ACR 2019


Conference summaries

Rheumatoid Arthritis

Safety of Synthetic and Biological DMARDs: A Systematic Literature Review Informing the 2019 Update of the EULAR Recommendations for Management of Rheumatoid Arthritis

Presented by: Alexandre Sepriano, MD
Leiden University Medical Center, Leiden, Netherlands
  • A systematic literature analysis was carried out to study the safety pattern of bDMARDs, csDMARDs, and tsDMARDs.
  • bDMARDs and tsDMARDs can be used safely to treat patients with RA.
  • Baricitinib 4 mg and tofacitinib 10 mg should be avoided in patients with risk factors for VTE.

A wide range of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), which can be used in different sequences and/or combinations, is at the disposal of rheumatologists to offer to patients with rheumatoid arthritis (RA). [1] This also implies that choices are to be made when deciding on the best treatment for the individual patient. In order to inform the task force responsible for the 2019 update of the European League Against Rheumatism (EULAR) RA management recommendations, we performed a systematic literature review (SLR) to update the evidence for the safety of csDMARDs, tsDMARDs and bDMARDs in patients with RA.

  • The research questions were structured according to a PICO format (Patients, Intervention, Comparator and Outcomes) and eligible study types were defined.
  • All newly included studies were published from 2016 onwards.
  • Cohort-studies/registries were the main study type of interest; for treatments still without registry data, RCTs and LTEs were used to extract safety data.
  • Participants were adults (aged ≥18 years) with a clinical diagnosis of RA.
  • Studies including patients with other diagnoses were eligible only if the results from patients with RA were presented separately.
  • The intervention was any DMARD (csDMARD, bDMARD—including biosimilars—or tsDMARD).
  • The comparator was a(nother) bDMARD, sDMARD, glucocorticoid, combination therapy, or the general population.
  • Studies were only eligible if they included a comparator group, as a formal comparison is the only insightful manner to take any conclusions about safety.
  • All safety outcomes were considered, namely infections (including serious infections, opportunistic infections such as tuberculosis and herpes zoster (HZ)), malignancies, mortality, cardiovascular disease, change in lipid levels, impairment in renal function, elevation of liver enzymes, hematological abnormalities, gastrointestinal effects, demyelinating disease, induction of autoimmune disease, and teratogenicity.
  • Risk of bias (RoB) was assessed according to Hayden’s tool for observational studies and the Cochrane Collaboration’s tool for RCTs.
  • In total, 8297 references were obtained, of which 102 studies were included, 42 observational and 60 randomized clinical studies/long-term extensions.
  • There was an increased risk of serious infections for TNF-inhibitors (TNF-i) and non-TNF-i vs. csDMARDs in two studies (none at low RoB).
  • There was no difference in the risk of serious infections across bDMARDs (TNF-i and non-TNF-i) and tofacitinib. (9 studies, 4 at low RoB).
  • For Herpes zoster, there was no difference in risk across bDMARDs, but a higher risk for tofacitinib vs. abatacept. (2 studies at high RoB).
  • There was no difference in risk of HZ comparing JAK inhibitors to adalimumab and methotrexate in 3 RCTs at low risk of bias.
  • For malignancies, there was no increased risk with bDMARDs vs. csDMARDs (5 studies, 4 low RoB), and no difference comparing TNF-i to non-TNF-i (2 studies at low RoB).
  • Considering major cardiac adverse events (MACE), there was no increased risk of MACE with bDMARDs vs. csDMARDs (3 studies, 1 low RoB), and no difference in MACE across bDMARDs (4 studies, 1 low RoB).
  • For venous thromboembolism (VTE), three was no difference in risk comparing abatacept and tofacitinib to TNF-i (2 observational studies, both at high RoB).
  • Data from RCTs suggest increased risk with BAR 4 and one yet unpublished study with TOFA 10, especially in patients with risk factors for VTE.
  • bDMARDs and tsDMARDs can be used safely to treat patients with RA.
  • The risk of serious infections was moderately increased with bDMARDs compared to csDMARDs and no difference was found across bDMARDs.
  • The risk of Herpes zoster is not increased with bDMARDs, but is with JAK inhibitors, especially in certain ethnicities.
  • The overall risk of malignancies and MACE was not increased for bDMARDs or tsDMARDs.
  • VTE after JAK inhibition has been reported and led to warning by the FDA/EMA to avoid baricitinib 4 mg and tofacitinib 10 mg in patients with risk factors for VTE.

Key messages/Clinical perspectives

  • These findings add further information about the known safety pattern of bDMARDs, csDMARDs, and tsDMARDs.
  • Baricitinib 4 mg and tofacitinib 10 mg should be avoided in patients with risk factors for VTE.



  1. 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 Jun;76(6):960-77.

Presenter disclosure: The presenter has reported that no relationships exist relevant to the contents of this presentation.

Written by: Patrick Moore, PhD

Reviewed by: Alessia Alunno, MD, PhD

Local reviewers: Alessia Alunno, MD, PhD (Italian); Aurélie Najm, MD (French); Yukinori Okada, MD, PhD (Japanese); Fabian Proft, MD (German); Javier Rodríguez-Carrio, MSc, PhD (Spanish); Priscilla Wong, MD (Chinese)

Scientific Editor:  Leonard H. Calabrese, DO


A Comparative Analysis of Upadacitinib Monotherapy and Upadacitinib Combination Therapy for the Treatment of Rheumatoid Arthritis from Two Phase 3 Trials

Presented by: Maya H. Buch, MD, PhD - University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, United Kingdom

Rheumatoid Arthritis Treatment with Filgotinib: Week 156 Safety and Efficacy Data from a Phase 2b Open-Label Extension Study

Presented by: Arthur Kavanaugh, MD - University of California, San Diego School of Medicine, La Jolla, CA, USA


A Phase 1b/2a Trial of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus

Presented by: Sarfaraz Hasni, MD - National Institute of Arthritis, Musculoskeletal, and Skin diseases/ National Institutes of Health, Bethesda, MD, USA

A Phase 3 Randomized Controlled Trial of Anifrolumab in Patients with Moderate to Severe Systemic Lupus Erythematosus

Presented by: Richard A. Furie, MD - Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA


The Burden of Comorbidity in Patients with RA, PsA or SPA in a General Practice Registry

Presented by: Diederik De Cock, PhD - KU Leuven, Leuven, Belgium



Ixekizumab Demonstrates Improvement Comparable to Adalimumab Across ACR Components in Biologic-Naïve Patients with Psoriatic Arthritis

Presented by: M. Elaine Husni, MD, MPH - Dept. of Rheumatologic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA

Tildrakizumab Efficacy on Psoriasis in Patients with Psoriatic Arthritis—An Analysis from a Phase 2 Study

Presented by: Alan M. Mendelsohn, MD - Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA, Princeton, NJ, USA

Development of a Set of ASAS Quality Standards for Adults with Axial Spondyloarthritis

Presented by: Uta Kiltz, MD - Rheumazentrum Ruhrgebiet/Ruhr University Bochum, Herne, Germany

Ixekizumab in Non-Radiographic Axial Spondyloarthritis: Primary Results from a Phase 3 Trial

Presented by: Atul Deodhar, MD, MRCP - Oregon Health & Science University, Portland, OR, USA


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