Rheumatoid arthritis of menopause: there are more questions than answers

The article is devoted to an urgent issue - rheumatoid arthritis (RA). The symptoms of arthritis appear in women during menopause. Literature data show that it is often during period of poor reproductive function that the disease first manifests itself in women. RA significantly affects the prognosis of women’s life expectancy and quality. The clinical and pathogenetic relationships between autoimmune diseases (one of which is RA) and the features of menopause remain poorly understood and require research. Basically, papers devoted to the problem present epidemiological studies and the study of the relationships between sex hormones levels and inflammatory mediators that are specific to RA.

A literature review on the features of the onset and course of rheumatoid arthritis in menopausal women is presented. The most accepted in the literature explanations characterizing the relationship between changes during menopause and RA are arguments about the protective effect of estrogens on the cells of the musculoskeletal system and the ability of estrogens to influence the intensity of inflammation (systemic inflammation of low intensity associated with age). In the case of the development of rheumatoid arthritis in old age, higher levels of IL-6 and lower TNFa are revealed. This fact gives rise to the choice of basic therapy in favor of a humanized monoclonal antibody to the human interleukin-6 receptor - tocilizumab.

The review may be of interest to both practising rheumatologists, neurologists, and gynecologists and general practitioners.

1. Nasonov E.L. (ed.). Russian Clinical Guidelines. Rheumatology. Moscow: GEOTAR-Media; 2017. 464 p. (In Russ.) Available at: https://www.rosm-edlib.ru/book/ISBN9785970442616.html.

2. Barysheva Yu.V., Ershova O.B., Beloselsky K.N. Quality of Life in Postmenopausal Women with Rheumatoid Arthritis and Osteoporosis. Osteoporoz i osteopatii = Osteoporosis and Osteopathy 2002;(3):6-12. (In Russ.) Available at: https://cyberleninka.ru/article/n/kachestvo-zhizni-u-zhenschin-s-revmatoidnym-artritom-i-osteoporozom-v-postmenopauze/viewer.

3. Carette S., Marcoux S., Gingras S. Postmenopausal Hormones and the Incidence of Rheumatoid Arthritis. J Rheumatol. 1989;16(7):911-913. Available at: https://pubmed.ncbi.nlm.nih.gov/2769663/.

4. Goemaere S., Ackerman C., Goethals K., De Keyser F., Van der Straeten C., Verbruggen G. et al. Onset of Symptoms of Rheumatoid Arthritis in Relation to Age, Sex and Menopausal Transition. J Rheumatol. 1990;17(12):1620-1622. Available at: https://pubmed.ncbi.nlm.nih.gov/2084234/.

5. Gabriel S.E. The Epidemiology of Rheumatoid Arthritis. Rheum Dis Clin North Am. 2001;27(2):269-281. https://doi.org/10.1016/s0889-857x(05)70201-5.

6. Ahlmen M., Svensson B., Albertsson K., Forslind K., Hafstrom I. Influence of Gender on Assessments of Disease Activity and Function in Early Rheumatoid Arthritis in Relation to Radiographic Joint Damage. Ann Rheum Dis. 2010;69(1):230-233. https://doi.org/10.1136/ard.2008.102244.

7. Sukhikh G.T., Smetnik V.P., Yureneva S.V., Ermakova E.I., Chernukha G.E., Yakushevskaya O.V. Menopause and Climacteric State in a Woman. Clinical Guidelines. Moscow: Ministry of Health of the Russian Federation; 2016. 45 p. (In Russ.) Available at: http://naonob.ru/media/2018/07/07/1241338634/Menopauza_i_klimaktericheskoe_sostoyanie_u_zhenshhiny.pdf.

8. Lleo A., Battezzati P.M., Selmi C., Gershwin M.E., Podda M. Is Autoimmunity a Matter of Sex? Autoimmun Rev. 2008;7(8):626-630. https://doi.org/10.1016/j.autrev.2008.06.009.

9. Ostensen M., Aune B., Husby G. Effect of Pregnancy and Hormonal Changes on the Activity of Rheumatoid Arthritis. ScandJ Rheumatol. 1983;12(2):69-72. https://doi.org/10.3109/03009748309102886.

10. Barrett L., Henzi P.S., Weingrill T., Lycett J.L., Hill R.A. Female Baboons Do Not Raise the Stakes But They Give As Good As They Get. Anim Behav. 2000;59(4):763-770. https://doi.org/10.1006/anbe.1999.1361.

11. Kanik K.S., Wilder R.L. Hormonal Alterations in Rheumatoid Arthritis, Including the Effects of Pregnancy. Rheum Dis Clin North Am. 2000;26(4):805-823. https://doi.org/10.1016/s0889-857x(05)70170-8.

12. Ostensen M. Sex Hormones and Pregnancy in Rheumatoid Arthritis and Systemic Lupus Erythematosus. Ann N Y Acad Sci. 1999;876:131-143. https://doi.org/10.1111/j.1749-6632.1999.tb07630.x.

