Роль аутоантител в ранней диагностике системных иммуновоспалительных ревматических заболеваний

Большинство системных иммуновоспалительных ревматических заболеваний (САРЗ) протекают стадийно. Важнейшая характеристика САРЗ — патологическая активация В-клеток и гиперпродукция органонеспецифических аутоантител (аутоАТ), которые реагируют с разными пептидами и клеточными компонентами и рассматриваются как биологические маркеры ревматических заболеваний. К основным серологическим маркерам САРЗ относят антинуклеарные антитела, ревматоидные факторы, антитела к циклическому цитруллинированному пептиду, антифосфолипидные антитела и антинейтрофильные цитоплазматические антитела. Положительные тесты на эти аутоАТ входят в число классификационных критериев САРЗ, а также применяются для оценки активности и тяжести заболеваний, идентификации отдельных клинико-лабораторных подтипов, предсказания развития и прогрессирования органной патологии, эффективности терапии и др., кроме того, они служат предикторами возникновения САРЗ на доклинической стадии. Доказано, что иммунопатологические нарушения, связанные с потерей иммунологической толерантности к собственным антигенам и инициацией системного аутоиммунитета и воспаления, развиваются в среднем за 5лет до появления первых клинических симптомов. Поэтому выявление серологических маркеров САРЗ в предклинической фазе, т. е. при отсутствии развернутых клинических проявлений, делает возможным применение превентивных стратегий у лиц с высоким риском развития этих заболеваний.

В статье на примере ревматоидного артрита, системной красной волчанки и системной склеродермии анализируется клиническое значение обнаружения аутоАТ на доклинической или ранней стадии САРЗ, когда иммунопатологические нарушения еще не достигли выраженного и/или необратимого характера.

1. Насонов ЕЛ, Насонова ВА, редакторы. Ревматология. Национальное руководство. Москва: ГОЭТАР-Медиа; 2008. С. 290-331.

2. Wahren-Herlenius M, Dorner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013 Aug 31; 382(9894):819-31. doi: 10.1016/S0140-6736(13)60954-X.

3. Goldblatt F, O'Neill SG. Clinical aspects of autoimmune rheumatic diseases. Lancet. 2013 Aug 31;382(9894):797-808. doi: 10.1016/S0140-6736(13)61499-3.

4. Alarcon Gs, Williams GV, Singer JZ, et al. Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol. 1991 Sep;18(9):1332-9.

5. Esdaile JM, Joseph L, MacKenzie T, et al. The benefit of early treatment with immunosuppressive agents in lupus nephritis. J Rheumatol. 1994 Nov;21(11):2046-51.

6. Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol. 2006 Aug;33(8):1563-9.

7. Ciruelo E, De la Cruz J, Lopez I, Gomez-Reino JJ. Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide. Arthritis Rheum. 1996 Dec; 39(12):2028-34.

8. Doria A, Iaccarino L, Ghirardello A, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006 Aug;119(8):700-6.

9. Doria A, Rinaldi S, Ermani M, et al. Health related quality of life in Italian patients with systemic lupus erythematosus. II. Role of clinical, immunological, and psychological determinants. Rheumatology (Oxford). 2004 Dec;43(12):1580-6. Epub 2004 Sep 14.

10. Faurschou M, Dreyer L, Kamper AL, et al. Long-term mortality and renal outcome in a cohort of 100 patients with lupus nephritis. Arthritis Care Res (Hoboken). 2010 Jun;62(6): 873-80. doi: 10.1002/acr.20116.

11. Nihtyanova SI, Tang EC, Coghlan JG, et al. Improved survival in systemic sclerosis in assiciated with better ascertainment of internal organ disease: a retrospective cohort study. QJM. 2010 Feb;103(2):109-15. doi: 10.1093/qjmed/hcp174. Epub 2009 Dec 4.

12. Combe B, Landewe R, Lukas C, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007 Jan;66(1):34-45. Epub 2006 Jan 5.

13. Finckh A, Liang MH, van Herckenrode CM, de Pablo P. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Ann Rheum Dis. 2007 Jan;66(1):34-45. Epub 2006 Jan 5.

14. Александрова ЕН, Новиков АА, Насонов ЕЛ. Современные подходы к лабораторной диагностике ревматических заболеваний: роль молекулярных и клеточных биомаркеров. Научно-практическая ревматология. 2016;54(3):324—38. doi: 10.14412/1995-4484-2016-324-338

15. Gerlag DM, Raza K, van Baarsen LG, 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 May;71(5):638-41. doi: 10.1136/annrheumdis-2011-200990. Epub 2012 Mar 2.

16. Shi J, Knevel R, Suwannalai P, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci US A. 2011 Oct 18; 108(42):17372-7. doi: 10.1073/pnas.1114465108. Epub 2011 Oct 10.

17. Juarez M, Bang H, Hammar F, et al. Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann Rheum Dis. 2016 Jun;75(6):1099-107. doi: 10.1136/annrheumdis-2014-206785. Epub 2015 Jul 9.

18. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic cit-rullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2741-9.

19. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004 Feb;50(2):380-6.

