title: Efficacy of treatment intensification with adalimumab, etanercept and infliximab in rheumatoid arthritis: a systematic review of cohort studies with focus on dose.
abstract: OBJECTIVE
  To summarize the empirical evidence regarding the effect of treatment intensification on clinical outcomes in patients with rheumatoid arthritis treated with one of the TNF-α-inhibitors, adalimumab, etanercept or infliximab.
  
  
  METHODS
  A systematic search of the bibliographic databases Embase, Medline, Web of Science and Cochrane Central identifying articles concerning treatment with adalimumab, etanercept or infliximab in adult patients with rheumatoid arthritis exposed to dose increase or shortening of dosing intervals was performed. Longitudinal cohorts, both clinical trials and observational studies, were included. ACR and EULAR response criteria and DAS28 were the preferred outcome measures.
  
  
  RESULTS
  Out of 1135 records, eleven studies were included in the final evidence synthesis. One article concerned all the three TNF-α-inhibitors, eight used infliximab, one adalimumab and one etanercept. According to GRADE, evidence was weakened in particular by the lack of control groups, and for treatment intensification with adalimumab and etanercept, no conclusions could be drawn. With infliximab, two trials of high quality revealed contradictory results, but six studies described an improved clinical outcome following intensified treatment strategies. Some studies (2/2) also indicated that for infliximab, frequency increase was superior to dose increase.
  
  
  CONCLUSIONS
  Available studies indicate that intensifying treatment with infliximab in rheumatoid arthritis patients, preferably by increasing the frequency of drug administration, may lead to improved clinical outcome in some patients, but the evidence is weak. There is an urgent need for prospectively designed cohort studies to be able to draw a final conclusion.
authors.affiliation: Department of Rheumatology, Copenhagen University Hospital at Køge, Lykkebækvej 1, DK-4600 Køge, Denmark; Department of Clinical Biochemistry, Copenhagen University Hospital at Køge, Lykkebækvej 1, DK-4600 Køge, Denmark; The Parker Institute, Department of Rheumatology, Copenhagen University Hospitals at Frederiksberg and Bispebjerg, DK-2000 Copenhagen F, Denmark. Electronic address: eng@dadlnet.dk.
authors.forename: Grith
authors.initials: G
authors.lastname: Eng
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stoltenberg
authors.forename: Marcin
authors.initials: M
authors.lastname: Szkudlarek
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Bouchelouche
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
authors.forename: Henning
authors.initials: H
authors.lastname: Bliddal
authors.forename: Else
authors.initials: E
authors.lastname: Marie Bartels
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use*; D000069285:Infliximab; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept
keywords: Adalimumab; Dose escalation; Etanercept; Infliximab; Rheumatoid arthritis