A Brief History of RA Therapies
This supplement explores the current shortfalls in the care of patients with rheumatoid arthritis (RA), the similarities and differences between small molecules and biologics, the role of Janus kinase ( JAK) inhibition in RA pathogenesis, and the current and potential future role of JAK inhibitors in the treatment of RA.
In 1998, the US Food and Drug Administration (FDA) approved infliximab for the treatment of Crohn disease, marking the dawn of the biologic era in inflammatory diseases (Figure 1). A few months later, etanercept became the first tumor necrosis factor (TNF) inhibitor to be approved by the FDA for the treatment of RA. As the rheumatology community gained a more thorough understanding of the role of cytokines and immune system cells in RA, additional biologics were introduced that targeted TNF, interleukin (IL) 1 and 6, and T- and B-cell function.1
Method of Participation
Participants should read the CME/CE information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it out at that time.
After completing this activity, participants should be better able to:
- Design optimal treatment strategies for patients with rheumatoid arthritis (RA) to improve remission rates and/or minimize levels of disease
- Recognize the role that Janus kinase (JAK) plays in the pathogenesis of RA and the corresponding impact of JAK inhibition in the management of RA
- Discuss treatment options for RA, including the use of JAK inhibitors, as reflected in current practice guideline
Roy Fleischmann, MD, MACR
Iain B. McInnes, FRCP, PhD, FRSE, FMedSci
Physician Accreditation Statement
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Global Academy for Medical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.
Physician Credit Designation
Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing Continuing Education
Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.
This educational activity for 1.0 contact hour is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity.
Current guidelines for the management of rheumatoid arthritis (RA) address the concern that many patients fail to respond, or lose response, to first-line therapy with disease-modifying antirheumatic drugs (DMARDs). Lack of understanding about the optimal use of avail- able RA therapies—including combination therapy or switching to other drugs within a class or in a different class—means that many patients may fail to achieve remission (the ideal goal) or minimal levels of disease activity. Clinicians who are unaware of current practice guidelines may not be providing optimal management for their patients with RA. In addition, clinicians should be aware of data concerning the safety and efficacy of newly available drugs so as to ensure selection of optimal therapies for patients with RA. Knowledge of agents that have novel mechanisms of action, including Janus kinase inhibitors, can improve clinicians’ confidence when switching therapies in patients who have suboptimal response despite appropriate use of DMARD therapies.
Joint Providership Statement
This activity is jointly provided by Global Education Group and Global Academy for Medical Education.
Term of Offering
This activity was released on October 1, 2017, and is valid for 1 year. Requests for credit must be made no later than October 31, 2018.
Global Education Group Contact Information
For information about the accreditation of this activity, please contact Global Education Group at 303-395-1782 or [email protected] group.com.
Instructions for Obtaining Credit
In order to receive credit, participants must complete the online evalua- tion and post-test at the end of this activity. Participants must also score at least a 65% on the post-test. Statements of credit will be issued upon completion of the evaluation and post-test.
Fee Information and Refund/Cancellation Policy
There is no fee for this educational activity.
Disclosure of Conflicts of Interest
Global Education Group requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global Education Group for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appro- priateness of patient care recommendations.
The faculty reported the following financial relationships or relation- ships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity:
Name of Faculty or Presenter: Roy Fleischmann, MD, MACR
Reported Financial Relationship: Consultant: AbbVie, Lilly, Pfizer. Grant/Research Support: AbbVie, Lilly, Pfizer.
Name of Faculty or Presenter: Iain B. McInnes, FRCP, PhD, FRSE, FMedSci
Reported Financial Relationship: Consultant: AbbVie; Galapagos Pharma; Lilly; Pfizer. Grant/Research Support: Bristol-Myers Squibb; Janssen; Pfizer; UCB.
The planners and managers reported the following financial relation- ships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Ashley Marostica, RN, MSN; Laura Gilsdorf; Ron Schaumburg; Mike LoPresti; Shirley Jones, MBA; and Scott Kober all have nothing to disclose.
Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global Education Group and Global Academy of Medical Education do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organiza- tion associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medi- cations, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
1. Mócsai A, Kovács L, Gergely P. What is the future of targeted therapy in rheumatology: Biologics or small molecules? BMC Med. 2014;12:43.
2. Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: A current perspective. Rheumatol Int. 2016;36:685-695.
3. Curtis JR, Singh JA. Use of biologics in rheumatoid arthritis: Current and emerging paradigms of care. Clin Ther. 2011;33:679-707.
4. Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert Committee. Treating rheumatoid arthritis to target: Recommendations of an international task force. Ann Rheum Dis. 2010;69:631-637.
5. Solomon DH, Bitton A, Katz JN, Radner H, Brown EM, Fraenkel L. Review: Treat to target in rheumatoid arthritis: Fact, fiction, or hypothesis? Arthritis Rheumatol. 2014;66:775-782.
6. Schmajuk G, Trivedi AN, Solomon DH, et al. Receipt of disease-modifying antirheumatic drugs among patients with rheumatoid arthritis in Medicare managed care plans. JAMA. 2011;305:480-486.
7. American College of Rheumatology Committee on Rheumatology Training and Workforce Issues. Regional distribution of adult rheumatologists. Arthritis Rheum. 2013;65:3017-3025.
8. Wolfe F, Michaud K. Resistance of rheumatoid arthritis patients to changing therapy: Discordance between disease activity and patients’ treatment choices. Arthritis Rheum. 2007;56:2135-2142.
9. Garcês S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: A systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72:1947-1955.
