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EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update
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  1. Josef S Smolen1,
  2. Robert B M Landewé2,3,
  3. Johannes W J Bijlsma4,
  4. Gerd R Burmester5,
  5. Maxime Dougados6,
  6. Andreas Kerschbaumer1,
  7. Iain B McInnes7,
  8. Alexandre Sepriano8,
  9. Ronald F van Vollenhoven9,
  10. Maarten de Wit10,
  11. Daniel Aletaha1,
  12. Martin Aringer11,
  13. John Askling12,
  14. Alejandro Balsa13,
  15. Maarten Boers14,
  16. Alfons A den Broeder15,
  17. Maya H Buch16,
  18. Frank Buttgereit5,
  19. Roberto Caporali17,
  20. Mario Humberto Cardiel18,
  21. Diederik De Cock19,
  22. Catalin Codreanu20,
  23. Maurizio Cutolo21,
  24. Christopher John Edwards22,
  25. Yvonne van Eijk-Hustings23,
  26. Paul Emery24,
  27. Axel Finckh25,
  28. Laure Gossec26,
  29. Jacques-Eric Gottenberg27,
  30. Merete Lund Hetland28,
  31. Tom W J Huizinga29,
  32. Marios Koloumas30,31,
  33. Zhanguo Li32,
  34. Xavier Mariette33,
  35. Ulf Müller-Ladner34,
  36. Eduardo F Mysler35,
  37. Jose A P da Silva36,
  38. Gyula Poór37,
  39. Janet E Pope38,
  40. Andrea Rubbert-Roth39,
  41. Adeline Ruyssen-Witrand40,
  42. Kenneth G Saag41,
  43. Anja Strangfeld42,
  44. Tsutomu Takeuchi43,
  45. Marieke Voshaar44,
  46. René Westhovens19,
  47. Désirée van der Heijde29
  1. 1 Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
  2. 2 Amsterdam University Medical Center, Amsterdam, The Netherlands
  3. 3 Zuyderland Medical Center, Heerlen, The Netherlands
  4. 4 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  5. 5 Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Free University and Humboldt University Berlin, Berlin, Germany
  6. 6 Rhumatologie B, Hopital Cochin, 27 rue du Fbg Saint-Jacques, Paris, France
  7. 7 Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  8. 8 NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal, and Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  9. 9 Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  10. 10 EULAR Patient Research Partner; Department Medical Humanities, Amsterdam University Medical Center, Amsterdam, The Netherlands
  11. 11 Division of Rheumatology, Department of Medicine III, University Medical Center and Faculty of Medicine Carl Gustav Carus, Dresden, Germany
  12. 12 Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
  13. 13 Servicio de Reumatologia Hospital Universitario La Paz, Instituto de Investigacion IdiPAZ, Madrid, Spain
  14. 14 Department of Epidemiology and Biostatistics and Amsterdam Rheumatology and Immunology Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
  15. 15 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
  16. 16 Division of Musculoskeletal and Dermatological Sciences, University of Manchester; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK
  17. 17 Department of Clinical Sciences and Community Health, University of Milan, and IRCCS S Matteo Foundation, Pavia, Italy
  18. 18 Centro de Investigación Clínica de Morelia SC, Morelia, Michoacán, Mexico
  19. 19 Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven; Rheumatology, University Hospitals Leuven, Leuven, Belgium
  20. 20 Center of Rheumatic Diseases, University of Medicine and Pharmacy, Bucharest, Romania
  21. 21 Research Laboratory and Division of Clinical Rheumatology, Department of Internal Medicine - University of Genoa, Genoa, Italy
  22. 22 Musculoskeletal Research Unit, NIHR Clinical Research Facility, University Hospital Southampton, Southampton, UK
  23. 23 Department of Patient & Care and Department of Rheumatology, University of Maastricht, Maastricht, The Netherlands
  24. 24 NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  25. 25 Division of Rheumatology, University Hospitals of Geneva, Geneva, Switzerland
  26. 26 Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris and Pitié Salpêtrière hospital, AP-HP, Rheumatology Department, Paris, France
  27. 27 Strasbourg University Hospital and University of Strasbourg, CNRS, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie, et Chimie Thérapeutique, Strasbourg, France
  28. 28 Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  29. 29 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  30. 30 European League Against Rheumatism, Zurich, Switzerland
  31. 31 Cyprus League against Rheumatism, Nikosia, Cyprus
  32. 32 Department of Rheumatology and Immunology, Beijing University People's Hospital, Beijing, China
  33. 33 Université Paris-Sud, AP-HP, Université Paris-Saclay, Le Kremlin Bicêtre, France
  34. 34 Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig University Giessen, Bad Nauheim, Germany
  35. 35 Organización Médica de Investigación, Buenos Aires, Argentina
  36. 36 Serviço de Reumatologia, Centro Hospitalar e Universitário de Coimbra Praceta Mota Pinto, and Coimbra Institute for Clinical and Biomedical Research (i-CRB), Faculty of Medicine of Coimbra, Coimbra, Portugal
  37. 37 National Institute of Rheumatology & Physiology, Semmelweis University, Budapest, Hungary
  38. 38 University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Medicine, London, Ontario, Canada
  39. 39 Klinik für Rheumatologie, Kantonsspital St Gallen, St Gallen, Switzerland
  40. 40 UMR 1027, Inserm, Université Paul Sabatier Toulouse III, Toulouse, France
  41. 41 Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham, Brmingham, Alabama, USA
  42. 42 Programme Area Epidemiology, Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany
  43. 43 Keio University School of Medicine, Keio University Hospital, Tokyo, Japan
  44. 44 Department of Psychology, Health and Technology, University of Twente, Enschede, The Netherlands
  1. Correspondence to Professor Josef S Smolen, Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna A-1090, Austria; josef.smolen{at}meduniwien.ac.at

