Clinical Rheumatology

, Volume 36, Issue 1, pp 1–8 | Cite as

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice

  • Aleksander LenertEmail author
  • Petar Lenert
Review Article


Optimal rheumatoid arthritis (RA) therapy in daily clinical practice is based on the treat-to-target strategy. Quicker escalation of therapy and earlier introduction of biological disease-modifying anti-rheumatic drugs have led to improved outcomes in RA. However, chronic immunosuppressive therapy is associated with adverse events and higher costs. In addition, our patients frequently express a desire for lower dosing and drug holidays. Current clinical practice guidelines from the American College of Rheumatology and European League Against Rheumatism suggest that rheumatologists consider tapering treatment after achieving remission. However, the optimal approach for tapering therapy in RA, specifically de-escalation of biologics, remains unknown. This clinical review discusses biologic tapering strategies in RA. We draw our recommendations for everyday clinical practice from the most recent observational, pragmatic, and controlled clinical trials on de-escalation of biologics in RA. For each biologic, we highlight clinically relevant outcomes, such as flare rates, recapture of the disease control with retreatment, radiographic progression, side effects, and functional impact. We discuss the use of musculoskeletal ultrasound to select patients for successful tapering. In conclusion, we provide the reader with a practical guide for tapering biologics in the rheumatology clinic.


Biologic therapy Discontinuation Musculoskeletal ultrasound Rheumatoid arthritis Tapering Treat to target 


Compliance with ethical standards




No specific funding was received from any funding bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this manuscript.


