Biological treatment and exercise as an alternative to typical rheumatoid arthritis therapy: pathophysiology and effects
DOI:
https://doi.org/10.12775/JEHS.2023.13.04.001Keywords
rheumatoid arthritis, bDMARDs, exercises, pathomechanismAbstract
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology that mainly affects the joints, but extra-articular symptoms may also occur. The global prevalence of RA is approximately 5 cases per 1,000 adults[1]. A better understanding of the pathophysiology of the disease in the treatment of RA has led to the development of more effective treatments. Current drugs include glucocorticoids (GCs) and synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs). Apart from these, the most commonly used analgesics are non-steroidal anti-inflammatory drugs (NSAIDs). BLMPs work by targeting specific molecules involved in the inflammatory process, not just symptom relief.
Purpose: To review the currently available PubMed data on biologics and exercise for RA and their mechanisms in the context of disease pathophysiology and future prospects.
Brief description of the state of knowledge: BLMPs are a necessary alternative in patients who have not achieved the treatment goal for 6 months or have experienced side effects during treatment with conventional disease-modifying drugs. We also analyzed the effect of exercise on the course of RA.
Conclusions: The introduction of bDMARDs has opened a new era in the treatment of diseases such as RA. However, due to the difficult access to this form of therapy, side effects, contraindications to currently used drugs, and increasingly well-known mechanisms, there is also a need to constantly search for new solutions. A growing body of evidence in recent years suggests that regular physical activity has a positive effect on various aspects of RA, including disease-related outcomes, mental well-being, and cardiovascular health. Also in this non-pharmacological field, further research is needed to fully understand the mechanisms behind these effects.
References
Aletaha D., Smolen J.S. Diagnosis and management of rheumatoid arthritis: A review. JAMA. 2018;320:1360–1372. doi: 10.1001/jama.2018.13103.
Firestein G.S., McInnes I.B. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017;46:183–196. doi: 10.1016/j.immuni.2017.02.006.
Guo Q., Wang Y., Xu D., Nossent J., Pavlos N.J., Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:1–14. doi: 10.1038/s41413-018-0016-9
Lin Y.-J., Anzaghe M., Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells. 2020;9:880. doi: 10.3390/cells9040880
Altawil R., Saevarsdottir S., Wedrén S., Alfredsson L., Klareskog L., Lampa J. Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate. Arthritis Care Res. 2016;68:1061–1068. doi: 10.1002/acr.22790.
Westhovens, R.; Robles, M.; Ximenes, AC; Nayiager, S.; Wollenhaupt, J.; Durez, P.; Gomez-Reino, J.; Grassi, W.; Haraoui, B.; Shergi, W.; et al. Clinical efficacy and safety of abatacept in methotrexate-naïve patients with early rheumatoid arthritis and poor prognostic factors. Ann. Runny nose. dis. 2009, 68, 1870–1877.
Lebre, M.C.; Jongbloed, S.L.; Tas, S.W.; Smeets, T.J.; McInnes, I.; Tak, P.P. Rheumatoid Arthritis Synovium Contains Two Subsets of CD83−DC-LAMP− Dendritic Cells with Distinct Cytokine Profiles. Am. J. Pathol. 2008, 172, 940–950.
Charles, P.; Elliott, M.J.; Davis, D.; Potter, A.; Kalden, J.; Antoni, C.; Breedveld, F.C.; Smolen, J.S.; Eberl, G.; DeWoody, K.; et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J. Immunol. 1999, 163, 1521–1528.
Malmstrom V, Gronwall C. The Parallel Worlds of ACPA-Positive and RF-Positive B Cells. Nat Rev Rheumatol (2018) 14:626–8.
Martel-Pelletier J, Welsch DJ, Pelletier JP. Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol 2001; 15: 805–29.
Nielen MM, van Schaardenburg D, Reesink WH, et al. Specifi c autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50: 380–86.
Bohler C, Radner H, Smolen JS, Aletaha D. Serological changes in the course of traditional and biological disease modifying therapy of rheumatoid arthritis. Ann Rheum Dis 2013; 72: 241–44.
Smolen J.S., Landewé R.B.M., Bijlsma J.W.J., Burmester G.R., Dougados M., Kerschbaumer A., McInnes I.B., Sepriano A., van Vollenhoven R.F., de Wit M., et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020;79:685–699. doi: 10.1136/annrheumdis-2019-216655.
Van Ede A.E., Laan R.F., Rood M.J., Huizinga T.W., Van De Laar M.A., Denderen C.J.V., Westgeest T.A., Romme T.C., De Rooij D.J.R., Jacobs M.J. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: A forty-eight-week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. Off. J. Am. Coll. Rheumatol. 2001;44:1515–1524.
