title: Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis.
abstract: OBJECTIVE
  To assess the safety of synthetic (s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA) to inform the European League Against Rheumatism recommendations for the management of RA.
  
  
  METHODS
  Systematic literature review (SLR) of observational studies comparing any DMARD with another intervention for the management of patients with RA. All safety outcomes were included. A comparator group was required for the study to be included. Risk of bias was assessed with the Hayden's tool.
  
  
  RESULTS
  Twenty-six observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria (15 on serious infections, 4 on malignancies). Substantial heterogeneity precluded meta-analysis. Together with the evidence from the 2013 SLR, based on 15 studies, 7 at low risk of bias, patients on bDMARDs compared with patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1 to 1.8)-without differences across bDMARDs-a higher risk of tuberculosis (aHR 2.7 to 12.5), but no increased risk of infection by herpes zoster. Patients on bDMARDs did not have an increased risk of malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5).
  
  
  CONCLUSIONS
  These findings confirm the known safety pattern of bDMARDs, including both tumour necrosis factor-α inhibitor (TNFi) and non-TNFi, for the treatment of RA.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sofia
authors.identifier: http://orcid.org/0000-0002-8899-9087
authors.initials: S
authors.lastname: Ramiro
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.|CEDOC, Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Alexandre
authors.identifier: http://orcid.org/0000-0003-1954-0229
authors.initials: A
authors.lastname: Sepriano
authors.affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden.
authors.forename: Katerina
authors.initials: K
authors.lastname: Chatzidionysiou
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital Leeds, Leeds, UK.|NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Jackie L
authors.initials: JL
authors.lastname: Nam
authors.affiliation: Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.|Department of Medicine, Hietzing Hospital, Vienna, Austria.
authors.forename: Josef S
authors.identifier: http://orcid.org/0000-0002-8899-9087
authors.initials: JS
authors.lastname: Smolen
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Désirée
authors.identifier: http://orcid.org/0000-0002-5781-158X
authors.initials: D
authors.lastname: van der Heijde
authors.affiliation: Department of Rheumatology, Paris Descartes University, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, INSERM (U1153): Clinical Epidemiology and Biostatistics, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Dougados
authors.affiliation: Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Vollenhoven
authors.affiliation: Department of Rheumatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Bijlsma
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Burmester
authors.affiliation: Department of Psychology, Health and Technology, University of Twente, Enschede, The Netherlands.|EULAR Standing Committee of People with Arthritis/Rheumatism in Europe.
authors.forename: Marieke
authors.initials: M
authors.lastname: Scholte-Voshaar
authors.affiliation: Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Falzon
authors.affiliation: Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands.|Department of Rheumatology, Zuyderland Medical Center, Heerlen, The Netherlands.
authors.forename: Robert B M
authors.initials: RBM
authors.lastname: Landewé
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001688:Biological Products / Q000009:adverse effects*; D006801:Humans; D007239:Infections / Q000453:epidemiology*; D009369:Neoplasms / Q000453:epidemiology*; D064887:Observational Studies as Topic; D017410:Practice Guidelines as Topic; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D001688:Biological Products; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha
keywords: Anti-TNF; DMARDs (biologic); DMARDs (synthetic); Outcomes research; Rheumatoid Arthritis