13. Pikwer M., Bergstrom U., Nilsson J.A., Jacobsson L., Turesson C. Early Menopause Is an Independent Predictor of Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(3):378-381. https://doi.org/10.1136/ard.2011.200059.

14. Ali E.T., Alsharrad A.K., Shari F.H. 17p-Estradiol Hormone and Interleukin 1-Beta Change Related to Menopause in the Women with Rheumatoid Arthritis. Asian J Pharm. 2019;13(2):110-118. Available at: https://www.researchgate.net/publication/332849001.

15. Goemaere S., Ackerman C., Goethals K., De Keyser F., Van der Straeten C., Verbruggen G. et al. Onset of Symptoms of Rheumatoid Arthritis in Relation to Age, Sex and Menopausal Transition. J Rheumatol. 1990;17(12):1620-1622. Available at: https://pubmed.ncbi.nlm.nih.gov/2084234/.

16. Farage M.A., Miller K.W., Maibach H.I. Effects of Menopause on Autoimmune Diseases. Expert Rev Obstet Gynecol. 2012;(7):557-571. https://doi.org/10.1586/eog.12.63.

17. Kuiper S., van Gestel A.M., Swinkels H.L., de Boo T.M., da Silva J.A., van Riel P.L. Influence of Sex, Age, and Menopausal State on the Course of Early Rheumatoid Arthritis. J Rheumatol. 2001;(28):1809-1816. Available at: https://pubmed.ncbi.nlm.nih.gov/11508583/.

18. Camacho E.M., Verstappen S., Chipping J., Symmons D. Learned Helplessness Predicts Functional Disability, Pain and Fatigue in Patients with Recent-Onset Inflammatory Polyarthritis. Rheumatology. 2013;(52):1233-1238. https://doi.org/10.1093/rheumatology/kes434.

19. Gabriel S.E. The Epidemiology of Rheumatoid Arthritis. Rheum Dis Clin North Am. 2001;27(2):269-281. https://doi.org/10.1016/s0889-857x(05)70201-5.

20. Islander U., Jochems C., Lagerquist M.K., Forsblad-d'Elia H., Carlsten H. Estrogens in Rheumatoid Arthritis; the Immune System and Bone. Mol Cell Endocrinol. 2011;335(1):14-29. https://doi.org/10.1016/j.mce.2010.05.018.

21. Eun Y., Jeon K.H., Han K., Kim D., Lee J., Lee D. Menopausal Factors and Risk of Seropositive Rheumatoid Arthritis in Postmenopausal Women: A Nationwide Cohort Study of 1.36 Million Women. Sci Rep. 2020;10(1):20793. https://doi.org/10.1038/s41598-020-77841-1.

22. Ilyina L.M. Arthritis in Menopause (the Effect of Hormone Replacement Therapy). Ginekologiya = Gynecology. 2003;(2):79-81. (In Russ.) Available at: http://elib.fesmu.ru/elib/Article.aspx?id=94390.

23. Beydoun H.A., El-Amin R., McNeal M., Perry C., Archer D.F. Reproductive History and Postmenopausal Rheumatoid Arthritis among Women 60 Years or Older: Third National Health and Nutrition Examination Survey. Menopause. 2013;(20):930-935. https://doi.org/10.1097/GME.0b013e3182a14372.

24. Kokkonen H., Soderstrom I., Rocklov J., Hallmans G., Lejon K., Rantapaa Dahlqvist S. Up-Regulation of Cytokines and Chemokines Predates the Onset of Rheumatoid Arthritis. Arthritis Rheum. 2010;62(2):383-391. https://doi.org/10.1002/art.27186.

25. Chen D.Y. Hsieh T.Y., Chen Y.M., Hsieh C.W., Lan J.L., Lin FJ. Proinflammatory Cytokine Profiles of Patients with Elderly-Onset Rheumatoid Arthritis: A Comparison with Younger-Onset Disease. Gerontology. 2009;55(3):250-258. https://doi.org/10.1159/000164393.

26. Nasonov E.L., Lila A.M. Inhibition of Interleukin 6 in Immune Inflammatory Rheumatic Diseases: Achievements, Prospects, and Hopes. Nauchno-praktiches-kaya revmatologiya = Rheumatology Science and Practice. 2017;55(6):590-599. (In Russ.) https://doi.org/10.14412/1995-4484-2017-590-599.

27. Singh J.A., Hossain A., Tanjong Ghogomu E., Mudano A.S., Maxwell LJ., Buchbinder R. et al. Biologics or Tofacitinib for People with Rheumatoid Arthritis Unsuccessfully Treated with Biologics: A Systematic Review and Network Meta-Analysis. Cochrane Database Syst Rev. 2017;3:CD012591. https://doi.org/10.1002/14651858.CD012591.

