

Kinetics, 0736074333, Champaign.

0172-8172 (Print), 0172-8172 (Linking)

(435-46), ISSN 0090-6964 (Print), 0090-6964 (Linking)

1874-1924 (Electronic)

interleukin 10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10 combination therapy than with IL-10 treatment alone. *Cytokine* Vol.10, No.5, (May

inflammatory rheumatic disease. *Nat Clin Pract Rheumatol* Vol.4, No.11, (Nov 2008),

& S. Agarwal (2006). Biomechanical signals exert sustained attenuation of proinflammatory gene induction in articular chondrocytes. *Osteoarthritis Cartilage* Vol.14, No.10, (Oct 2006), pp. (1023-32), ISSN 1063-4584 (Print), 1063-4584 (Linking)

(2007). Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes. *J Immunol* Vol.179, No.9, (Nov

arthritis, In: *Oxford Textbook of Rheumatology,* D. Isenberg, P. J. Maddison, P. Woo, D.

reverse cachexia in patients with rheumatoid arthritis? Results of a pilot study. *J Rheumatol* Vol.32, No.6, (Jun 2005), pp. (1031-9), ISSN 0315-162X (Print), 0315-162X

properties in rheumatoid arthritis patients. *Med Sci Sports Exerc* Vol.42, No.12, (Dec

characterization of the murine beta(3) integrin gene promoter: identification of an interleukin-4 responsive element and regulation by STAT-6. *J Cell Biochem* Vol.81,

*Management for Persons with Chronic Diseases and Disabilities-3rd Edition* Human

exercise therapy and IGF-1 and IGFBP-3 concentrations in the patients with rheumatoid arthritis. *Rheumatol Int* Vol.26, No.4, (Feb 2006), pp. (309-13), ISSN

& G. D. Kitas (2010). Vascular function and inflammation in rheumatoid arthritis: the role of physical activity. *Open Cardiovasc Med J* Vol.4, (2010), pp. (89-96), ISSN

chondrocyte mechanotransduction. *Ann Biomed Eng* Vol.32, No.3, (Mar 2004), pp.


Molecular Effects of Exercise in Rheumatoid Arthritis 329

Starkie, R., S. R. Ostrowski, S. Jauffred, M. Febbraio, & B. K. Pedersen (2003). Exercise

Steensberg, A., C. P. Fischer, C. Keller, K. Moller, & B. K. Pedersen (2003). IL-6 enhances

No.2, (Aug 2003), pp. (E433-7), ISSN 0193-1849 (Print), 0193-1849 (Linking) Stenstrom, C. H., & M. A. Minor (2003). Evidence for the benefit of aerobic and

Sun, H. B. (2010). Mechanical loading, cartilage degradation, and arthritis. *Ann N Y Acad Sci*

Suzuki, K., H. Nakajima, K. Ikeda, Y. Maezawa, A. Suto, H. Takatori, Y. Saito, & I. Iwamoto

Takeda, K., T. Tanaka, W. Shi, M. Matsumoto, M. Minami, S. Kashiwamura, K. Nakanishi,

van den Berg, M. H., H. K. Ronday, A. J. Peeters, S. le Cessie, F. J. van der Giesen, F. C.

van den Ende, C. H., F. C. Breedveld, S. le Cessie, B. A. Dijkmans, A. W. de Mug, & J. M.

van den Ende, C. H., J. M. Hazes, S. le Cessie, W. J. Mulder, D. G. Belfor, F. C.

van der Woude, D., A. Young, K. Jayakumar, B. J. Mertens, R. E. Toes, D. van der

2003), pp. (428-34), ISSN 0004-3591 (Print), 0004-3591 (Linking)

(13555-60), ISSN 0027-8424 (Print), 0027-8424 (Linking)

ISSN 0022-1007 (Print), 0022-1007 (Linking)

ISSN 0004-3591 (Print), 0004-3591 (Linking)

0003-4967 (Print), 0003-4967 (Linking)

(615-21), ISSN 0003-4967 (Print), 0003-4967 (Linking)

75), ISSN 1468-2060 (Electronic), 0003-4967 (Linking)

0892-6638 (Linking)

0028-0836 (Linking)

modifying antirheumatic drugs. *Ann Rheum Dis* Vol.69, No.6, (Jun 2010), pp. (964-

and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. *FASEB J* Vol.17, No.8, (May 2003), pp. (884-6), ISSN 1530-6860 (Electronic),

plasma IL-1ra, IL-10, and cortisol in humans. *Am J Physiol Endocrinol Metab* Vol.285,

strengthening exercise in rheumatoid arthritis. *Arthritis Rheum* Vol.49, No.3, (Jun

Vol.1211, (Nov 2010), pp. (37-50), ISSN 1749-6632 (Electronic), 0077-8923 (Linking) Sun, H. B., Y. X. Zhu, T. Yin, G. Sledge, & Y. C. Yang (1998). MRG1, the product of a

melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. *Proc Natl Acad Sci U S A* Vol.95, No.23, (Nov 1998), pp.

