Доклинический ревматоидный артрит: современный взгляд на патогенез и возможности профилактики

Ревматоидный артрит (РА) представляет собой хроническое аутоиммунное заболевание с многофакторной патогенетической основой, характеризующееся прогрессивным развитием, предшествующим клиническим проявлениям. Рассмотрена естественная история заболевания, включающая этапы от генетической предрасположенности и воздействия внешних провоцирующих факторов до формирования доклинического аутоиммунитета и последующего воспалительного поражения суставов. Центральную роль в патогенезе играет взаимодействие ключевых генетических детерминант, таких как аллели HLA-DRB1, с экзогенными триггерами, включая курение и инфекционные факторы, приводящее к продукции специфических аутоантител – антицитруллинированных белковых антител и ревматоидного фактора. Эти серологические маркеры могут регистрироваться за годы до появления суставных симптомов, что указывает на длительный доклинический период заболевания. Продромальные этапы РА, сопровождающиеся системным воспалением и иммунной дисрегуляцией, рассматриваются как критические «окна возможностей» для профилактических мероприятий, направленных на предотвращение перехода заболевания в клинически выраженную фазу. Особую важность приобретают исследования, направленные на восстановление иммунологической толерантности и модуляцию микробиома, что открывает перспективы для разработки инновационных терапевтических подходов. Они должны быть ориентированы на предотвращение заболевания на самых ранних этапах его патогенеза, задолго до появления клинических признаков. Кроме того, разработка методов визуализации субклинических изменений и уточнение критериев стратификации риска станут критически важными для идентификации лиц, нуждающихся в целенаправленном воздействии. Современные принципы первичной и вторичной профилактики включают модификацию факторов риска (отказ от курения табака, коррекцию микробиома и диеты). Эти подходы открывают перспективы для снижения заболеваемости РА среди лиц с генетической предрасположенностью или наличием иммунологических маркеров на доклинической стадии заболевания.

1. Finckh A, Gilbert B, Hodkinson B, Bae SC, Thomas R, Deane KD et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(10):591–602. https://doi.org/10.1038/s41584-022-00827-y.

2. Gerlag DM, Raza K, van Baarsen LG, Brouwer E, Buckley CD, Burmester GR et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–641. https://doi.org/10.1136/annrheumdis-2011-200990.

3. Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Asklingj. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013;65(11):2773–2782. https://doi.org/10.1002/art.38097.

4. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376–381. https://doi.org/10.1038/nature12873.

5. Gorman JD, Lum RF, Chen JJ, Suarez-Almazor ME, Thomson G, Criswell LA. Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients. Arthritis Rheum. 2004;50(2):400–412. https://doi.org/10.1002/art.20006.

6. Viatte S, Plant D, Han B, Fu B, Yarwood A, Thomson W et al. Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA. 2015;313(16):1645–1656. https://doi.org/10.1001/jama.2015.3435.

7. van der Woude D, Lie BA, Lundström E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ et al. Protection against anti-citrullinated protein antibodypositive rheumatoid arthritis is predominantly associated with HLADRB1*1301: a meta-analysis of HLA-DRB1 associations with anticitrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations. Arthritis Rheum. 2010;62(5):1236–1245. https://doi.org/10.1002/art.27366.

8. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75(3):330–337. https://doi.org/10.1086/422827.

9. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis – a genome-wide study. N Engl J Med. 2007;357(12):1199–1209. https://doi.org/10.1056/NEJMoa073491.

10. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357(10):977–986. https://doi.org/10.1056/NEJMoa073003.

11. Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K et al. Multiancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nat Genet. 2022;54(11):1640–1651. https://doi.org/10.1038/s41588-022-01213-w.

12. Webster AP, Plant D, Ecker S, Zufferey F, Bell JT, Feber A et al. Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins. Genome Med. 2018;10(1):64. https://doi.org/10.1186/s13073018-0575-9.