Abstract

Objectives To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field.

Methods An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items.

Results The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high.

Conclusions These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

  • rheumatoid arthritis
  • DMARDs (biologic)
  • DMARDs (synthetic)
  • treatment
  • economic evaluations
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Footnotes

  • JSS and RBML are joint first authors.

  • Handling editor Dimitrios T Boumpas

  • Twitter @cardielmh

  • JSS and RBML contributed equally.

  • Correction notice This article has been corrected since it published Online First. A typographical error in the footnote of table 2 has been corrected.

  • Contributors The paper was drafted by JSS and RBML and all authors contributed with specific comments and revisions to the paper.

  • Funding This study was funded by European League Against Rheumatism (grant number:CLI111).

  • Competing interests DA: grants from Abbvie, Novartis, Roche and honoraria from Abbvie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme; MA: honoraria from AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Chugai, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; JA: grants from Abbvie, BMS, Lilly, Merck, Pfizer, Roche, Samsung Bioepis, UCB; AB: grants from Pfizer, Bristol-Myers Squibb and honoraria from Pfizer, Roche, AbbVie, Bristol-Myers Squibb, UCB, MSD, Novartis, Sanofi, Biogen, Sandoz, Celltrion, Nordic, Gilead; JWJB: honoraria from Lilly, Roche, Sanofi; MB: honoraria from BMS, Teva, Novartis, Pfizer, GSK; AdB: grants from Abbvie, Biogen, Celltrion and honoraria from Abbvie, Biogen, Boehringer-Ingelheim, Celgene, Fresenius, MSD, Roche.

