J Korean Med Sci.  2020 Jun;35(22):e155. 10.3346/jkms.2020.35.e155.

Tocilizumab Increases Body Weight and Serum Adipokine Levels in Patients with Rheumatoid Arthritis Independently of Their Treatment Response: a Retrospective Cohort Study

• Choi IA
• Sagawa A
• Lee EY
• Lee EB
• Song YW

• KMID: 2502605
• DOI: http://doi.org/10.3346/jkms.2020.35.e155

Abstract

Background
Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA).
Methods
In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24–72 weeks).
Results
No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, −0.2 kg; P = 0.630), but was observed after 24 weeks of tocilizumab treatment (mean difference, +0.9 kg; P = 0.010). Weight changed regardless of the treatment response in both treatment groups. The leptin–adiponectin ratio (P = 0.015) and levels of adiponectin (P < 0.001), leptin (P < 0.001), and resistin (P = 0.003) increased significantly after 24 weeks of tocilizumab, but not methotrexate treatment. After 24, 48 and 72 weeks of tocilizumab treatment in Cohort II, mean (95% confidence interval [CI]) weight changes from baseline were +0.7 (0.0–1.4), +1.2 (0.4–2.0) and +1.1 (0.2–2.0) kg, respectively, and mean (95% CI) percent weight changes from baseline were +1.3% (0.1%–2.6%), +2.2% (0.7%–3.6%), and +2.0% (0.4%–3.7%) at 24, 48, and 72 weeks, respectively.
Conclusion
Weight and the leptin–adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients.

Keyword

Adipokine; Interleukin-6 Receptor Inhibition; Rheumatoid Arthritis; Weight Gain

Figure

• 

  Fig. 1 Study population and design. Cohorts I and II were extracted from clinical trial data of tocilizumab in patients with active rheumatoid arthritis. Cohort I comprised 44 patients who received methotrexate for 24 weeks, followed by tocilizumab for 48 weeks. Cohort II comprised 46 patients who received tocilizumab for 72 weeks. Cohort III comprised 41 patients who received tocilizumab with or without methotrexate for 24 weeks on clinical practice.NSAIDs = nonsteroidal anti-inflammatory drugs.

• 

  Fig. 2 Weight changes in the study's cohorts. (A) Percentage of patients whose weights changed after 24 weeks of treatment in the 3 cohorts. In cohort I, 40.9% of the patients gained weight, 15.9% of the patients' weights remained stable, and 43.2% of the patients lost weight following methotrexate treatment. In cohort II, 63.0% of the patients gained weight and 28.3% of the patients lost weight following tocilizumab treatment. In cohort III, 61.0% of the patients gained weight and 36.6% of the patients lost weight following tocilizumab treatment. (B) Overall percent changes in body weight in cohort II after 24, 48, and 72 weeks of tocilizumab treatment compared with baseline. The mean (95% confidence interval) percent changes in body weight were 1.3% (0.1%–2.6%) at 24 weeks, 2.2% (0.7%–3.6%) at 48 weeks, and 2.0% (0.4%–3.7%) at 72 weeks.MTX = methotrexate, TCZ = tocilizumab.

• 

  Fig. 3 Patients' body weight changes during treatment. (A) Weight changes in cohorts I and II over 72 weeks. Body weight was assessed every 4 weeks in the 2 cohorts. (B) Joinpoint regression analysis of Cohort I showed that the mean body weight started to increase at 24 weeks when tocilizumab treatment was introduced, and it plateaued at 56 weeks, creating a significant joinpoint at weeks 24 and 56. *Indicates that the slope is significantly different from zero at the alpha = 0.05 level.

• 

  Fig. 4 Serum adipokine levels after methotrexate treatment. Levels of (A) adiponectin, (B) leptin, and (C) resistin at baseline (0 weeks) and after 24 weeks of methotrexate treatment (cohort I). The serum adiponectin, leptin, and resistin levels did not change significantly (P = 0.081 for adiponectin, P = 0.682 for leptin, and P = 0.070 for resistin). The data presented are the medians with their 25th and 75th percentiles.

• 

  Fig. 5 Serum adipokine levels after tocilizumab treatment. Serum levels of (A) adiponectin, (B) leptin, and (C) resistin at baseline (0 weeks) and after 24 weeks of tocilizumab treatment (cohort III). The serum adiponectin, leptin, and resistin levels increased significantly (**P < 0.01; ***P < 0.001). The data presented are the medians with their 25th and 75th percentiles.

Reference

1. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011; 70(6):929–934. PMID: 21389043.

2. Meune C, Touzé E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2009; 48(10):1309–1313. PMID: 19696061.

3. Humphreys JH, Warner A, Chipping J, Marshall T, Lunt M, Symmons DP, et al. Mortality trends in patients with early rheumatoid arthritis over 20 years: results from the Norfolk Arthritis Register. Arthritis Care Res (Hoboken). 2014; 66(9):1296–1301. PMID: 24497371.