13. de Andres MC, Perez-Pampin E, Calaza M, Santaclara FJ, Ortea I, Gomez-Reino JJ, Gonzalez A. Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res Ther. 2015;17(1):233. Available at: https://arthritis-research.biomedcentral.com/articles/10.1186/s13075015-0748-5.

14. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38–46. https://doi.org/10.1002/art.21575.

15. Kim K, Jiang X, Cui J, Lu B, Costenbader KH, Sparks JA et al. Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. Arthritis Rheumatol. 2015;67(10):2611–2623. https://doi.org/10.1002/art.39228.

16. Qin B, Yang M, Fu H, Ma N, Wei T, Tang Q et al. Body mass index and the risk of rheumatoid arthritis: a systematic review and dose-response meta-analysis. Arthritis Res Ther. 2015;17(1):86. https://doi.org/10.1186/s13075-015-0601-x.

17. Gan RW, Bemis EA, Demoruelle MK, Striebich CC, Brake S, Feser ML et al. The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology. 2017;56(12):2229–2236. https://doi.org/10.1093/rheumatology/kex360.

18. Alpizar-Rodriguez D, Mueller RB, Möller B, Dudler J, Ciurea A, Zufferey P et al. Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. Rheumatology. 2017;56(9):1579–1585. https://doi.org/10.1093/rheumatology/kex239.

19. Kudaeva FM, Speechley MR, Pope JE. A systematic review of viral exposures as a risk for rheumatoid arthritis. Semin Arthritis Rheum. 2019;48(4):587–596. https://doi.org/10.1016/j.semarthrit.2018.03.011.

20. Ono K, Kishimoto M, Shimasaki T, Uchida H, Kurai D, Deshpande GA et al. Reactive arthritis after COVID-19 infection. RMD Open. 2020;6(2):e001350. https://doi.org/10.1136/rmdopen-2020-001350.

21. Аронова ЕС, Белов БС. Полиартрит, ассоциированный с COVID-19 (клинический случай). Современная ревматология. 2021;15(1):76–79. https://doi.org/10.14412/1996-7012-2021-5-76-79.

22. Joo YB, Lee J, Park YJ, Bang SY, Kim K, Lee HS. Associations of upper respiratory mucosa microbiota with rheumatoid arthritis, autoantibodies, and disease activity. PLoS ONE. 2024;19(1):e0308010. https://doi.org/10.1371/journal.pone.0308010.

23. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Venables PJ. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010;233(1):34–54. https://doi.org/10.1111/j.0105-2896.2009.00850.x.

24. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67(10):1488–1492. https://doi.org/10.1136/ard.2007.075192.

25. Johansson L, Sherina N, Kharlamova N, Potempa B, Larsson B, Israelsson L et al. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res Ther. 2016;18(1):201. https://doi.org/10.1186/s13075-016-1100-4.

26. Tong Y, Zheng L, Qing P, Zhao H, Li Y, Su L et al. Oral Microbiota Perturbations Are Linked to High Risk for Rheumatoid Arthritis. Front Cell Infect Microbiol. 2020;9:475. https://doi.org/10.3389/fcimb.2019.00475.

27. Jubair WK, Hendrickson JD, Severs EL, Schulz HM, Adhikari S, Ir D et al. Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation. Arthritis Rheumatol. 2018;70(8):1220–1233. https://doi.org/10.1002/art.40490.

28. Chen B, Sun L, Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. J Autoimmun. 2017;83:31–42. https://doi.org/10.1016/j.jaut.2017.03.009.

29. Luo Y, Tong Y, Wu L, Niu H, Li Y, Su LC et al. Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance. Arthritis Rheumatol. 2023;75(10):1736–1748. https://doi.org/10.1002/art.42616.

30. Seifert JA, Bemis EA, Ramsden K, Lowell C, Polinski K, Feser M et al. Association of Antibodies to Prevotella copri in Anti-Cyclic Citrullinated Peptide-Positive Individuals At Risk of Developing Rheumatoid Arthritis and in Patients With Early or Established Rheumatoid Arthritis. Arthritis Rheumatol. 2023;75(4):507–516. https://doi.org/10.1002/art.42370.

31. Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016;8(1):43. https://doi.org/10.1186/s13073-016-0299-7.

32. Tajik N, Frech M, Schulz O, Schälter F, Lucas S, Azizov V et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun. 2020;11(1):1995. https://doi.org/10.1038/s41467020-15831-7.

33. Tripathy A, Khanna S, Padhan P, Smita S, Raghav S, Gupta B. Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis. Sci Rep. 2017;7(1):933. https://doi.org/10.1038/s41598-017-01033-7.

34. Kitamura K, Sasaki M, Matsumoto M, Shionoya H, Iida K. Protective effect of Bacteroides fragilis LPS on Escherichia coli LPS-induced inflammatory changes in human monocytic cells and in a rheumatoid arthritis mouse model. Immunol Lett. 2021;233:48–56. https://doi.org/10.1016/j.imlet.2021.03.008.

35. Edilova MI, Akram A, Abdul-Sater AA. Innate immunity drives pathogenesis of rheumatoid arthritis. Biomedj. 2021;44(2):172–182. https://doi.org/10.1016/j.bj.2020.06.010.

36. Ricchiuti V, Chun KY, Yang JM, Aure MA, Gomez L, Norman GL, Mahler M. Anti-Carbamylated Protein (Anti-CarP) Antibodies in Patients Evaluated for Suspected Rheumatoid Arthritis. Diagnostics. 2022;12(7):1661. https://doi.org/10.3390/diagnostics12071661.

37. Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017;46(2):183–196. https://doi.org/10.1016/j.immuni.2017.02.006.

38. Li Z, Guo J, Bi L. Role of the NLRP3 inflammasome in autoimmune diseases. Biomed Pharmacother. 2020;130:110542. https://doi.org/10.1016/j.biopha.2020.110542.

39. Petrovská N, Prajzlerová K, Vencovský J, Šenolt L, Filková M. The preclinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis. Autoimmun Rev. 2021;20(5):102797. https://doi.org/10.1016/j.autrev.2021.102797.

40. Achudhan D, Lai YL, Lin YY, Huang YL, Tsai CH, Ho TL et al. CXCL13 promotes TNF-α synthesis in rheumatoid arthritis through activating ERK/p38 pathway and inhibiting miR-330-3p generation. Biochem Pharmacol. 2024;221:116037. https://doi.org/10.1016/j.bcp.2024.116037.

41. Wu T, Li Y, Liu Y, Chu CQ. Preclinical RA: How to halt its progression. Best Pract Res Clin Rheumatol. 2025;39(1):102030. https://doi.org/10.1016/j.berh.2024.102030.

42. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–328. https://doi.org/10.1146/annurevmed-051113-024537.

43. Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol. 2023;20(3):217–251. https://doi.org/10.1038/s41423-023-00974-6.

44. Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19–30. https://doi.org/10.1136/annrheumdis-2019-215672.

45. Tanner S, Dufault B, Smolik I, Meng X, Anaparti V, Hitchon C et al. A Prospective Study of the Development of Inflammatory Arthritis in the Family Members of Indigenous North American People With Rheumatoid Arthritis. Arthritis Rheumatol. 2019;71(9):1494–1503. https://doi.org/10.1002/art.40880.

46. Bemis EA, Demoruelle MK, Seifert JA, Polinski KJ, Weisman MH, Buckner JH et al. Factors associated with progression to inflammatory arthritis in firstdegree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting. Ann Rheum Dis. 2021;80(2):154–161. https://doi.org/10.1136/annrheumdis-2020-217066.

47. Duquenne L, Hensor EM, Wilson M, Garcia-Montoya L, Nam JL, Wu J et al. Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification. Ann Intern Med. 2023;176(8):1027–1036. https://doi.org/10.7326/M23-0272.

48. Heutz JW, Rogier C, Niemantsverdriet E, van den Eeden SJF, de Jong PHP, Lubberts E et al. The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis. Rheumatology. 2024;63(2):563–570. https://doi.org/10.1093/rheumatology/kead238.

