Адипоцитокины при раннем ревматоидном артрите: взаимосвязь с про- и антивоспалительными маркерами

Цель исследования – уточнить взаимосвязь адипонектина и лептина с показателями активности заболевания и уровнями про- и антивоспалительных цитокинов у больных с ранним ревматоидным артритом (РА).
Материал и методы. В исследование включены 27 больных РА, соответствующих критериям ACR/EULAR 2010 г., никогда не получавших глюкокортикоиды (ГК) или базисные противовоспалительные препараты. Медиана возраста пациентов составила 56 [46; 64] лет, длительности заболевания – 8 [6; 15] мес. Все больные имели умеренную или высокую активность РА по индексу DAS28. Большинство были серопозитивными по ревматоидному фактору – 88,9% и антителам к циклическому цитруллинированному пептиду – 96,3%. В контрольную группу вошли 30 человек без воспалительных заболеваний суставов, сходных по полу, возрасту и индексу массы тела (ИМТ) с больными РА. Концентрации адипонектина и лептина определяли с помощью иммуноферментного анализа, для измерения концентрации интерлейкина 1β (ИЛ1β), ИЛ2, ИЛ4, ИЛ5, ИЛ6, ИЛ7, ИЛ8, ИЛ9, ИЛ10, ИЛ12, ИЛ13, ИЛ15, ИЛ17 и макрофагальных белков воспаления (MIP) – MIP1α, MIP1β – применялась мультиплексная технология X-MAP.
Результаты и обсуждение. У больных РА концентрация адипонектина оказалась выше (р<0,001), а содержание лептина и соотношение лептин/адипонектин (Л/А) – ниже, чем в контроле (p=0,04 и р<0,001 соответственно). При РА обнаружены прямые корреляции уровня лептина с ИЛ17 (r=0,4; p=0,03), ИЛ4 (r=0,39; p=0,04) и скоростью оседания эритроцитов (СОЭ; r=0,3; p=0,05), а также отношения Л/А с СОЭ (r=0,38; p=0,05), уровнями СРБ (r=0,4; p=0,04) и MIP1β (r=0,55; p=0,03). Нарастание концентрации адипонектина ассоциировалось со снижением содержания MIP1β (r=-0,63; p<0,01). У лиц с ИМТ ≥25 кг/м2 концентрации лептина при РА и в контроле оказались сопоставимы (р=0,1), различия в содержании адипонектина и в отношении Л/А сохранялись (р<0,001 в обоих случаях). В данной подгруппе у пациентов с РА оставались значимыми корреляции между уровнями лептина и ИЛ17 (r=0,52; p=0,03), концентрациями адипонектина и MIP1β (r=-0,59; p=0,01), отношением Л/А и содержанием MIP1β (r=0,55; p=0,02).
Заключение. При раннем РА снижается синтез лептина и увеличивается продукция адипонектина. Корреляции между уровнями адипоцитокинов и ИЛ17, MIP1β, с одной стороны, свидетельствуют о влиянии жировой ткани на системное воспаление, с другой – подтверждают участие провоспалительных цитокинов в развитии инсулинорезистентности и ожирения.

1. Crowson CS, Matteson EL, Davis III JM, Gabriel SE. Contribution of obesity to the rise in incidence of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013 Jan;65(1):71-7. doi: 10.1002/acr.21660

2. Symmons DP, Bankhead CR, Harrison BJ, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum. 1997;40:1955-61. doi: 10.1002/1529-0131(199711)40:11&lt;1955::AID-ART6&gt;3.0.CO;2-A

3. Tedeschi SK, Cui J, Arkema EV, et al. Elevated BMI and antibodies to citrullinated proteins interact to increase rheumatoid arthritis risk and shorten time to diagnosis: A nested case-control study of women in the Nurses' Health Studies. Semin Arthritis Rheum. 2017;46(6):692-8. doi: 10.1016/j.semarthrit.2016.09.001

4. Sierra-Johnson J, Romero-Corral A, Lopez-Jimenez F, et al. Relation of increased leptin concentrations to history of myocardial infarction and stroke in the United States population. Am J Cardiol. 2007;100(2):234-9. doi: 10.1016/j.amjcard.2007.02.088

5. Shankar A, Xiao J. Positive relationship between plasma leptin level and hypertension. Hypertension. 2010 Oct;56(4):623-8. doi: 10.1161/HYPERTENSIONAHA.109.148213

6. Yang H, Guo W, Li J, et al. Leptin concentration and risk of coronary heart disease and stroke: A systematic review and meta-analysis. PLoS One. 2017;12(3):e0166360. doi: 10.1371/journal.pone.0166360. eCollection 2017.