Jamilloux Y., El Jammal T., Vuitton L., Gerfaud-Valentin M., Kerever S., Sève P. JAK inhibitors for the treatment of autoimmune and inflammatory diseases. Autoimmun. Rev. 2019;18:102390. doi: 10.1016/j.autrev.2019.102390.
Smolen J.S., Landewé R.B.M., Bijlsma J.W.J., Burmester G.R., Dougados M., Kerschbaumer A., McInnes I.B., Sepriano A., van Vollenhoven R.F., de Wit M., et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020;79:685–699. doi: 10.1136/annrheumdis-2019-216655.
Ho C.T.K., Mok C.C., Cheung T.T., Kwok K.Y., Yip R.M.L. Management of rheumatoid arthritis: 2019 updated consensus recommendations from the Hong Kong Society of Rheumatology. Clin. Rheumatol. 2019;38:3331–3350. doi: 10.1007/s10067-019-04761-5.
Daien C.I., Charlotte H., Combe B., Landewe R. Non-pharmacological and pharmacological interventions in patients with early arthritis: A systematic literature review informing the 2016 update of EULAR recommendations for the management of early arthritis. RMD Open. 2017;3:e000404. doi: 10.1136/rmdopen-2016-000404.
Knut L. Radiosynovectomy in the therapeutic management of arthritis. World J. Nucl. Med. 2015;14:10. doi: 10.4103/1450-1147.150509.
Radu, A.-F.; Bungau, S.G. Management of Rheumatoid Arthritis: An Overview. Cells 2021, 10, 2857. https://doi.org/10.3390/cells10112857 Radu, A.-F.; Bungau, S.G. Management of Rheumatoid Arthritis: An Overview. Cells 2021, 10, 2857. https://doi.org/10.3390/cells10112857
Bonek K.; Roszkowski L.; Massalska, M.; Masliński W.; Ciechomska, M. Biological drugs for rheumatoid arthritis in the context of biosimilars, genetics, epigenetics and treatment of COVID-19. Cells 2021, 10, 323.
Üceyler N, Schäfers M, Sommer C (2009) Mode of action of cytokines on nociceptive neurons. Exp Brain Res 196:67–78
Furst, D.E.; Schiff, M.; Fleischmann, R.; Strand, V.A.; Birbara, C.; Compagnone, D.A.; Fischkoff, S.; Chartash, E.K. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: Results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J. Rheumatol. 2003, 30, 2563–2571.
Torrente-Segarra, V.; Arana, A.U.; Sanchez-Andrade, A.; Tovar, J.; Muñoz, Á.; Martinez, A.; Gonzalez, J.; Fernández, M.; Vazquez, N.; Corominas, H. RENACER Study: Assessment of 12-month efficacy and safety of 168 certolizumab-PEGol rheumatoid arthritis treated patients from a Spanish multicenter National database. Mod. Rheumatol. 2015, 26, 1–18.
Singh, J. A.; Christensen, R.; Wells, Georgia; Suarez-Almazor, ME; Buchbinder R.; Lopez-Olivo, MA; Ghogomu, ET; Tugwell, P. Network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane review. They can. Med. doc. J. 2009, 181, 787–796.
Jorgensen, T.; Turesson, C.; Kapetanovic, M.; Englund, M.; Turkiewicz, A.; Christensen, R.; Bliddal, H.; Geborek, P.; Kristensen, L. EQ-5D drug utility, response and survival in patients with rheumatoid arthritis in biologic monotherapy: a prospective observational study of patients enrolled in the South Swedish SSATG registry. PLOS ONE 2017, 12, e0169946.
Iannone F., Favalli E.G., Caporali R., D’Angelo S., Cantatore F.P., Sarzi-Puttini P., Foti R., Conti F., Carletto A., Gremese E., et al. Golimumab Effectiveness in Biologic Inadequate Responding Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Spondyloarthritis in Real-Life from the Italian Registry GISEA. Joint Bone Spine. 2021;88:105062.
Ramírez, J.; Cañete, J.D. Anakinra for the treatment of rheumatoid arthritis: A safety evaluation. Expert Opin. Drug Saf. 2018, 17, 727–732.
Minozzi, S.; Bonovas, S.; Lytras, T.; Pecoraro, V.; González-Lorenzo, M.; Bastiampillai, A.J.; Gabrielli, E.M.; Lonati, A.C.; Moja, L.; Cinquini, M.; et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: A systematic review and meta-analysis. Expert. Opin. Drug Saf. 2016, 15, 11–34.
Kang, E.H.; Jin, Y.; Tong, A.Y.; Desai, R.J.; Kim, S.C. Risk of Serious Infection Among Initiators of Tumor Necrosis Factor Inhibitors Plus Methotrexate Versus Triple Therapy for Rheumatoid Arthritis: A Cohort Study. Arthritis Care Res. 2020, 72, 1383–1391
Scher, J.U. B-cell therapies for rheumatoid arthritis. Bull. Nyu Hosp. Jt. Dis. 2012, 70, 200–203.