(2003). IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNFalpha production in mast cells. *J Exp Med* Vol.198, No.11, (Dec 2003), pp. (1717-27),

N. Yoshida, T. Kishimoto, & S. Akira (1996). Essential role of Stat6 in IL-4 signalling. *Nature* Vol.380, No.6575, (Apr 1996), pp. (627-30), ISSN 0028-0836 (Print),

Breedveld, & T. P. Vliet Vlieland (2006). Using internet technology to deliver a home-based physical activity intervention for patients with rheumatoid arthritis: A randomized controlled trial. *Arthritis Rheum* Vol.55, No.6, (Dec 2006), pp. (935-45),

Hazes (2000). Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial. *Ann Rheum Dis* Vol.59, No.8, (Aug 2000), pp.

Breedveld, & B. A. Dijkmans (1996). Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial. *Ann Rheum Dis* Vol.55, No.11, (Nov 1996), pp. (798-805), ISSN

Heijde, T. W. Huizinga, & A. H. van der Helm-van Mil (2009). Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts.


Pedersen, B. K., & M. A. Febbraio (2008). Muscle as an endocrine organ: focus on muscle-

Pedersen, B. K., & B. Saltin (2006). Evidence for prescribing exercise as therapy in chronic

Petersen, A. M., & B. K. Pedersen (2005). The anti-inflammatory effect of exercise. *J Appl* 

Petersen, A. M., & B. K. Pedersen (2006). The role of IL-6 in mediating the anti-inflammatory

Peterson, M. D., & P. M. Gordon (2011). Resistance exercise for the aging adult: clinical

Rall, L. C., S. N. Meydani, J. J. Kehayias, B. Dawson-Hughes, & R. Roubenoff (1996). The

Resnick, B. (2001). Managing arthritis with exercise. *Geriatr Nurs* Vol.22, No.3, (May-Jun

Roubenoff, R., R. A. Roubenoff, L. M. Ward, S. M. Holland, & D. B. Hellmann (1992).

Ryan, J. J., L. J. McReynolds, H. Huang, K. Nelms, & W. E. Paul (1998). Characterization of a

Seguin, C. A., & S. M. Bernier (2003). TNFalpha suppresses link protein and type II collagen

Smolen, J. S., R. Landewe, F. C. Breedveld, M. Dougados, P. Emery, C. Gaujoux-Viala, S.

(Aug 1998), pp. (1811-21), ISSN 0022-1767 (Print), 0022-1767 (Linking) Scott, D. L., F. Wolfe, & T. W. Huizinga (2010). Rheumatoid arthritis. *Lancet* Vol.376,

2001), pp. (143-50), ISSN 0197-4572 (Print), 0197-4572 (Linking)

(1505-10), ISSN 0315-162X (Print), 0315-162X (Linking)

0031-9333 (Print), 0031-9333 (Linking)

1899-1505 (Electronic), 0867-5910 (Linking)

(194-8), ISSN 1555-7162 (Electronic), 0002-9343 (Linking)

(Print), 0905-7188 (Linking)

(Linking)

(Linking)

(Linking)

9541 (Linking)

derived interleukin-6. *Physiol Rev* Vol.88, No.4, (Oct 2008), pp. (1379-406), ISSN

disease. *Scand J Med Sci Sports* Vol.16 Suppl 1, (Feb 2006), pp. (3-63), ISSN 0905-7188

*Physiol* Vol.98, No.4, (Apr 2005), pp. (1154-62), ISSN 8750-7587 (Print), 0161-7567

effects of exercise. *J Physiol Pharmacol* Vol.57 Suppl 10, (Nov 2006), pp. (43-51), ISSN

implications and prescription guidelines. *Am J Med* Vol.124, No.3, (Mar 2011), pp.