7. Abdella NA, Mojiminiyi OA, Moussa MA, et al. Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance. Diabet Med. 2005;22:278-85. doi: 10.1111/j.1464-5491.2004.01405.x

8. Sainz N, Barrenetxe J, Moreno-Aliaga MJ, Martinez JA. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 2015 Jan;64(1):35-46. doi: 10.1016/j.metabol.2014.10.015

9. Tian G, Liang J-N, Wang Z-Y, Zhou D. Emerging role of leptin in rheumatoid arthritis. Clin Exper Immunol. 2014;177:557-70. doi: 10.1111/cei.12372

10. Versini M, Jeandel P-Y, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev. 2014;13(9):981-1000. doi: 10.1016/j.autrev.2014.07.001

11. Nigro E, Scudiero O, Monaco ML, et al. New insight into adiponectin role in obesity and obesity-related diseases. Biomed Res Int. 2014;2014:658913. doi: 10.1155/2014/658913

12. Wolk R, Berger P, Lennon RJ, et al. Association between plasma adiponectin levels and unstable coronary syndromes. Eur Heart J. 2007 Feb;28(3):292-8. doi: 10.1093/eurheartj/ehl361

13. Ebina K, Fukuhara A, Ando W, et al. Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction. Clin Rheumatol. 2009;28(4):445-51. doi: 10.1007/s10067-008-1074-y

14. Giles JT, Allison M, Bingham CO 3rd, et al. Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis. Arthritis Rheum. 2009;61(9):1248-56. doi: 10.1002/art.24789

15. Klein-Wieringa IR, van der Linden MPM, Knevel R, et al. Baseline Serum Adipokine Levels Predict Radiographic Progression in Early Rheumatoid Arthritis. Arthritis Rheum. 2011;63(9):2567-74. doi: 10.1002/art.30449

16. Giles JT, van der Heijde DM, Bathon JM. Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis. Ann Rheum Dis. 2011;70(9):1562-8. doi: 10.1136/ard.2011.150813

17. Rho YH, Solus J, Sokka T, et al. Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis. Arthritis Rheum. 2009 Jul;60(7):1906-14. doi: 10.1002/art.24626

18. Yoshino T, Kusunoki N, Tanaka N, et al. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med. 2011;50(4):269-75. doi: 10.2169/internalmedicine.50.4306

19. Seven A, GЯzel S, Aslan M, Hamuryudan V. Serum and synovial fluid leptin levels and markers of inflammation in rheumatoid arthritis. Rheumatol Int. 2009 May;29(7):743-7. doi: 10.1007/s00296-008-0764-8

20. Otero M, Lago R, Gomez R, et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis. 2006 Sep;65(9):1198-201. doi: 10.1136/ard.2005.046540

21. Derdemezis CS, Filippatos TD, Voulgari PV, et al. Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid arthritis. Fundam Clin Pharmacol. 2009 Oct;23(5):595-600. doi: 10.1111/j.1472-8206.2009.00717.x

22. Popa C, Netea MG, de Graaf J, et al. Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis. J Rheumatol. 2009 Apr;36(4):724-30. doi: 10.3899/jrheum.080626

23. Kopec-Medrek M, Kotulska A, Widuchowska M, et al. Plasma leptin and neuropeptide Y concentrations in patients with rheumatoid arthritis treated with infliximab, a TNF-α antagonist. Rheumatol Int. 2012 Nov;32(11):3383-9. doi: 10.1007/s00296-011-2182-6

24. Kontny E, Zielinska A, Skalska U, et al. Distinct secretory activity and clinical impact of subcutaneous abdominal adipose tissue in women with rheumatoid arthritis and osteoarthritis. Inflammation. 2017 Feb;40(1):106-16. doi: 10.1007/s10753-016-0459-3