20. Gan RW, Trouw LA, Shi J, et al. Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis. J Rheumatol. 2015 Apr;42(4):572-9. doi: 10.3899/jrheum.140767. Epub 2015 Jan 15.

21. Deane KD, Norris JM, Holers VM. Preclinical rheumatoid arthritis: identification, evaluation, and future directions for investigation. Rheum Dis Clin North Am. 2010 May;36(2):213-41. doi: 10.1016/j.rdc.2010.02.001.

22. Giacomellia R, Afeltrab A, Alunnoc A. Guidelines for biomarkers in autoimmune rheumatic diseases — evidence based analysis. Autoimmun Rev. 2019 Jan;18(1):93-106. doi: 10.1016/j.autrev.2018.08.003. Epub 2018 Nov 5.

23. Mclnnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011 Dec 8;365(23):2205-19. doi: 10.1056/NEJMra1004965.

24. Bizzaro N, Tozzoli R, Shoenfeld Y. Are we at a stage to predict autoimmune rheumatic diseases? Arthritis Rheum. 2007 Jun; 56(6):1736-44.

25. Jonsson R, Theander E, Sjostrom B, et al. Autoantibodies present before symptom onset in primary Sjоgren syndrome. JAMA. 2013 Nov 6;310(17):1854-5. doi: 10.1001/jama.2013.278448.

26. Deane KD, El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat Rev Rheumatol. 2014 Apr;10(4):212-28. doi: 10.1038/nrrheum.2014.6. Epub 2014 Feb 11.

27. Damoiseaux J, Andrade LE, Fritzler MJ, Shoenfeld Y. Autoantibodies 2015: From diagnostic biomarkers toward prediction, prognosis and prevention. Autoimmun Rev. 2015 Jun;14(6):555-63. doi:10.1016/j.autrev. 2015.01.017. Epub 2015 Feb 3.

28. Arbuckle MR, McClain MT, Rubertone MV, et al. Developmentof autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33.

29. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8): 2677-86. doi: 10.1002/art.34473.

30. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 2007 Jul;56(7): 2344-51.

31. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401-9.

32. Rees F, Doherty M, Lanyon P, et al. Early Clinical Features in Systemic Lupus Erythematosus: Can They Be Used to Achieve Earlier Diagnosis? A Risk Prediction Model. Arthritis Care Res (Hoboken). 2017 Jun;69(6):833-841. doi: 10.1002/acr.23021. Epub 2017 May 8.

33. Ozbek S, Sert M, Paydas S, Soy M. Delay in the diagnosis of SLE: the importance of arthritis/arthralgia as the initial symptom. Acta Med Okayama. 2003 Aug;57(4):187-90.

34. Morgan С, Bland AR, Maker C, et al. Individuals living with lupus: findings from the LUPUS UK Members Survey 2014. Lupus. 2018;27(4):681 —7.

35. Wandstrat A, Carr-Johnson F, Branch V, et al. Autoantibody profiling to identify individuals at risk for systemic lupus erythematosus. J Autoimmun. 2006 Nov;27(3):153-60. Epub 2006 Oct 17.

36. Pisetsky DS, Lipsky PE. The Role of ANA Determinations in Classification Criteria for SLE. Arthritis Care Res (Hoboken). 2018 Mar 26. doi: 10.1002/acr.23559. [Epub ahead of print].

37. Li QZ, Karp DR, Quan J, et al. Risk factors for ANA positivity in healthy persons. Arthritis Res Ther. 2011 Mar 2;13(2):R38. doi: 10.1186/ar3271.

38. Chakravarty E, Bush T, Manzi S, et al. Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum. 2007 Jun;56(6):2092-4.

39. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis. J Dermatol. 2010 Jan;37(1):42-53. doi: 10.1111/j.1346-8138.2009.00762.x.

40. Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008 Dec;58(12):3902-12. doi: 10.1002/art.24038.

41. Minier T, Guiducci S, Bellando-Randone S, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2014 Dec; 73(12):2087-93. doi: 10.1136/annrheumdis-2013-203716. Epub 2013 Aug 12.

42. Avouac J, Fransen J, Walker UA, et al. EUSTAR Group. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis. 2011 Mar;70(3): 476-81. doi: 10.1136/ard.2010.136929. Epub 2010 Nov 15.

43. Van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737-47. doi: 10.1002/art.38098. Epub 2013 Oct 3.

44. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327-1339. doi: 10.1136/annrheumdis-2016-209909. Epub 2016 Nov 9.

45. Ананьева ЛП, Александрова ЕН. Аутоантитела при системной склеродермии: спектр, клинические ассоциации и прогностическое значение. Научно-практическая ревматология. 2016;54(1):86-99. doi: 10.14412/1995-4484-2016-86-99

46. Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol. 2010 Feb;6(2):112-6. doi: 10.1038/nrrheum.2009.238.

47. Nagy G, van Vollenhoven RF. Sustained biologic-free and drugfree remission in rheumatoid arthritis, where are we now? Arthritis Res Ther. 2015 Aug 3;17:181. doi: 10.1186/s13075-015-0707-1.