Edwards, J.C.W.; Szczepanski, L.; Szchechinski, J.; Filipowiz-Sosonowska, A.; Emery, P.; Close, D.R.; Stevens, R.M.; Shaw, T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 2004, 350, 2572–2581.
Harrold LR, John A, Best J, Zlotnick S, Karki C, Li Y, Greenberg JD, Kremer JM (2017) Impact of rituximab on patient-reported outcomes in patients with rheumatoid arthritis from the US Corrona Registry. Clin Rheumatol 36(9):2135–2140.
Avci, A.B.; Feist, E.; Burmester, G.R. Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What’s the Difference? BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2018, 32, 531–546.
Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081–91.
Pawar, A.; Desai, R.J.; Solomon, D.H.; Santiago Ortiz, A.J.; Gale, S.; Bao, M.; Sarsour, K.; Schneeweiss, S.; Kim, S.C. Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: A multidatabase cohort study. Ann. Rheum. Dis. 2019, 78, 456–464.
Jeon, H.L.; Kim, S.C.; Park, S.H.; Shin, J.Y. The risk of serious infection in rheumatoid arthritis patients receiving tocilizumab compared with tumor necrosis factor inhibitors in Korea. Semin. Arthritis Rheum. 2021, 51, 989–995.
Koike, T.; Harigai, M.; Inokuma, S.; Ishiguro, N.; Ryu, J.; Takeuchi, T.; Takei, S.; Tanaka, Y.; Ito, K.; Yamanaka, H. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: Interim analysis of 3881 patients. Ann. Rheum. Dis. 2011, 70, 2148–2151.
McInnes IB, Schett G. Pathogenesis of rheumatoid arthritis. N English J Med. 2011; 365 (23): 2205–2219.
Schiff M. Abatacept treatment of rheumatoid arthritis. Rheumatology (Oxford) 2011; 50(3):437–449.
Peichl, P.; Alten, R.; Galeazzi, M.; Lorenz, H.-M.; Nußlein, H.; Navarro, F.; Elbez, Y.; Chartier, M.; Hackl, R.; Rauch, C.; et al. Abatacept retention and clinical outcomes in Austrian rheumatoid arthritis patients: real-world data from the 2-year ACTION trial. Vienna. Med. Wochenschr. 2019, 170, 1–9.
Sokołów, J.; Schiff, M.; Fleischmann R.; Weinblatt, I; Connolly, SE; Johnson, A.; Zhu, J.; Maldonado, MA; Patel S.; Robinson, WH Robinson, Effect of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes after treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE study. Ann. Runny nose. dis. 2015, 75, 709–714.
Westhovens, R.; Robles, M.; Ximenes, A.C.; Nayiager, S.; Wollenhaupt, J.; Durez, P.; Gomez-Reino, J.; Grassi, W.; Haraoui, B.; Shergy, W.; et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann. Rheum. Dis. 2009, 68, 1870–1877.
Alten, R.; Kaine, J.; Keystone, E.; Nash, P.; Delaet, I.; Genovese, M.C. Long-term safety of subcutaneous abatacept in rheumatoid arthritis: Integrated analysis of clinical trial data representing more than four years of treatment. Arthritis Rheumatol. 2014, 66, 1987–1997.
Chen, S.K.; Liao, K.P.; Liu, J.; Kim, S.C. Risk of Hospitalized Infection and Initiation of Abatacept Versus Tumor Necrosis Factor Inhibitors Among Patients with Rheumatoid Arthritis: A Propensity Score-Matched Cohort Study. Arthritis Care Res. 2020, 72, 9–17.
Klontzas, M.E.; Kenanidis, E.I.; Heliotis, M.; Tsiridis, E.; Mantalaris, A. Bone and cartilage regeneration with the use of umbilical cord mesenchymal stem cells. Expert Opin. Boil. Ther. 2015, 15, 1541–1552.
Lopez-Santalla M., Bueren J.A., Garin M.I. Mesenchymal stem/stromal cell-based therapy for the treatment of rheumatoid arthritis: An update on preclinical studies. EBioMedicine. 2021;69:103427. doi: 10.1016/j.ebiom.2021.103427.
Uccelli A., de Rosbo N.K. The immunomodulatory function of mesenchymal stem cells: Mode of action and pathways. Ann. N. Y. Acad. Sci. 2015;1351:114–126. doi: 10.1111/nyas.12815
Ansboro S., Roelofs A.J., De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: Immune modulation, repair or both? Curr. Opin. Rheumatol. 2017;29:201–207. doi: 10.1097/BOR.0000000000000370.