25. Dessein PH, Norton GR, Badenhorst M, et al. Rheumatoid arthritis impacts on the independent relationships between circulating adiponectin concentrations and cardiovascular metabolic risk. Mediators Inflamm. 2013;2013:461849. doi: 10.1155/2013/461849

26. Lee SW, Park MC, Park YB, Lee SK. Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis. Rheumatol Int. 2007 Apr;27(6):537-40. doi: 10.1007/s00296-006-0253-x

27. Targonska-Stepniak B, Majdan M, Dryglewska M. Leptin serum levels in rheumatoid arthritis patients: relation to disease duration and activity. Rheumatol Int. 2008 Apr;28(6):585-91. doi: 10.1007/s00296-007-0480-9

28. Xibille-Friedmann D, Bustos-Bahena C, Hernandez-Gongora S, et al. Two-year follow-up of plasma leptin and other cytokines in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69(5):930-1. doi: 10.1136/ard.2009.111732

29. Popa C, Netea MG, Radstake TR, et al. Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis. Ann Rheum Dis. 2005 Aug;64(8):1195-8. doi: 10.1136/ard.2004.032243

30. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, et al. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol. 2009;16:222-8.

31. Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multibiomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. 2012 Oct;71(10):1692-7. doi: 10.1136/annrheumdis-2011-200963

32. Raza K, Falciani F, Curnow SJ, et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7(4):R784-95. doi: 10.1186/ar1733

33. Насонов ЕЛ. Новые возможности фармакотерапии иммуновоспалительных заболеваний: фокус на ингибиторы интерлейкина 17. Научно-практическая ревматология. 2017;55(1):68-86 [Nasonov EL. New possibilities of pharmacotherapy for immunoinflammatory rheumatic diseases: a focus on inhibitors of interleukin-17. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2017;55(1):68-86 (In Russ.)]. doi: 10.14412/1995-4484-2017-68-86

34. Metawi SA, Abbas D, Kamal MM, Ibrahim MK. Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol. 2011 Sep;30(9):1201-7. doi: 10.1007/s10067-011-1737-y

35. Deng J, Liu Y, Yang M, et al. Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis Rheum. 2012;64:3564-73. doi: 10.1002/art.34637

36. Shoda H, Nagafuchi Y, Tsuchida Y, et al. Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis. Arthritis Res Ther. 2017;19:111. doi: 10.1186/s13075-017-1308-y

37. Briolay J, Dechanet J, Blanchard D, et al. Interleukin 4 inhibits polyclonal immunoglobulin secretion and cytokine production by peripheral blood mononuclear cells from rheumatoid arthritis patients. J Clin Immunol. 1992 Jan;12(1):36-44. doi: 10.1007/BF00918271

38. Miossec P, Chomarat P, Dechanet J, et al. Interleukin-4 inhibits bone resorption through an effect on osteoclasts and proinflammatory cytokines in an ex vivo model of bone resorption in rheumatoid arthritis. Arthritis Rheum. 1994 Dec;37(12):1715-22. doi: 10.1002/art.1780371202

39. Van Roon JA, van Roy JL, Duits A, et al. Proinflammatory cytokine production and cartilage damage due to rheumatoid synovial T helper-1 activation is inhibited by interleukin-4. Ann Rheum Dis. 1995 Oct;54(10):836-40. doi: 10.1136/ard.54.10.836

40. Dechanet J, Briolay J, Rissoan MC, et al. IL-4 inhibits growth factor-stimulated rheumatoid synoviocyte proliferation by blocking the early phases of the cell cycle. J Immunol. 1993 Nov 1;151(9):4908-17.