  1. 1.
    Spector TD (1990) Rheumatoid arthritis. Rheum Dis Clin N Am 16(3):513–537Google Scholar
  2. 2.
    Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. Lancet 358(9285):903–911. doi: 10.1016/s0140-6736(01)06075-5 CrossRefPubMedGoogle Scholar
  3. 3.
    McInnes IB, Liew FY (2005) Cytokine networks—towards new therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 1(1):31–39. doi: 10.1038/ncprheum0020 CrossRefPubMedGoogle Scholar
  4. 4.
    Perricone C, Ceccarelli F, Valesini G (2011) An overview on the genetic of rheumatoid arthritis: a never-ending story. Autoimmun Rev 10(10):599–608. doi: 10.1016/j.autrev.2011.04.021 CrossRefPubMedGoogle Scholar
  5. 5.
    Jutley G, Raza K, Buckley CD (2015) New pathogenic insights into rheumatoid arthritis. Curr Opin Rheumatol 27(3):249–255. doi: 10.1097/bor.0000000000000174 CrossRefPubMedGoogle Scholar
  6. 6.
    Yarwood A, Huizinga TW, Worthington J (2016) The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford) 55(2):199–209. doi: 10.1093/rheumatology/keu323 CrossRefGoogle Scholar
  7. 7.
    Singh JA, Saag KG, Bridges SL Jr et al (2016) 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1–26. doi: 10.1002/art.39480 CrossRefPubMedGoogle Scholar
  8. 8.
    Smolen JS, Landewe R, Breedveld FC et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73(3):492–509. doi: 10.1136/annrheumdis-2013-204573 CrossRefPubMedGoogle Scholar
  9. 9.
    Fautrel B, Den Broeder AA (2015) De-intensifying treatment in established rheumatoid arthritis (RA): why, how, when and in whom can DMARDs be tapered? Best Pract Res Clin Rheumatol 29(4–5):550–565. doi: 10.1016/j.berh.2015.09.006 CrossRefPubMedGoogle Scholar
  10. 10.
    Tanaka Y, Hirata S, Saleem B, Emery P (2013) Discontinuation of biologics in patients with rheumatoid arthritis. Clin Exp Rheumatol 31(4 Suppl 78):S22–S27PubMedGoogle Scholar
  11. 11.
    Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, Rispens T, Wolbink G (2015) Key findings towards optimising adalimumab treatment: the concentration-effect curve. Ann Rheum Dis 74(3):513–518. doi: 10.1136/annrheumdis-2013-204172 CrossRefPubMedGoogle Scholar
  12. 12.
    Betegnie AL, Gauchet A, Lehmann A et al (2016) Why do patients with chronic inflammatory rheumatic diseases discontinue their biologics? An assessment of patients’ adherence using a self-report questionnaire. J Rheumatol 43(4):724–730. doi: 10.3899/jrheum.150414 CrossRefPubMedGoogle Scholar
  13. 13.
    Detert J, Bastian H, Listing J et al (2013) Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis 72(6):844–850. doi: 10.1136/annrheumdis-2012-201612 CrossRefPubMedGoogle Scholar
  14. 14.
    Kavanaugh A, Fleischmann RM, Emery P et al (2013) Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis 72(1):64–71. doi: 10.1136/annrheumdis-2011-201247 CrossRefPubMedGoogle Scholar
  15. 15.
    Tanaka Y, Yamanaka H, Ishiguro N, Miyasaka N, Kawana K, Hiramatsu K, Takeuchi T (2016) Adalimumab discontinuation in patients with early rheumatoid arthritis who were initially treated with methotrexate alone or in combination with adalimumab: 1 year outcomes of the HOPEFUL-2 study. RMD Open 2(1):e000189. doi: 10.1136/rmdopen-2015-000189 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tanaka Y, Hirata S, Kubo S et al (2015) Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis 74(2):389–395. doi: 10.1136/annrheumdis-2013-204016 CrossRefPubMedGoogle Scholar
  17. 17.
    Chatzidionysiou K, Turesson C, Teleman A et al (2016) A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission. RMD Open 2(1):e000133. doi: 10.1136/rmdopen-2015-000133 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Moghadam MG, Vonkeman HE, Ten Klooster PM et al (2016) Stopping tumor necrosis factor inhibitor treatment in patients with established rheumatoid arthritis in remission or with stable low disease activity: a pragmatic multicenter, open-label randomized controlled trial. Arthritis Rheumatol 68(8):1810–1817. doi: 10.1002/art.39626 CrossRefGoogle Scholar
  19. 19.
    Emery P, Hammoudeh M, FitzGerald O et al (2014) Sustained remission with etanercept tapering in early rheumatoid arthritis. N Engl J Med 371(19):1781–1792. doi: 10.1056/NEJMoa1316133 CrossRefPubMedGoogle Scholar
  20. 20.
    Smolen JS, Nash P, Durez P et al (2013) Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 381(9870):918–929. doi: 10.1016/s0140-6736(12)61811-x CrossRefPubMedGoogle Scholar
  21. 21.
    van Vollenhoven RF, Ostergaard M, Leirisalo-Repo M et al (2016) Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 75(1):52–58. doi: 10.1136/annrheumdis-2014-205726 CrossRefPubMedGoogle Scholar
  22. 22.
    van Herwaarden N, van der Maas A, Minten MJ et al (2015) Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 350:h1389. doi: 10.1136/bmj.h1389 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fautrel B, Pham T, Alfaiate T et al (2016) Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Ann Rheum Dis 75(1):59–67. doi: 10.1136/annrheumdis-2014-206696 CrossRefPubMedGoogle Scholar
  24. 24.
    van den Broek M, Klarenbeek NB, Dirven L et al (2011) Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study. Ann Rheum Dis 70(8):1389–1394. doi: 10.1136/ard.2010.147751 CrossRefPubMedGoogle Scholar
  25. 25.
    Schett G, Emery P, Tanaka Y et al (2016) Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis 75(8):1428–1437. doi: 10.1136/annrheumdis-2016-209201 CrossRefPubMedGoogle Scholar
  26. 26.
    Smolen JS, Emery P, Ferraccioli GF et al (2015) Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial. Ann Rheum Dis 74(5):843–850. doi: 10.1136/annrheumdis-2013-204632 CrossRefPubMedGoogle Scholar
  27. 27.
    Emery P, Burmester GR, Bykerk VP et al (2015) Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis 74(1):19–26. doi: 10.1136/annrheumdis-2014-206106 CrossRefPubMedGoogle Scholar
  28. 28.
    Westhovens R, Robles M, Ximenes AC et al (2015) Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis. Ann Rheum Dis 74(3):564–568. doi: 10.1136/annrheumdis-2014-206149 CrossRefPubMedGoogle Scholar
  29. 29.
    Takeuchi T, Matsubara T, Ohta S et al (2015) Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: a prospective, multicentre, observational study in Japan. Rheumatology (Oxford) 54(4):683–691. doi: 10.1093/rheumatology/keu338 CrossRefGoogle Scholar
  30. 30.
    Nishimoto N, Amano K, Hirabayashi Y et al (2014) Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study. Mod Rheumatol 24(1):17–25. doi: 10.3109/14397595.2013.854079 CrossRefPubMedGoogle Scholar
  31. 31.
    Nishimoto N, Amano K, Hirabayashi Y et al (2014) Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study. Mod Rheumatol 24(1):26–32. doi: 10.3109/14397595.2013.854080 CrossRefPubMedGoogle Scholar
  32. 32.
    Iwamoto T, Ikeda K, Hosokawa J et al (2014) Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total gray-scale and power Doppler scores that represent residual synovial inflammation before discontinuation. Arthritis Care Res (Hoboken) 66(10):1576–1581. doi: 10.1002/acr.22303 CrossRefGoogle Scholar
  33. 33.
    Naredo E, Valor L, De la Torre I et al (2015) Predictive value of Doppler ultrasound-detected synovitis in relation to failed tapering of biologic therapy in patients with rheumatoid arthritis. Rheumatology (Oxford) 54(8):1408–1414. doi: 10.1093/rheumatology/kev006 CrossRefGoogle Scholar
  34. 34.
    Alivernini S, Peluso G, Fedele AL, Tolusso B, Gremese E, Ferraccioli G (2016) Tapering and discontinuation of TNF-alpha blockers without disease relapse using ultrasonography as a tool to identify patients with rheumatoid arthritis in clinical and histological remission. Arthritis Res Ther 18:39. doi: 10.1186/s13075-016-0927-z CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2016

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicineUniversity of KentuckyLexingtonUSA
  2. 2.Division of Immunology, Department of Internal MedicineThe University of IowaIowa CityUSA

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