49. van Steenbergen HW, Aletaha D, Beaart-van de Voorde LJ, Brouwer E, Codreanu C, Combe B et al. EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis. Ann Rheum Dis. 2017;76(3):491–496. https://doi.org/10.1136/annrheumdis-2016-209846.

50. Sahin D, Di Matteo A, Emery P. Biomarkers in the diagnosis, prognosis and management of rheumatoid arthritis: A comprehensive review. Ann Clin Biochem. 2025;62(1):3–21. https://doi.org/10.1177/00045632241285843.

51. van Steenbergen HW, Mangnus L, Reijnierse M, Huizinga TW, van der Helmvan Mil AH. Clinical factors, anticitrullinated peptide antibodies and MRIdetected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis. Ann Rheum Dis. 2016;75(10):1824–1830. https://doi.org/10.1136/annrheumdis-2015-208138.

52. Zufferey P, Rebell C, Benaim C, Ziswiler HR, Dumusc A, So A. Ultrasound can be useful to predict an evolution towards rheumatoid arthritis in patients with inflammatory polyarthralgia without anticitrullinated antibodies. Joint Bone Spine. 2017;84(3):299–303. https://doi.org/10.1016/j.jbspin.2016.05.011.

53. Molina Collada J, López Gloria K, Castrejón I, Nieto-González JC, Rivera J, Montero F et al. Ultrasound in clinically suspect arthralgia: the role of power Doppler to predict rheumatoid arthritis development. Arthritis Res Ther. 2021;23(1):299. https://doi.org/10.1186/s13075-021-02685-7.

54. Zayat AS, Ellegaard K, Conaghan PG, Terslev L, Hensor EM, Freeston JE et al. The specificity of ultrasound-detected bone erosions for rheumatoid arthritis. Ann Rheum Dis. 2015;74(5):897–903. https://doi.org/10.1136/annrheumdis-2013-204864.

55. Brunet SC, Finzel S, Engelke K, Boyd SK, Barnabe C, Manske SL. Bone changes in early inflammatory arthritis assessed with High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT): A 12-month cohort study. Joint Bone Spine. 2021;88(1):105065. https://doi.org/10.1016/j.jbspin.2020.07.014.

56. Hirata S, Dirven L, Shen Y, Centola M, Cavet G, Lems WF et al. A multibiomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology. 2013;52(7):1202–1207. https://doi.org/10.1093/rheumatology/kes362.

57. Meznerics FA, Kemény LV, Gunther E, Bakó E, Dembrovszky F, Szabó B et al. Multibiomarker disease activity score: an objective tool for monitoring rheumatoid arthritis? A systematic review and meta-analysis. Rheumatology. 2023;62(6):2048–2059. https://doi.org/10.1093/rheumatology/keac715.

58. AbdulRaheem Y. Unveiling the Significance and Challenges of Integrating Prevention Levels in Healthcare Practice. J Prim Care Community Health. 2023;14:21501319231186500. https://doi.org/10.1177/21501319231186500.

59. Gwinnutt JM, Wieczorek M, Balanescu A, Bischoff-Ferrari HA, Boonen A, Cavalli G et al. 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2023;82(1):48–56. https://doi.org/10.1136/annrheumdis-2021-222020.

60. Lin L, Zhang K, Xiong Q, Zhang J, Cai B, Huang Z et al. Gut microbiota in preclinical rheumatoid arthritis: From pathogenesis to preventing progression. J Autoimmun. 2023;141:103001. https://doi.org/10.1016/j.jaut.2023.103001.

61. Cannarella LAT, Mari NL, Alcântara CC, Iryioda TMV, Costa NT, Oliveira SR et al. Mixture of probiotics reduces inflammatory biomarkers and improves the oxidative/nitrosative profile in people with rheumatoid arthritis. Nutrition. 2021;89:111282. https://doi.org/10.1016/j.nut.2021.111282.