41. Lubberts E, Joosten LAB, Chabaud M, et al. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. J Clin Invest. 2000 Jun 15;105(12):1697-710. doi: 10.1172/JCI7739

42. Rivas D, Mozo L, Zamorano J, et al. Upregulated expression of IL-4 receptors and increased levels of IL-4 in rheumatoid arthritis patients. J Autoimmun. 1995 Aug;8(4):587-600. doi: 10.1016/0896-8411(95)90010-1

43. Vidal C, Barnetche T, Morel J, et al. Association of body mass index categories with disease activity and radiographic joint damage in rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol. 2015;42(12):2261-9. doi: 10.3899/jrheum.150224

44. Iannone F, Lopalco G, Rigante D, et al. Impact of obesity on the clinical outcome of rheumatologic patients in biotherapy. Autoimmun Rev. 2016 May;15(5):447-50. doi: 10.1016/j.autrev.2016.01.010

45. Laurberg TB, Frystyk J, Ellingsen T, et al. Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid- and disease-modifying antirheumatic drugnaive compared with patients with osteoarthritis and controls. J Rheumatol. 2009 Sep;36(9):1885-91. doi: 10.3899/jrheum.080907

46. Finucane FM, Luan J, Wareham NJ, et al. Correlation of the leptin: adiponectin ratio with measures of insulin resistance in nondiabetic individuals. Diabetologia. 2009 Nov;52(11):2345-9. doi: 10.1007/s00125-009-1508-3

47. Kang Y, Park HJ, Kang MI, et al. Adipokines, inflammation, insulin resistance, and carotid atherosclerosis in patients with rheumatoid arthritis. Arthritis Res Ther. 2013;15(6):R194. doi: 10.1186/ar4384

48. Schultz O, Oberhauser F, Saech J, et al. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One. 2010 Dec 13;5(12):e14328. doi: 10.1371/journal.pone.0014328

49. Shahin D, Eltoraby E, Mesbah A, Houssen M. Insulin resistance in early untreated rheumatoid arthritis patients. Clin Biochem. 2010 May;43(7-8):661-5. doi: 10.1016/j.clinbiochem.2010.01.012

50. Mü ller R, Kull M, Polluste K, et al. The metabolic profile in early rheumatoid arthritis: a high prevalence of metabolic obesity. Rheumatol Int. 2017 Jan;37(1):21-7. doi: 10.1007/s00296-016-3464-9

51. Chung CP, Oeser A, Solus JF, et al. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 2008 Jul;58(7):2105-12. doi: 10.1002/art.23600

52. Robinson E, Keystone EC, Schall TJ, et al. Chemokine expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells. Clin Exp Immunol. 1995 Sep;101(3):398-407. doi: 10.1111/j.1365-2249.1995.tb03126.x

53. Tatara Y, Ohishi M, Yamamoto K, et al. Macrophage inflammatory protein-1beta induced cell adhesion with increased intracellular reactive oxygen species. J Mol Cell Cardiol. 2009 Jul;47(1):104-11. doi: 10.1016/j.yjmcc.2009.03.012

54. Tang C-H, Chiu Y-C, Tan T-W, et al. Adiponectin Enhances IL-6 production in human synovial fibroblast via an adipoR1 receptor, AMPK, p38, and NF-κB pathway. J Immunol. 2007;179(8):5483-5492. doi: 10.4049/jimmunol.179.8.5483

55. Kitahara K, Kusunoki N, Kakiuchi T, et al. Adiponectin stimulates IL-8 production by rheumatoid synovial fibroblasts. Biochem Biophys Res Commun. 2009 Jan 9;378(2):218-23. doi: 10.1016/j.bbrc.2008.11.017

56. Lee YA, Choi HM, Lee SH, et al. Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin- 8, and cyclooxygenase-2 in fibroblast-like synoviocytes. Exp Mol Med. 2012 Jul 31;44(7):440-7. doi: 10.3858/emm.2012.44.7.049

57. Tong KM, Shieh DC, Chen CP, et al. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cell Signal. 2008 Aug;20(8):1478-88. doi: 10.1016/j.cellsig.2008.04.003

58. Muraoka S, Kusunoki N, Takahashi H, et al. Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts. Clin Exp Rheumatol. 2013 Jul-Aug;31(4):589-95.

59. Olama SM, Senna MK, Elarman M. Synovial/serum leptin ratio in rheumatoid arthritis: the association with activity and erosion. Rheumatol Int. 2012 Mar;32(3):683-90. doi: 10.1007/s00296-010-1698-5