BackgroundUncontrolled rheumatoid arthritis (RA) activity and acute disease flares are associated with higher risk of adverse outcomes such as cardiovascular (CV) disease, venous thromboembolism (VTE), malignancy and infection.1-4ObjectivesTo evaluate associations of acute and cumulative Clinical Disease Activity Index (CDAI) measurements with major CV, malignancy, or infectious adverse events (AEs) of special interest in ORAL Surveillance.MethodsORAL Surveillance (NCT02092467) was a post-authorisation safety study of tofacitinib vs TNF inhibitors (TNFi) in patients (pts) aged ≥50 yrs with active RA despite methotrexate (MTX), and ≥1 additional CV risk factor. Pts were randomised 1:1:1 to tofacitinib 5 or 10 mg twice daily (BID) or subcutaneous TNFi. Two post hoc analyses were performed: (1) a time-varying multivariate Cox model examined risks of major AEs when pts were in CDAI-defined low (>2.8–≤10; LDA), moderate (>10–≤22; MDA) or high (>22; HDA) disease activity vs remission (≤2.8). The Cox model also included pt demographics, medical history, RA characteristics, prior treatments, baseline (BL) medications and treatment arm, pre-selected using backward selection; (2) area under the curve (AUC) per yr for CDAI prior to event or to study end (pts without event) was calculated and compared using an analysis of variance model with treatment arm, event status and interaction (supportive). Nominal p values <0.10 were considered evidence of associations.Results4362 pts were included. Mean RA duration at BL was approximately 10 yrs. All pts were on MTX at BL, and 28% had previously been on one other synthetic disease-modifying antirheumatic drug (DMARD). Overall, 10% of pts had been on one biologic DMARD. Hazard ratios suggested that when pts had LDA, MDA or HDA vs remission, they were potentially at higher risk of developing major adverse CV events (MACE), VTE and non-serious infections (NSIs) excluding herpes zoster (HZ), but not malignancies, serious infections or HZ (Figure 1). Similarly, mean CDAI AUC trended higher for MACE, VTE and NSIs (Table 1).Table 1.Cumulative CDAI (from BL to event) for pts with vs without events (AUC/yr)Major AEPts with eventsPts without eventsLS mean difference in pts with vs without eventsp valueTreatmentnLS mean AUC/yrnLS mean AUC/yrMACETofacitinib 5 mg BID426275.413364607.31668.10.0018*Tofacitinib 10 mg BID505237.413064482.6754.80.1253TNFi365234.513124851.5383.00.5069VTETofacitinib 5 mg BID156546.713634614.41932.30.0293*Tofacitinib 10 mg BID316688.213234458.52229.70.0003*TNFi86423.613394839.41584.10.1907Malignancy excl. NMSCTofacitinib 5 mg BID595249.313194618.9630.40.1655Tofacitinib 10 mg BID554793.713014482.2311.50.5077TNFi395561.413084826.3735.10.1854Serious infectionsTofacitinib 5 mg BID1275710.212424577.51132.70.0004*Tofacitinib 10 mg BID1505425.211974476.4948.80.0013*TNFi1056058.412404807.71250.70.0003*HZTofacitinib 5 mg BID1755184.511994738.1446.40.1101Tofacitinib 10 mg BID1635549.111864481.31067.80.0002*TNFi565667.212914875.5791.80.0930*NSIs excl. HZTofacitinib 5 mg BID7606608.34635122.51485.8<0.0001*Tofacitinib 10 mg BID7506587.84265009.61578.2<0.0001*TNFi7226737.65215217.51520.1<0.0001**p<0.10. Data collected after pts who were randomised to tofacitinib 10 mg BID had their dose reduced to 5 mg BID were included in the tofacitinib 10 mg BID group LS, least squares; n, number of pts in analysis of variance modelConclusionIn ORAL Surveillance, the risk of MACE, VTE and NSIs excluding HZ appeared higher when pts had active disease than when in remission. Greater cumulative RA disease activity was seen in pts who suffered these AEs vs those who did not. Our findings support treat-to-target recommendations for RA.