Di Nicola, M.; Carlo-Stella, C.; Magni, M.; Milanesi, M.; Longoni, P.D.; Matteucci, P.; Grisanti, S.; Gianni, A.M. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002, 99, 3838–3843.
Krampera, M.; Glennie, S.; Dyson, J.; Scott, D.; Laylor, R.; Simpson, E.; Dazzi, F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003, 101, 3722–3729.
Aggarwal, S.; Pittenger, M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105, 1815–1822
Zheng, Z.H.; Li, X.Y.; Ding, J.; Jia, J.F.; Zhu, P. Allogeneic mesenchymal stem cell and mesenchymal stem cell-differentiated chondrocyte suppress the responses of type II collagen-reactive T cells in rheumatoid arthritis. Rheumatology 2008, 47, 22–30.
Zhang, Q.; Li, Q.; Zhu, J.; Guo, H.; Zhai, Q.; Li, B.; Jin, Y.; He, X.; Jin, F. Comparison of therapeutic effects of different mesenchymal stem cells on rheumatoid arthritis in mice. PeerJ 2019, 7, e7023.
Guo, C.; Fu, R.; Wang, S.; Huang, Y.; Li, X.; Zhou, M.; Zhao, J.; Yang, N. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 2018, 194, 231–243.
Sarsenova M, Issabekova A, Abisheva S, Rutskaya-Moroshan K, Ogay V, Saparov A. Mesenchymal Stem Cell-Based Therapy for Rheumatoid Arthritis. Int J Mol Sci. 2021 Oct 27;22(21):11592. doi: 10.3390/ijms222111592. PMID: 34769021; PMCID: PMC8584240.
Williamson, D.J.; Begley, C.G.; Vadas, M.A.; Metcalf, D. The detection and initial characterization of colony-stimulating factors in synovial fluid. Clin. Exp. Immunol. 1988, 72, 67–73.
Xu, W.D.; Firestein, G.S.; Taetle, R.; Kaushansky, K.; Zvaifler, N.J. Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J. Clin. Investig. 1989, 83, 876–882.
Berenbaum, F.; Rajzbaum, G.; Amor, B.; Toubert, A. Evidence for GM-CSF receptor expression in synovial tissue. An analysis by semi-quantitative polymerase chain reaction on rheumatoid arthritis and osteoarthritis synovial biopsies. Eur. Cytokine Netw. 1994, 5, 43–46
Cook, A.D.; Braine, E.L.; Campbell, I.K.; Rich, M.J.; Hamilton, J.A. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): Requirement for GM-CSF in the effector phase of disease. Arthritis Res. 2001, 3, 293–298.
Plater-Zyberk, C.; Joosten, L.A.B.; Helsen, M.M.A.; Hepp, J.; Baeuerle, P.A.; Berg, W.B.V.D. GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice. Ann. Rheum. Dis. 2006, 66, 452–457.
Roelofs, M.F.; Boelens, W.C.; Joosten, L.; Abdollahi-Roodsaz, S.; Geurts, J.; Wunderink, L.U.; Schreurs, B.W.; Berg, W.B.V.D.; Radstake, T.R.D.J. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J. Immunol. 2006, 176, 7021–7027.
Midwood, K.S.; Sacre, S.; Piccinini, A.M.; Inglis, J.; Trebaul, A.; Chan, E.; Drexler, S.; Sofat, N.; Kashiwagi, M.; Orend, G.; et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 2009, 15, 774–780.
Pierer, M.; Wagner, U.; Rossol, M.; Ibrahim, S. Toll-Like Receptor 4 Is Involved in Inflammatory and Joint Destructive Pathways in Collagen-Induced Arthritis in DBA1J Mice. PLoS ONE 2011, 6, e23539.
Monnet, E.; Choy, E.H.; McInnes, I.; Kobakhidze, T.; De Graaf, K.; Jacqmin, P.; Lapeyre, G.; De Min, C. Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: A phase II study. Ann. Rheum. Dis. 2019, 79, 316–323.
Steensberg A, Febbraio MA, Osada T, et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 2001;537:633-9
Febbraio MA, Hiscock N, Sacchetti M, et al. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004;53:1643-8
Metsios GS, Stavropoulos-Kalinoglou A, Panoulas VF, et al. New resting energy expenditure prediction equations for patients with rheumatoid arthritis. Rheumatology (Oxford) 2008;47:500-6
Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y, et al. Redefining overweight and obesity in rheumatoid arthritis patients. Ann Rheum Dis 2007;66:1316-21.
Metsios GS, Stavropoulos-Kalinoglou A, Veldhuijzen van Zanten JJ, et al. Individualised exercise improves endothelial function in patients with rheumatoid arthritis. Ann Rheum Dis 2014;73:748-51.
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