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Objective Despite the development of new biologic therapies, methotrexate (MTX) remains the preferred initial disease-modifying anti-rheumatic drug to treat rheumatoid arthritis (RA). Adherence to disease-modifying anti-rheumatic drugs is suspected to be highly variable potentially leading to reduced treatment effectiveness. This work aimed to develop and validate the Methotrexate Experience Questionnaire (MEQ), a tool to identify and characterize non-adherence to oral MTX. Methods MEQ development included a literature review and qualitative interviews with RA patients and physicians in the United States. A retrospective, cross-sectional study using data from Optimum Patient Care Research Database, a large primary care database of electronic medical records in the United Kingdom, was conducted to finalize the MEQ and evaluate its psychometric properties. Results Three hundred seven e-consented subjects (66% women, mean age of 65 years) completed the MEQ remotely, and were included in this analysis. Item-convergent and divergent validity were generally supportive of the construct validity of the MEQ and Cronbach’s alpha of 0.87 supported its reliability. The MEQ Total score presented statistically significant correlations of small to medium size with all selected concurrent scales, as expected; the highest correlation was obtained between the general acceptance score of ACCEPT and the MEQ Total score (0.55, p p Conclusion The 24-item MEQ is a reliable and valid instrument to assess the adherence of RA patients taking MTX, potentially improving over historical refill rate metrics by providing insights into the individual reasons for lack of adherence. This information should facilitate clinician-patient discussions and help inform treatment decisions.

ObjectiveOur study aimed to evaluate the cost effectiveness of initiating tocilizumab (TCZ) ± methotrexate (MTX) versus initiating MTX as treat-to-target treatment strategies over 5 years in early disease-modifying antirheumatic drug (DMARD)-naïve rheumatoid arthritis (RA).MethodsData on resource use were collected with questionnaires at baseline, 3, 6, 12, and 24 months, and yearly thereafter, and were converted to costs using Dutch reference prices. Quality-adjusted life-years (QALY) were calculated using the EQ5D5L, with utility based on Dutch tariff or estimated by the Health Assessment Questionnaire. To account for missing cost data and QALY data and for sample uncertainty, first bootstraps (10,000 samples) were obtained. Second, single imputation using chained equations nested within these bootstrap samples was performed. An economic evaluation was performed for TCZ + MTX and TCZ, compared to MTX, as initial treatment in a treat-to-target strategy from a healthcare and societal perspective over 5 years. Several sensitivity analyses were performed.ResultsMean differences in QALY were small and not significant (TCZ + MTX vs MTX: 0.06, 95% CI –0.02 to 0.13; TCZ vs. MTX: –0.03, 95% CI –0.05 to 0.11). Limited savings in indirect nonhealthcare costs and productivity loss costs (for TCZ only) were observed, but these did not compensate for the higher medication costs. Sensitivity analyses did not materially change these findings, although lower-priced TCZ, or reserving TCZ as initial therapy for prognostically unfavorable RA patients, improved cost effectiveness considerably but did not individually lead to a strategy being cost effective.ConclusionBased on our analyses, early initiation of TCZ + MTX is not cost effective compared to MTX initiation in a step-up treat-to-target treatment strategy over 5 years in early RA patients.

Objectives U-Act-Early was a 2-year, randomized placebo controlled, double-blind trial, in which DMARD-naïve early RA patients were treated to the target of sustained remission (SR). Two strategies initiating tocilizumab (TCZ), with and without methotrexate (MTX), were more effective than a strategy initiating MTX. The aim of the current study was to determine longer-term effectiveness in daily clinical practice. Methods At the end of U-Act-Early, patients were included in a 3-year post-trial follow-up (PTFU), in which treatment was according to standard care and data were collected every 3 months during the first year and every 6 months thereafter. Primary end point was disease activity score assessing 28 joints (DAS28) over time. Mixed effects models were used to compare effectiveness between initial strategy groups, correcting for relevant confounders. Between the groups as randomized, proportions of patients were tested for DMARD use, SR and radiographic progression of joint damage. Results Of patients starting U-Act-Early, 226/317 (71%) participated in the PTFU. Over the total 5 years, mean DAS28 was similar between groups (P > 0.20). During U-Act-Early, biologic DMARD use decreased in both TCZ initiation groups and increased in the MTX initiation group, but during follow-up this trend did not continue. SR was achieved at least once in 99% of patients. Of the 226 patients, only 30% had any radiographic progression over 5 years, without significant differences between the groups. Conclusion Although in the short-term the strategies initiating TCZ yielded the most clinical benefit, in the longer-term differences in important clinical outcomes between the strategies disappeared, probably due to continuation of the treat-to-target principle.

To compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model.Randomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed-effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied.Overall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear.Combination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration.

Background We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. Materials and methods In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. Results Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens—DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)—and in the tocilizumab arm against one antigen—neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm—G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor–positive versus–negative or anti-cyclic citrullinated test–positive versus test–negative rheumatoid arthritis (p ≥ 0.06). Conclusions Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.

ObjectiveTo explore possible associations of treatment with biological disease-modifying antirheumatic drugs (bDMARDs), including T-cell-based and interleukin-6 inhibition (IL-6i)-based therapies, and the risk for type 2 diabetes mellitus (T2DM) in patients with rheumatoid arthritis (RA).Study design, setting and participantsFive treatment groups were selected from a United States Electronic Medical Records database of 283 756 patients with RA (mean follow-up, 5 years): never received bDMARD (No bDMARD, n=125 337), tumour necrosis factor inhibitors (TNFi, n=34 873), IL-6i (n=1884), T-cell inhibitors (n=5935) and IL-6i+T cell inhibitor abatacept (n=1213). Probability and risk for T2DM were estimated with adjustment for relevant confounders.ResultsIn the cohort of 169 242 patients with a mean 4.5 years of follow-up and a mean 641 200 person years of follow-up, the adjusted probability of developing T2DM was significantly lower in the IL-6i (probability, 1%; 95% CI 0.6 to 2.0), T-cell inhibitor (probability, 3%; 95% CI 2.3 to 3.3) and IL-6i+T cell inhibitor (probability, 2%; 95% CI 0.1 to 2.9) groups than in the No bDMARD (probability, 5%; 95% CI 4.6 to 4.9) and TNFi (probability, 4%; 95% CI 3.7 to 4.7) groups. Compared with No bDMARD, the IL-6i and IL-6i+T cell inhibitor groups had 37% (95% CI of HR 0.42 to 0.96) and 34% (95% CI of HR 0.46 to 0.93) significantly lower risk for T2DM, respectively; there was no significant difference in risk in the TNFi (HR 0.99; 95% CI 0.93 to 1.06) and T-cell inhibitor (HR 0.96; 95% CI 0.82 to 1.12) groups.ConclusionsTreatment with IL-6i, with or without T-cell inhibitors, was associated with reduced risk for T2DM compared with TNFi or No bDMARDs; a less pronounced association was observed for the T-cell inhibitor abatacept.

Background We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. Methods Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. Results In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was “histidine metabolism” (p

Objectives This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use. Methods TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety. Results Of 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR

ObjectiveTo identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA).MethodsIn U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) ResultsWithin 1 year, 56/108 (52%) patients in U-Act-Early showed IR to ‘MTX+’. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively.ConclusionHigher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up ‘MTX+’ in DMARD-naive patients with new-onset RA.Trial registrationNCT01034137; Post-results, ISRCTN26791028; Post-results.