    MHB has received grants from Pfizer, Roche and UCB and consulting fees from Abbvie, Eli-Lilly, Merck.Serono, Pfizer, Sandoz, Sanofi; GB: grants from Abbvie, Pfizer, Sanofi, UCB and honoraria from Abbvie, Celgene, Gilead, Lilly, MSD, Novartis, Pfizer, Sanofi, Roche. FB: grants from Abbvie, BMS, Horizon, Medac, Pfizer, Roche, Lilly, Sanofi and honoraria from Abbvie, Galapagos, Horizon, Medac, Pfizer, Roche, Sanofi, Janssen, BMS, MSD, Lilly; RC: honoraria from Abbvie, BMS, Celgene, Celltrion, Gilead, Janssen, Lilly MSD, Mundipharma, Novartis-Sandoz, Pfizer, Roche, Sanofi and UCB; MC; honoraria from Abbvie, Astellas, BMS, Lilly, Pfizer and Roche; DDC: no conflict; CC: honoraria from AbbVie, Accord Healthcare, Alfasigma, Berlin Chemie, Egis, Eli Lilly, Ewopharma, Genesis, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB; MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz; CJE: grants from Abbvie, Biogen and honoraria from Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB; PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly; AF: grants from BMS, Pfizer and honoraria from AB2 BIO, Abbvie, BMS, Lilly, MSD, Pfizer, Roche, Sanofi; LG: grants from Abbvie, BMS, Lilly, UCB and honoraria from Abbvie, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, UCB; J-EG: grants from BMS, Pfizer and honoraria from Abbvie, BMS, Lilly, Sanofi-Genzyme, Roche, UCB; MLH: grants from Abbvie, Biogen, BMS, Celltrion, MSD, Novartis, Orion, Pfizer, Samsung, UCB; TH: grants from Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boeringher and honoraria from Abblynx, BMS, Janssen, Pfizer, Sanofi-Aventis, Crescendo Bioscience, Galapagos, Lilly; AK: honoraria from BMS, Pfizer, Celgene, MSD; MK: no conflicts of interest; RBML: honoraria from AbbVie, BMS, Celgene, Eli-Lilly, Jansen Pharmaceuticals, Galapagos, Novartis, MSD, Pfizer, UCB and Director of Rheumatology Consultancy BV; XM: honoraria from BMS, Gilead, Pfizer, Samsung, UCB; IBM: grants from Astra Zeneca, UCB, BMS, Janssen, GSK, Compugen, Boehringer, Celgene and honoraria from Abbvie, BMS, Janssen, Novartis, UCB, Astra Zeneca, Celgene, Causeway, Lilly, Leo, Novimmune; EM: grants from Pfizer, Lilly, BMS, AbbVie, GSK, Astra and honoraria from Pfizer, BMS, Roche, Lilly, AbbVie, Gemma, Sanofi; TWJH: grants from Eli Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boehringer and honoraria from Abblynx, Abbvie, BMS, Boehringer, Crescendo-Bioscience, Epirus, Galapagos, Janssen, Lilly, Merck, Novartis, Nycomed, Pfizer, Roche, Sanofi-Aventis, Takeda, UCB; ZL: no conflicts of interest; UM-L: honoraria from Abbvie, BMS, MSD, Chugai, Roche, Pfizer, Sanofi, Boehringer, Actelion, Medac, Lilly; GP: no conflicts of interest; JP: grants from BMS, Merck, UCB and honoraria from AbbVie, Actelion, Amgen, BMS, Bayer, GSK, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB; AR-R: honoraria from Abbvie, Chugai, BMS, Sanofi, Roche, Lilly, Janssen, Novartis, Celgene, MSD, UCB; AR-W: grants from Pfizer, Abbvie and honoraria from Abbvie, Amgen, BMS, Janssen, Lilly, Medac, Nordic Pharma, Novartis, Pfizer, Roche-Chugai, Sanofi, UCB; KS: grants from Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda and honoraria from AbbVie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin; MSV: no conflicts of interest. AS: honoraria from Novartis; JSS: grants from Abbvie, AstraZeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB; AS: grants from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG Lilly, MSD Sharp & Dome, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB and honoraria from AbbVie, BMS, MSD, Pfizer, Roche; TT: grants from AbbVie, Asahikasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Takeda and honoraria from AbbVie, Astellas, Astra Zeneca, BMS, Chugai, Diaichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Sanofi, Teijin, Taiho Pharmaceutical, Taisho Pharmaceutical, Takeda, UCB; DvdH: grants from UCB and honoraria from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB and Director Imaging Rheumatology BV; YvE-H: honoraria from Celgene; RFvV: grants from BMS, GSK, Lilly, UCB and honoraria from AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, Roche, UCB; RW: grants from Roche, BMS and honoraria from Celltrion, Galapagos-Gilead; MdW: honoraria from 'Stichting Tools', Janssen-Cilag.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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