28. Tarp S., Furst D.E., Dossing A., 0stergaard M., Lorenzen T., Hansen M.S., Singh J.A. et al. Defining the Optimal Biological Monotherapy in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomised Trials. Semin Arthritis Rheum. 2017;46(6):699-708. https://doi.org/10.1016/j.semarthrit.2016.09.003.

29. McKendry R., Smolen J.S., Churchill M., Tocilizumab Treatment Results in Rapid Improvements in the Signs and Symptoms of Moderate-to-Severe Rheumatoid Arthritis in Four Patient Populations with Different Prior Therapy Exposure. J Rheumatol. 2009;36. Available at: https://www.researchgate.net/publica-tion/278353202_Tocilizumab_Treatment_Results_in_Rapid_Improvements_in_the_Signs_and_Symptoms_of_Moderate-to-Severe_Rheumatoid_Arthritis_in_Four_Patient_Populations_with_Different_Prior_Therapy_Exposure.

30. Beaulieu A.D., McKay J.D., Pavelka K., Davies C., John A., Smolen J.S. Treatment with the Humanized Anti-Interleukin-6 Receptor Antibody Tocliizumab Results in Rapid Improvements in the Signs and Symptoms of Rheumatoid Arthritis: Results from a Pooled Analysis of Clinical Trial Data from OPTION and TOWARD. Ann Rheum Dis. 2008;67(Suppl II):195.

31. Forsblad-d'Elia H., Bengtsson K., Kristensen L.E., Jacobsson L.T. Drug Adherence, Response and Predictors Thereof for Tocilizumab in Patients with Rheumatoid Arthritis: Results from the Swedish Biologics Register. Rheumatology (Oxford). 2015;54(7):1186-1193. https://doi.org/10.1093/rheumatology/keu455.

32. Yamamoto K., Goto H., Hirao K., Nakajima A., Origasa H., Nakasone A. et al. SAT0194. Long Term Safety for Tocilizumab in Real-World Setting; 3 Year Follow-Up Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan. Ann Rheum Dis. 2015;74:725-726. http://doi.org/10.1136/annrheumdis-2015-eular.1569.

33. Chen Y.M., Chen H.H., Huang W.N., Liao T.L., Chen J.P., Chao W.C. et al. Tocilizumab Potentially Prevents Bone Loss in Patients with Anticitrullinated Protein Antibody-Positive Rheumatoid Arthritis. PLoS One. 2017;12(11):e0188454. https://doi.org/10.1371/journal.pone.0188454.

34. Briot K., Schaeverbeke T., Etchepare F., Gaudin P., Perdriger A., Vray M. et al. Positive Effects of Tocilizumab On Bone Remodeling in Patients with Rheumatoid Arthritis. 2012ACR/ARHPAnnual Meeting. Available at: https://acrabstracts.org/abstract/positive-effects-of-tocilizumab-on-bone-remodeling-in-patients-with-rheumatoid-arthritis/.

35. Koster MJ., Matteson E.L., Warrington KJ. Recent Advances in the Clinical Management of Giant Cell Arteritis and Takayasu Arteritis. Curr Opin Rheumatol. 2016;28(3):211-217. https://doi.org/10.1097/BOR.0000000000000265.

36. Toussirot Ё., Regent A., Devauchelle-Pensec V, Saraux A., Puechal X. Interleukin-6: A Promising Target for the Treatment of Polymyalgia Rheumatica or Giant Cell Arteritis? RMD Open. 2016;2(2):e000305. https://doi.org/10.1136/rmdopen-2016-000305.

37. Kume K., Amano K., Yamada S., Kanazawa T., Ohta H., Hatta K. et al. The Effect of Tocilizumab on Bone Mineral Density in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis. Rheumatology (Oxford). 2014;53(5):900-903. https://doi.org/10.1093/rheumatology/ket468.

38. Shin A., Park E.H., Dong Y.H., Ha YJ., Lee YJ., Lee E.B. et al. Comparative Risk of Osteoporotic Fracture among Patients with Rheumatoid Arthritis Receiving TNF Inhibitors versus Other Biologics: A Cohort Study. Osteoporos Int. 2020;31(11):2131-2139. https://doi.org/10.1007/s00198-020-05488-9.

39. Suzuki T., Nakamura Y., Kato H. Effects of Denosumab on Bone Metabolism and Bone Mineral Density with Anti-TNF Inhibitors, Tocilizumab, or Abatacept in Osteoporosis with Rheumatoid Arthritis Ther Clin Risk Manag. 2018;(14):453-459. https://doi.org/10.2147ACRM.S156350.

40. Pers Y.M., Schaub R., Constant E., Lambert J., Godfrin-Valnet M., Fortunet C. et al. Efficacy and Safety of Tocilizumab in Elderly Patients with Rheumatoid Arthritis. Joint Bone Spine. 2015;82(1):25-30. https://doi.org/10.1016/j.jbspin.2014.07.010.