RESULTS We retrieved 5881 citations for further evaluation (ﬁgure 1). Title and abstract screening according to our selection criteria (sup- plementary table S1) left 76 papers for detailed review. Among those, 17 trials published in full and 2 abstracts addressed direct assessment of treating to target. By hand search of references, we identiﬁed three additional papers; further, one full paper and one abstract were included based on expert opinion. This gave a total of 24 publications for this review (ﬁgure 1), of which only 7 were strategic trials: 4 trials randomised patients to routine or targeted treatment,26–29 two compared different randomised targets30 31 and one compared targeted treatment to historical control.32 Randomised strategic trials comparing targeted versus routine care Only four trials had randomised patients to a targeted treatment algorithm versus routine care. In Tight Control of Rheumatoid Arthritis (TICORA),26 treatment of early RA aimed at low dis- ease activity (LDA) by Disease Activity Score (DAS), comparing DAS-driven treatment adaptations upon monthly assessments with 3-monthly routine care. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA)27 aimed at remission of early RA, comparing monthly treatment adaptation by com- puterised decision if >20% (50%) reduction of several variables Extended report was not attained with 3-monthly routine care. A cluster ran- domised trial by Fransen et al 28 compared the proportion of patients reaching LDA at the end of follow-up and the number of disease-modifying antirheumatic drug (DMARD) changes dur- ing 24 weeks (co-primary end points) in outpatient centres using systematic, DAS28-steered treatment protocols with centres pro- viding routine care. The treatment decision in the DAS28-driven group depended on a threshold of 3.2, indicating LDA. Finally, Symmons et al29 tested the effect of aggressive versus symptom- atic therapy on physical outcome (Health Assessment Questionnaire (HAQ)) in established RA. Decisions for treatment adaption were driven by joint count- and C reactive protein (CRP) thresholds. Designs of these trials are depicted in ﬁgure 2; baseline character- istics are tabulated in supplementary table S3. Characteristics of the core trials, including treatment targets and visit intervals, as well as clinical, functional and radiographic outcomes are summarised in table 1 and will be detailed below. Signiﬁcantly greater DAS reduction and higher likeliness to achieve remission following intensive disease manage- ment was evident in all four trials. In TICORA,26 the primary end point, EULAR good response, as well as DAS remission were signiﬁcantly more frequent upon intensive than routine care. CAMERA27 showed signiﬁcant beneﬁts of targeted treat- ment regarding its primary end point, remission for 3 months. Papers retrieved and selection process Medline n=2083 12/2008 Embase n=3215 12/2008 Cochrane n=398 12/2008 ACR & EULAR 2007+2008 n=185 5881 For detailed review n=34 For detailed review n=25 For detailed review n=17 Non-human (n=26) Non-fulltext (n=1116) Non-english (n=49) > Title Abstract Screening: 892 Duplicates (n=25) No RA (n=3) Wrong treat (n=36) Wrong outcome (n=276) Irrelevant (n=47) No trial (n=228) No strategy trial (n=243) Excluded, n=19 Dose titration standard dose (n=3) Definition of suboptimal response (n=1) Treating to target optional extension (n=1) No strategy trial (n=14) Included n=15 Non-human (n=58) Non-full text (n=1854) Non-english (n=70) > Title Abstract Screening: 1233 No RA (n=12) Wrong treat (n=70) Wrong outcome (n=416) Review of interest (n=1) Irrelevant (n=35) No trial (n=213) No strategy trial (n=461) Excluded, n=23 Duplicates medline (n=20) No strategy trial (n=3) Included n=2 Included n=0 Excluded Title/AB: Non-human (n=1) Non-english (n=29) Wrong treat (n=28) Wrong outcome (n=82) No trial (n=7) No strategy trial (n=234) 76 Excluded, n=17 Duplicates medline (n=17) Excluded: 183 No treatment of interest (n=138) No outcome of interest (n=18) No strategic trial (n=26) Already published paper (n=1) Included n=2 24 Handsearch Expert opinion n=3 n=2 Figure 1 Flow chart of the systematic literature search. Illustrated are the results of the initial search and the selection process of abstract screening, full text review and hand search. AB, abstract; ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; RA, rheumatoid arthritis. Ann Rheum Dis 2010;69:638–643. doi:10.1136/ard.2009.123976 03_ar123976.indd 639 639 3/10/2010 11:52:40 AM