4. Solomon DH, Kremer J, Curtis JR, Hochberg MC, Reed G, Tsao P, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010; 69(11):1920–1925. PMID: 20444756.

5. Summers GD, Metsios GS, Stavropoulos-Kalinoglou A, Kitas GD. Rheumatoid cachexia and cardiovascular disease. Nat Rev Rheumatol. 2010; 6(8):445–451. PMID: 20647995.

6. Kerekes G, Nurmohamed MT, González-Gay MA, Seres I, Paragh G, Kardos Z, et al. Rheumatoid arthritis and metabolic syndrome. Nat Rev Rheumatol. 2014; 10(11):691–696. PMID: 25090948.

7. Jacobsson LT, Turesson C, Hanson RL, Pillemer S, Sievers ML, Pettitt DJ, et al. Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians. Arthritis Rheum. 2001; 44(5):1170–1176. PMID: 11352251.

8. Poole CD, Conway P, Currie CJ. An evaluation of the association between C-reactive protein, the change in C-reactive protein over one year, and all-cause mortality in chronic immune-mediated inflammatory disease managed in UK general practice. Rheumatology (Oxford). 2009; 48(1):78–82. PMID: 19056800.

9. Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017; 76(1):17–28. PMID: 27697765.

10. Popkova TV, Novikova DS, Gasparyan AY, Nasonov EL. Cardiovascular effects of methotrexate in rheumatoid arthritis revisited. Curr Med Chem. 2015; 22(16):1903–1910. PMID: 25876749.

11. Micha R, Imamura F, Wyler von Ballmoos M, Solomon DH, Hernán MA, Ridker PM, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011; 108(9):1362–1370. PMID: 21855836.

12. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015; 74(3):480–489. PMID: 25561362.

13. Ferraz-Amaro I, González-Juanatey C, López-Mejias R, Riancho-Zarrabeitia L, González-Gay MA. Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm. 2013; 2013:710928. PMID: 23431244.

14. Szekanecz Z, Kerekes G, Soltész P. Vascular effects of biologic agents in RA and spondyloarthropathies. Nat Rev Rheumatol. 2009; 5(12):677–684. PMID: 19901918.

15. Lee JL, Sinnathurai P, Buchbinder R, Hill C, Lassere M, March L. Biologics and cardiovascular events in inflammatory arthritis: a prospective national cohort study. Arthritis Res Ther. 2018; 20(1):171. PMID: 30086795.

16. Rajbhandary R, Khezri A, Panush RS. Rheumatoid cachexia: what is it and why is it important? J Rheumatol. 2011; 38(3):406–408. PMID: 21362777.

17. Engvall IL, Tengstrand B, Brismar K, Hafström I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. Arthritis Res Ther. 2010; 12(5):R197. PMID: 20964833.

18. Peters MJ, Watt P, Cherry L, Welsh P, Henninger E, Dijkmans BA, et al. Lack of effect of TNFalpha blockade therapy on circulating adiponectin levels in patients with autoimmune disease: results from two independent prospective studies. Ann Rheum Dis. 2010; 69(9):1687–1690. PMID: 19640853.

19. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, et al. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol. 2009; 27(2):222–228. PMID: 19473561.

20. McInnes IB, Thompson L, Giles JT, Bathon JM, Salmon JE, Beaulieu AD, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis. 2015; 74(4):694–702. PMID: 24368514.

21. Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J, et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2016; 75(10):1806–1812. PMID: 26613768.

22. Zhang J, Xie F, Yun H, Chen L, Muntner P, Levitan EB, et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis. 2016; 75(10):1813–1818. PMID: 26792814.

23. Kim SC, Solomon DH, Rogers JR, Gale S, Klearman M, Sarsour K, et al. Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi-database cohort study. Arthritis Rheumatol. 2017; 69(6):1154–1164. PMID: 28245350.

24. Curtis JR, Perez-Gutthann S, Suissa S, Napalkov P, Singh N, Thompson L, et al. Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. Semin Arthritis Rheum. 2015; 44(4):381–388. PMID: 25300699.

25. Gottenberg JE, Morel J, Constantino A, Bardin T, Cantagrel A, Combe B, et al. Similar rates of death, serious infections, cancers, major cardiovascular events in patients treated with abatacept, rituximab and tocilizumab: long-term registry data in 4498 patients with rheumatoid arthritis. Arthritis Rheumatol. 2016; (Suppl):(10):2614.

26. Giles JT, Sattar N, Gabriel S, Ridker PM, Gay S, Warne C, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020; 72(1):31–40. PMID: 31469238.