Background In disease modifying anti-rheumatic drug (DMARD)-naive early rheumatoid arthritis (RA) patients, we previously identified networks of differentially co-expressed genes associated with achieving sustained drug-free remission (sDFR).[1 A better understanding of processes involved with translation of mRNA into proteins might be used to develop personalised treatment for early RA patients. Objectives To identify inflammatory proteins associated with achieving sDFR by performing multi-analyte profiling in pre-treatment serum and subsequently to study significantly enriched biological pathways and compare these with the pathways previously found in the transcriptomic analyses. Methods In this exploratory study, baseline serum was analysed of 24 patients (n=13 achieved sDFR, n=11 controls) treated-to-target with tocilizumab (TCZ) therapy in the U-Act-Early trial. TCZ (intravenously, 8 mg/kg) was given every 4 weeks; if no remission, hydroxychloroquine (HCQ) was added and if subsequently remission was still not achieved, HCQ was replaced by (oral) methotrexate. Thereafter, if the target, remission, still was not achieved, patients switched to standard of care (e.g. tumour necrosis factor inhibitor). Provided remission persisted, therapy was tapered and subsequently discontinued. sDFR was reached when patients remained ≥3 months in remission while being drug-free until the end of the study period; those not able to discontinue therapy were selected as controls. Luminex® multi-analyte profiling (xMAP)® was used to measure 85 inflammatory proteins; partial least square discriminant analyses (PLS-DA) was applied to identify relevant proteins associated with achieving sDFR. Results No significant differences in clinical baseline characteristics were found between those achieving sDFR vs controls (p>0.05). PLS-DA identified 14 proteins of which 6/14 (n/N) were associated with a decreased chance of achieving sDFR. The protein considered most important (i.e. highest variable on importance (VIP) score) was chemokine (C-C motif) ligand 20 (CCL20, VIP 1.49). In total, 88 significantly enriched Gene Ontology (GO) terms were identified analysing the proteins; 5 terms, of which “positive regulation of leukocyte migration” (p≤3.41E-02) and “leukocyte chemotaxis” (p≤3.49E-03) were found in both proteomic and transcriptomic analyses. Significant transcript-protein correlations are shown in figure 1; the TIMP metallopeptidase inhibitor 1 (TIMP-1) protein showed the highest number (n=12) of correlations. Blue dots=transcripts, green triangles=proteins. Conclusions Several relevant proteins were found associated with achieving sDFR after treatment with TCZ. When performing pathway analyses, several enriched pathways within the protein biomarkers were also previously identified in the transcriptomic analyses, providing further insight into gene expression and translation of inflammatory proteins in early RA patients. Reference [1] Teitsma XM, Jacobs JWH, Mokry M, et al. Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy. Arthritis Res Ther2017;19:170. Disclosure of Interest X. Teitsma: None declared, J. Jacobs Grant/research support from: The department of the author (JWGJ) who included patients in the U-Act-Early trial received reimbursements from Roche Nederland BV., A. Concepcion: None declared, A. Petho-Schramm Employee of: AP-S is an employee of F Hoffmann-La Roche, M. Borm Employee of: MEAB is an employee of Roche Nederland BV, J. van Laar Grant/research support from: JMvL received fees from Arthrogeen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech., J. Bijlsma Grant/research support from: JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and UCB., F. Lafeber Grant/research support from: FPJL reports grants from Roche.

Background: For rheumatoid arthritis (RA) patients included in clinical trials, background treatment with glucocorticoids (GCs) is quite common (40–60%), but their potential contribution to efficacy and safety of the disease modifying anti-rheumatic drug (DMARD) tested in that trial has rarely been evaluated. Objectives: To establish whether a stable GC dose at baseline and during the study contributed to the efficacy and safety of TCZ monotherapy initiated in RA patients in 4 TCZ RCTs. In addition, to investigate the same issue in the comparator arms of these trials, in which adalimumab (ADA) or methotrexate (MTX) was initiated. Methods: Data from 4 randomized controlled double-blind trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with TCZ monotherapy arms was analysed in this post hoc analysis [1–4]. Study participants were MTX-naive, intolerant or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Because of differences between the studies in region, and baseline RA duration and disease severity, analyses were done separately for each study. Stable GC dose at baseline was allowed and was to be continued unchanged during the first 24 weeks. Analyses of covariance (ANCOVA) of change from baseline to Week 24 in CDAI and DAS28 and logistic regression analyses at Week 24 for CDAI remission and ACR50 were performed. Repeated measures analyses using all visits up to week 24 were also done. Incidence rates of serious adverse events (SAEs) were assessed by GC use. Results: Baseline characteristics were mostly comparable between GC users and non-GC users in each treatment arm for each study. The adjusted differences (95% CIs) of CDAI change at week 24 between GC and non-GC users in TCZ arms of AMBITION, FUNCTION, ACT-RAY and ADACTA were -1.4 (-4.8, 2.1), 0.8 (-2.5, 4.1), 1.2 (-4.0, 6.3) and -4.2 (-9.7, 1.4), respectively (table 1). CDAI remission rates, ACR50 response rates and DAS28 score changes at 24 weeks neither were significantly different between GC users and non-GC users in the TCZ arms, nor in the MTX and ADA arms (table 1). Repeated measures analyses to week 24 showed no significant differences in DAS28 or CDAI. Statistically significant predictors for the various clinical outcomes included baseline CDAI, baseline DAS28, age, sex, RA duration and region. A numerically higher but not significantly different SAE rate was seen in the GC-arms of all four trials, compared to the non-GC-arms. Conclusions: No evidence was found that GC treatment at baseline and continued at a stable dose affects either clinical efficacy or safety over 24 weeks of TCZ, MTX, or ADA monotherapy initiated at baseline in RA clinical trials. References [1]Jones G, et al. Ann Rheum Dis2010;69:88–96. [2]Dougados M, et al. Ann Rheum Dis2013;72:43–50. [3]Gabay C, et al. Lancet2013;381:1541–50 [4]Burmester GR, et al. Ann Rheum Dis2017;76:1279–84. Disclosure of Interest: M. Safy Grant/research support from: Research grant from AZ, J. Jacobs: None declared, M. Edwardes Employee of: Everest Clinical Research, Canada, J. Pei Employee of: US Medical Affairs, Immunology, Genentech, Inc., M. De Hair: None declared, X. Teitsma: None declared, P. Welsing: None declared, M. Borm Employee of: employee of Roche Nederland BV., Y. Luder Employee of: 4 F Hoffmann-La Roche, Basel, Switzerland, J. Van Laar Consultant for: Arthrogen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech., A. Petho-Schramm Employee of: F Hoffmann-La Roche, J. Bijlsma Consultant for: Grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and UCB