effect of progressive resistance training in rheumatoid arthritis. Increased strength without changes in energy balance or body composition. *Arthritis Rheum* Vol.39, No.3, (Mar 1996), pp. (415-26), ISSN 0004-3591 (Print), 0004-3591

Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. *J Rheumatol* Vol.19, No.10, (Oct 1992), pp.

mobile Stat6 activation motif in the human IL-4 receptor. *J Immunol* Vol.161, No.4,

No.9746, (Sep 2010), pp. (1094-108), ISSN 1474-547X (Electronic), 0140-6736

expression in chondrocytes: Role of MEK1/2 and NF-kappaB signaling pathways. *J Cell Physiol* Vol.197, No.3, (Dec 2003), pp. (356-69), ISSN 0021-9541 (Print), 0021-

Gorter, R. Knevel, J. Nam, M. Schoels, D. Aletaha, M. Buch, L. Gossec, T. Huizinga, J. W. Bijlsma, G. Burmester, B. Combe, M. Cutolo, C. Gabay, J. Gomez-Reino, M. Kouloumas, T. K. Kvien, E. Martin-Mola, I. McInnes, K. Pavelka, P. van Riel, M. Scholte, D. L. Scott, T. Sokka, G. Valesini, R. van Vollenhoven, K. L. Winthrop, J. Wong, A. Zink, & D. van der Heijde (2010). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs. *Ann Rheum Dis* Vol.69, No.6, (Jun 2010), pp. (964- 75), ISSN 1468-2060 (Electronic), 0003-4967 (Linking)


**16** 

 *United Kingdom* 

**Perceptions Relating to Exercise** 

*School of Sport, Health and Exercise Sciences, Bangor University, Wales,* 

Historically, the recommendation of exercise for patients with rheumatoid arthritis (RA) has been avoided by clinicians due to fears that such activity may contribute to joint damage and result in worsening of disease. Hence, previous treatment of active RA has included bed rest and splinting of the affected joints (Partridge & Duthie, 1962). Over recent decades however, the numerous physiological advantages of exercise have become well-established and include improved cardiovascular health, increased muscular hypertrophy and increased bone mineral density. Enhanced physical function and psychosocial advantages have also been shown in followers of a continued exercise programme (Baillet et al., 2009; Bilberg et al., 2005; de Jong et al, 2003, 2004; Hakkinen et al., 2001; Lemmey et al., 2009; Marcora et al., 2005; Melikoglu et al., 2006; Van Den Berg et al., 2006; van den Ende et al., 1996, 2000). Importantly, it has also been found that high-intensity exercise training is of superior effectiveness, with no detrimental effect on disease activity. This has been confirmed in patients with controlled (Ekdahl et al., 1990; Lemmey et al., 2009; van den Ende et al., 1996) and active RA (van den Ende et al., 2000). Furthermore, as advances in pharmacological treatment work to effectively control disease, this patient group are now able to tolerate regular, progressive and intensive exercise (Lemmey, 2011). A recent systematic review also provides further information as to the benefits, effectiveness and

Patients with RA are also at an increased risk for cardiovascular disease (Metsios et al., 2008), cachexia (Walsmith & Roubenoff, 2002) and osteoporotic fracture (Van Staa et al., 2006). Therefore, the aforementioned improvements associated with exercise are vital in limiting the negative consequences inherent to the disease. Furthermore, physical activity has been found to be a significant predictor of the number of hospital admissions and the length of hospitalisation in RA (Metsios et al., 2011). In light of this evidence, exercise is now considered an essential component within the management of this condition. However, despite this it is apparent that RA patients are less physically active than the general population (Sokka et al., 2008), and greater medical costs are coupled with this inactivity (Wang et al., 2001). Therefore it is important for those involved in the care of RA patients to be aware of factors that may positively and negatively affect the uptake and maintenance of

**1. Introduction** 

safety of exercise in RA (Hurkmans et al., 2009).

an exercise prescription for this patient group.

 **in Rheumatoid Arthritis** 

Rebecca-Jane Law, David Markland, Peter Maddison and Jeanette M. Thom

*Arthritis Rheum* Vol.60, No.8, (Aug 2009), pp. (2262-71), ISSN 0004-3591 (Print), 0004-3591 (Linking)


Rebecca-Jane Law, David Markland, Peter Maddison and Jeanette M. Thom *School of Sport, Health and Exercise Sciences, Bangor University, Wales, United Kingdom* 