27. Gómez R, Conde J, Scotece M, Gómez-Reino JJ, Lago F, Gualillo O. What's new in our understanding of the role of adipokines in rheumatic diseases? Nat Rev Rheumatol. 2011; 7(9):528–536. PMID: 21808287.

28. Inoue M, Maehata E, Yano M, Taniyama M, Suzuki S. Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes. Metabolism. 2005; 54(3):281–286. PMID: 15736103.

29. Inoue M, Yano M, Yamakado M, Maehata E, Suzuki S. Relationship between the adiponectin-leptin ratio and parameters of insulin resistance in subjects without hyperglycemia. Metabolism. 2006; 55(9):1248–1254. PMID: 16919546.

30. Frühbeck G, Catalán V, Rodríguez A, Gómez-Ambrosi J. Adiponectin-leptin ratio: a promising index to estimate adipose tissue dysfunction. Relation with obesity-associated cardiometabolic risk. Adipocyte. 2018; 7(1):57–62. PMID: 29205099.

31. Baek HJ, Lim MJ, Park W, Park SH, Shim SC, Yoo DH, et al. Efficacy and safety of tocilizumab in Korean patients with active rheumatoid arthritis. Korean J Intern Med. 2019; 34(4):917–931. PMID: 29334721.

32. Yu B, Barrett M, Kim HJ, Feuer E. Estimating joinpoints in continuous time scale for multiple change-point models. Comput Stat Data Anal. 2007; 51(5):2420–2427.

33. Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gómez-Reino JJ, et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis. 2006; 65(9):1198–1201. PMID: 16414972.

34. Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011; 70(3):482–487. PMID: 21216812.

35. Robertson J, Peters MJ, McInnes IB, Sattar N. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol. 2013; 9(9):513–523. PMID: 23774906.

36. Baker JF, Billig E, Michaud K, Ibrahim S, Caplan L, Cannon GW, et al. Weight loss, the obesity paradox, and the risk of death in rheumatoid arthritis. Arthritis Rheumatol. 2015; 67(7):1711–1717. PMID: 25940140.

37. Challal S, Minichiello E, Boissier MC, Semerano L. Cachexia and adiposity in rheumatoid arthritis. Relevance for disease management and clinical outcomes. Joint Bone Spine. 2016; 83(2):127–133. PMID: 26184539.

38. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005; 26(3):439–451. PMID: 15897298.

39. Ebina K, Fukuhara A, Ando W, Hirao M, Koga T, Oshima K, et al. Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction. Clin Rheumatol. 2009; 28(4):445–451. PMID: 19085030.

40. 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):1562–1568. PMID: 21571734.

41. Popa C, Netea MG, de Graaf J, van den Hoogen FH, Radstake TR, Toenhake-Dijkstra H, et al. Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis. J Rheumatol. 2009; 36(4):724–730. PMID: 19273452.

42. Derdemezis CS, Filippatos TD, Voulgari PV, Tselepis AD, Drosos AA, Kiortsis DN. Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid arthritis. Fundam Clin Pharmacol. 2009; 23(5):595–600. PMID: 19563510.

43. Nagashima T, Okubo-Fornbacher H, Aoki Y, Kamata Y, Kimura H, Kamimura T, et al. Increase in plasma levels of adiponectin after administration of anti-tumor necrosis factor agents in patients with rheumatoid arthritis. J Rheumatol. 2008; 35(5):936–938. PMID: 18464318.

44. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995; 1(11):1155–1161. PMID: 7584987.

45. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006; 6(10):772–783. PMID: 16998510.

46. Tian G, Liang JN, Pan HF, Zhou D. Increased leptin levels in patients with rheumatoid arthritis: a meta-analysis. Ir J Med Sci. 2014; 183(4):659–666. PMID: 24510478.

47. Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, 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):269–275. PMID: 21325757.

48. Lee YH, Bae SC. Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis. Z Rheumatol. 2016; 75(10):1021–1027. PMID: 26820722.

49. Cao H, Lin J, Chen W, Xu G, Sun C. Baseline adiponectin and leptin levels in predicting an increased risk of disease activity in rheumatoid arthritis: a meta-analysis and systematic review. Autoimmunity. 2016; 49(8):547–553. PMID: 27690205.

50. Fioravanti A, Tenti S, Bacarelli MR, Damiani A, Li Gobbi F, Bandinelli F, et al. Tocilizumab modulates serum levels of adiponectin and chemerin in patients with rheumatoid arthritis: potential cardiovascular protective role of IL-6 inhibition. Clin Exp Rheumatol. 2019; 37(2):293–300. PMID: 30148441.

51. Virone A, Bastard JP, Fellahi S, Capeau J, Rouanet S, Sibilia J, et al. Comparative effect of tumour necrosis factor inhibitors versus other biological agents on cardiovascular risk-associated biomarkers in patients with rheumatoid arthritis. RMD Open. 2019; 5(2):e000897. PMID: 31413865.