Background The U-Act-Early trial was a 2 year placebo controlled, double-blind randomised controlled trial in early (DMARD-naive) RA patients treated to the target of sustained remission (SR), starting with tocilizumab (TCZ), methotrexate (MTX) or their combination (TCZ +MTX)1. When the treatment target was achieved, medication was tapered and stopped, if patients remained in remission. During the trial period, the strategies starting with TCZ were more effective than the strategy initiating MTX only. Subsequently, patients were followed for 3 years, during which treatment was open and according to usual care. Objectives To establish the effectiveness of step-up strategies starting with MTX, TCZ or their combination in early RA over a 5 year period. Methods 226 of the 317 patients starting in the U-Act-Early trial (initial strategy: 75 TCZ +MTX, 79 TCZ, 72 MTX) participated in the 3 year follow-up phase. DAS28 was collected every 3 months during the first year and every 6 months thereafter. The primary endpoint, was SR, defined as DAS28 24 weeks. Secondary endpoints were sustained drug free remission (sDFR), defined as remission for ≥3 months after tapering and stopping all medication during SR, and DAS28 over 5 years. Differences between the randomised strategies in proportions of patients achieving SR and sDFR and durations of SR and sDFR were tested with Cochran-Mantel-Haenszel and Kruskal-Wallis tests, respectively. A mixed model analysis was used to compare DAS28 over time, with a random intercept and fixed effects for: treatment, visit-week, the interaction visit-week*treatment, and it was corrected for gender, age, and for DAS28, RA-duration, CRP and RF-positivity at baseline. Results Baseline characteristics at the start of U-Act-Early of the patients included in this 3 year follow-up study were not significantly different from those of all patients included in U-Act-Early trial. Over 5 years, SR was achieved in 224/226 (99%) patients without significant differences (p=0.15) between the initial treatment strategies in proportions of patients achieving it, nor in durations (p=0.96) of these endpoints (table 1). Neither between-group significant differences were found for sDFR (proportion; p=0.10, duration; p=0.27), only a tendency for longer duration in TCZ +MTX. The mean DAS28 over 5 years was not significantly different between initial strategy groups (figure 1), but it was on average 0.15 (95% CI −0.12 to 0.42) units higher in the TCZ(+MTX) groups, compared to MTX initiation group. Conclusions On the short term, initiation of TCZ-based strategies yields the most benefit, but on longer term, no difference in important clinical outcomes was found anymore between initial strategy groups, probably due to continuation of the treat-to-target principle2. Almost all patients achieved SR over 5 years, with a tendency for longer duration of sDFR in the TCZ+MTX strategy. References [1] Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Lancet. 2016;388:343–55. [2] Smolen JS, Landewe R, Bijlsma J, et al. Ann Rheum Dis. 2017;76:960–77. Disclosure of Interest M. Verhoeven: None declared, M. de Hair: None declared, P. Welsing: None declared, A. Petho-Schramm Employee of: an employee of F Hoffmann-La Roche, M. Borm Employee of: an employee of Roche Nederland BV, X. Teitsma: None declared, J. van Laar Grant/research support from: received fees from Arthrogeen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech, F. Lafeber Grant/research support from: reports grants from Roche, J. Bijlsma Grant/research support from: The department of the author who included patients (JWJB) in the U-Act-Early trial received reimbursements from Roche Nederland BV. JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and UCB, J. Jacobs Grant/research support from: The department of the author who included patients (JWGJ) in the U-Act-Early trial received reimbursements from Roche Nederland BV

