Looking Ahead: Tackling the Challenges

According to Dr Curtis and Dr Singh, “presently, even with early aggressive combination therapy, only about one-third of patients meet the criteria for clinical remission of RA.”6


Continue Reading

Clearly, there is a continuing need for the development of new, effective, and affordable therapies for RA. However, multiple challenges exist on this path.

One of them is the need to clarify the mechanisms that govern the persistent overproduction of IL-6 in RA and those that make IL-6 blockade efficacious.8 Furthermore, a better understanding of the effects of IL-6 inhibition on the predisposition to opportunistic infections is needed.29

Another major challenge is identifying those patients with RA who are most likely to benefit from treatment with a specific biologic agent. Predictive biomarkers of response to treatment have not been adopted in RA,30 which makes the therapeutic decision-making process largely empiric: those patients who fail to respond adequately to initial treatment are switched between therapies with the aim of achieving a response. This approach results in inadequately controlled disease in approximately 40% of patients.6

Finally, there are concerns about the cost of treating RA with biologics. One study estimated that the mean annual direct cost of treating patients with biologic agents is 3-times greater than the cost of treatment that did not include biologics.31 However, researchers warn that only a small number of cost-benefit analyses to date have looked at the long-term cost-effectiveness of biologics.6

“Importantly, improving outcomes with early treatment strategies may reduce healthcare costs and morbidity (eg, need for joint replacement, premature disability) in the long term, thereby offsetting the relatively high direct treatment costs associated with biologics,” Dr Curtis and Dr Singh emphasized, adding that “although biologics are more costly in the short term than conventional DMARDs, cost will clearly be influenced by factors such as dosing intervals and routes of administration, which vary between agents.”6

Related Articles

References

1.     Siebert S, Tsoukas A, Robertson J, et al. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev. 2015;67(2):280-309.

2.     Gibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: a synopsis. Am J Manag Care. 2014;20(7):S128-S135.

3.     Schinnerling K, Aguillón JC, Catalán D, et al. The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis. Clin Exp Immunol. 2017;189(1):12-20.

4.     Fontana A, Hengartner H, Weber E, et al. Interleukin 1 activity in the synovial fluids of patients with rheumatoid arthritis. Rheumat Int. 1982;2:49.

5.     McInnes B, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365(23):2205-2219.

6.     Curtis JR, Singh JA. The use of biologics in rheumatoid arthritis: current and emerging paradigms of care. 2011;33(6):679-707.

7.     Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology 2012;51(6):vi28-vi36.

8.     Yoshida Y, Tanaka T. Interleukin 6 and rheumatoid arthritis. Biomed Res Int. 2014;2014:698313.

9.     Rose-John S. IL-6 trans-signaling via the soluble receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237-1247.

10.  Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727.

11.  Scheller J, Garbers C, Rose-John S. Interleukin‑6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol. 2014;26(1):2-12.

12.  Scheller J, Chalaris A, Schmidt-Arras D, et al. The pro- and anti-inflammatory properties of the cytokine interleukin‑6. Biochim Biophys Acta. 2011;1813(5):878-888.

13.  Rose-John S. The soluble interleukin 6 receptor: advanced therapeutic options in inflammation. Clin Pharmacol Ther. 2017;102(4):591-598.

14.  Madhok R, Crilly A, Watson J, et al. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1993;52(3):232-234.

15.  Straub RH, Müller-Ladner U, Lichtinger T. Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying antirheumatic drugs. Br J Rheumatol. 1997;36(12):1298-1303.

16.  Thiolat A, Semerano L, Pers YM, et al. Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 2014;66(2):273-283.

17.  Suzuki M, Hashizume M, Yoshida H, et al. Antiinflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule. Rheumatol Int. 2010;30(3):309-315.

18.  Nakahara H, Song J, Sugimoto M, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003;48(6):1521-1529.

19.  Castell JV, Gomez-Lechon MJ, David M, et al. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 1988; 232(2):347-350.

20.  Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(8):2499-2503.

21.  Boe A, Baiocchi M, Carbonatto M, et al. Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine. 1999;11(12):1057-1064.

22.  Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88-96.

23.  Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141.

24. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67:1424-1437.

25. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.

26. Regeneron and Sanofi announce FDA approval of Kevzara® (sarilumab) for the treatment of moderately to severely active rheumatoid arthritis in adult patients [news release]. Regeneron Pharmaceuticals, Inc: Tarrytown, NY; May 22, 2017. http://www.prnewswire.com/news-releases/regeneron-and-sanofi-announce-fda-approval-of-kevzara-sarilumab-for-the-treatment-of-moderately-to-severely-active-rheumatoid-arthritis-in-adult-patients-300461766.html. Accessed May 30, 2017.

27.  Genovese MC, Fleischmann R, Hagino O, et al. The effect of sarilumab in combination with DMARDs on fasting glucose and glycosylated hemoglobin in patients with rheumatoid arthritis with and without diabetes. Presented at: ACR/ARHP 2017 Annual Meeting; November 3-8, 2017; San Diego, CA. Poster 1822.

28.   Burmester GR, Fiore S, Hu C-C, Fay J, Lee EB,  Genovese MC. Efficacy and safety of    switching from adalimumab to sarilumab in an open-label extension of a phase 3 monotherapy trial in patients with active rheumatoid arthritis. Presented at: ACR/ARHP 2017 Annual Meeting; November 3-8, 2017; San Diego, CA. Poster 2482.

29. Rose-John S, Withrop K, Calabrese L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol. 2017;13(7):399-409.

30. Gavrilă BI, Ciofu C, Stoica V. Biomarkers in rheumatoid arthritis, what is new? J Med Life. 2016;9(2):144-148.

31. Michaud K, Messer J, Choi HK, et al. Direct medical costs and their predictors in patients with rheumatoid arthritis: a three-year study of 7,527 patients. Arthritis Rheum. 2003;48:2750-2762.