10. Felis-Giemza A, Moots RJ. Measurement of anti-drug antibodies to biologic drugs. Rheumatology (Oxford). 2015;54:1941-1943.
11. Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008;47:249-255.
12. BluettJ,MorganC,ThurstonL,etal;BRAGGSS.Impactofinadequateadherence on response to subcutaneously administered anti-tumour necrosis factor drugs: Results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort. Rheumatology (Oxford). 2015;54:494-499.
13. Park SK, Lee MY, Jang EJ, Kim HL, Ha DM, Lee EK. A comparison of discontinuation rates of tofacitinib and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis: A systematic review and Bayesian network meta- analysis. Clin Exp Rheumatol. 2017;35:689-699.
14. Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib – an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:318-328.
15. Genovese MC, Jarosova K, Cieślak D, et al. Apremilast in patients with active rheumatoid arthritis: A phase II, multicenter, randomized, double-blind, placebo- controlled, parallel-group study. Arthritis Rheumatol. 2015;67:1703-1710.
16. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1-26.
17. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: Abridged Cochrane systematic review and network meta-analysis. BMJ. 2016;353:i1777.
18. Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. Comparative efficacy of novel DMARDs as monotherapy and in combination with rheumatoid arthritis patients with inadequate response to conventional DMARDs: A network meta- analysis. J Manag Care Spec Pharm. 2015;21:409-423.
19. SinghJA,CameronC,NoorbaloochiS,etal.Riskofseriousinfectioninbiological treatment of patients with rheumatoid arthritis: A systematic review and metaanalysis. Lancet. 2015;386:258-265.
20. Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti- tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63:522-529.
21. Zhang J, Xie F, Yun H, et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75:1813-1818.
22. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: A meta- analysis of observational studies. Ann Rheum Dis. 2012;71:1524-1529.
23. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13:234-243.
24. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease- modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960-977.
25. vanVollenhovenRF,FleischmannR,CohenS,etal;ORALStandardInvestigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. New Engl J Med. 2012;367:508-519.
26. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376:652-662.
27. Fleischmann R, Kremer J, Cush J, et al; ORAL Solo Investigators. Placebo- controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495-507.
28. Lee EB, Fleischmann R, Hall S, et al; ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377-2386.
29. Strand V, Kremer JM, Gruben D, et al. Tofacitinib in combination with conventional disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: Patient-reported outcomes from a phase III randomized controlled trial. Arthritis Care Res (Hoboken). 2017;69:592-598.
30. Fleischmann R, Mease PJ, Schwartzman S, et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group. Clin Rheumatol. 2017;36:15-24.
31. BurmesterGR,BlancoR,Charles-SchoemanC,etal.Tofacitinib(CP-690,550)in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: A randomised phase 3 trial. Lancet. 2013;381:451-460.
32. Genovese MC, van Vollenhoven RF, Wilkinson B, et al. Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18:145.
33. Dale J, Stirling A, Zhang R, et al. Targeting ultrasound remission in early rheumatoid arthritis: The results of the TaSER study, a randomized clinical trial. Ann Rheum Dis. 2016;75:1043-1050.
34. Charles-Schoeman C, Gonzalez-Gay MA, Kaplan I, et al. Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: Implications for the rheumatologist. Semin Arthritis Rheum. 2016;46:71-80.
35. Giles JT, Sattar N, Gabriel SE, et al. Comparative cardiovascular safety of tocilizumab vs etanercept in rheumatoid arthritis: Results of a randomized, parallel-group, multicenter, noninferiority, phase 4 clinical trial. Presented at: American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 2016 Annual Meeting; November 11-16, 2016; Washington, DC. Abstract 3L.
36. Strand V, Lee EB, Fleischmann R, et al. Tofacitinib versus methotrexate in rheumatoid arthritis: Patient-reported outcomes from the randomised phase III ORAL Start trial. RMD Open. 2016;2:e000308.
37. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. New Engl J Med. 2016;374:1243-1252.
38. Taylor PC, Keystone E, Ortmann R, et al. Efficacy and safety of switching from adalimumab to baricitinib: Phase 3 data in patients with rheumatoid arthritis. Presented at: 2016 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting; November 11-16, 2015; Washington, DC. Abstract 1591.
39. Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: Results from the RA-BUILD study. Ann Rheum Dis. 2017;76:88-95.
40. Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease- modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69:506-517.
41. Westhovens R, Taylor PC, Alten R, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: Results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. 2017;76:998-1008.
42. Kavanaugh A, Kremer J, Ponce L, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: Results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. 2017;76:1009-1019.
43. Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol. 2016;68:2857-2866.
44. Genovese MC, Greenwald M, Codding C, et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol. 2017;69:932-942.
This continuing education supplement was developed from interviews with the faculty. It is the second activity in the two-part curriculum, From Science to Practice: Understanding the Role of Janus Kinase in RA Pathogenesis to Appropriately Incorporate JAK Inhibition in RA Management. The supplement content was derived from the key teaching points from the previous online activity, which may be found at: www.globalacademycme.com/specialties/rheumatology.
The faculty acknowledge the editorial assistance of Global Academy for Medical Education, LLC, and Scott Kober, medical writer, in the development of this supplement.
Neither the editors of Rheumatology News nor the Editorial Advisory Board nor the reporting staff contributed to its content. The ideas and opinions expressed are those of the faculty and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, Global Education Group, or the Publisher.
Copyright © 2017 by Global Academy for Medical Education, LLC, Frontline Medical Communications Inc., and its Licensors. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Global Academy for Medical Education, LLC, Frontline Medical Communications, and Global Education Group will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.