Background In new-onset rheumatoid arthritis (RA), therapy should be aimed at achieving sustained remission according to current guidelines, in which methotrexate (MTX) is recommend to be included in the initial treatment strategy. However, a large proportion (~30%) eventually need additional treatment to control inflammation making it necessary to find predictors which helps clinicians in choosing the optimal initial therapy to further improve the long-term outcome of early RA patients. Objectives To identify and validate clinical baseline predictors associated with inadequate response (IR) to MTX therapy in disease modifying anti-rheumatic drug (DMARD)-naive early RA patients. Methods For identifying clinical predictors, data was used from the U-Act-Early trial of newly diagnosed RA patients treated-to-target with a MTX strategy (n=108, development sample). MTX (oral) was started at 10 mg/week and increased in monthly steps up to 30 mg/week or maximum tolerable dose until remission. If no remission, hydroxychloroquine (HCQ) was added and, if the target, remission, thereafter still was not achieved, HCQ was replaced by tocilizumab. Patients in the tREACH trial who initiated MTX (25 mg/week) in combination with a prednisone tapering scheme were used as validation sample (n=83). In tREACH, if disease activity score (DAS) was ≥2.4 after three months, etanercept was added. When three months thereafter the target still was not achieved, patients switched to another tumour necrosis factor alpha inhibitor. In both studies, the definition of IR to MTX, (designated here “MTX+” therapy), was met if patients needed a biological DMARD within the first year. Clinical predictors were identified using logistic regression with backward selection (p≤0.10). Results In the development sample, the following predictors for IR to “MTX+” therapy were identified: DAS assessing 28 joints (DAS28), adjusted odds ratio (ORadj) 2.1, 95% CI 1.4–3.1; p 80% as cut off in the development sample, the positive predictive value (PPV) was 65% (sensitivity: 0.89, specificity: 0.52). The AUROC of the model in the validation sample was 0.67 (95% CI 0.55–0.79) with no significant difference (p=0.28) between observed and predicted probabilities, indicating good calibration. In the validation sample, a cut-off of NPV >80%, the PPV was 54% (sensitivity: 0.88, specificity: 0.38). Conclusions Higher DAS28, current smoking and no alcohol consumption were associated with an increased risk of IR to “MTX+” therapy in newly diagnosed RA patients. Disclosure of Interest X. Teitsma: None declared, J. Jacobs Grant/research support from: The department of the author (JWGJ) who included patients in the U-Act-Early trial received reimbursements from Roche Nederland BV., P. Welsing: None declared, P. de Jong: None declared, J. Hazes: None declared, A. Weel: None declared, A. Petho-Schramm Employee of: AP-S is an employee of F Hoffmann-La Roche, M. Borm Employee of: MEAB is an employee of Roche Nederland BV, J. van Laar Grant/research support from: JMvL received fees from Arthrogeen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech., F. Lafeber Grant/research support from: FPJGL reports grants from Roche, J. Bijlsma Grant/research support from: JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and UCB

Background The arterial uptake of 18fluorine-2-deoxy-d-glucose (FDG) by positron emission tomography-computed tomography (PET/CT) has been used for the diagnosis of giant cell arteritis (GCA). The role for PET/CT in following disease activity and monitoring treatment effects, however, remains unclear Objectives To examine the degree of FDG uptake within the large arteries of GCA patients after 1 year of treatment Methods We studied a subgroup of patients enrolled in the GiACTA trial.1 Patients received either tocilizumab (TCZ) given weekly or every other week plus a 26 week prednisone taper, or placebo (PBO) plus either a 26- or 52 week prednisone taper. PET/CTs were done according to site feasibility and not as part of the GiACTA protocol. For this analysis, the 2 TCZ and PBO groups, respectively, were combined. Patients had whole-body PET/CT imaging within 16 weeks of week 52 visit. The ascending aorta, carotid artery and subclavian artery territories were assessed by maximum standardised FDG uptake values (mSUV) measurement. For each territory, we calculated average, most diseased segment (MDS) and most diseased slide mSUVs and target background ratios (TBR). PET/CTs were read centrally by investigators blinded to the clinical and treatment data Results From 251 patients enrolled in GiACTA, 24 patients underwent PET/CT within 16 weeks of week 52 visit. Seventeen patients (71%) received TCZ plus a prednisone taper (TCZ group) and 7 patients received a prednisone taper alone (PBO group). There were no significant differences between groups in baseline characteristics (table 1). Mean (SD) cumulative prednisone dose at week 52 was 2.5 g (1.7 g) in the TCZ group and 3.2 g (1.2 g) in the PBO group (p=0.11). FDG uptake was consistently numerically lower in all vascular territories in TCZ-treated patients compared to PBO-treated patients except in the ascending aorta. However, the between-group differences were statistically significant only in the left subclavian artery (table 2). Adjustment for selected confounders (new onset disease, baseline prednisone dose, prednisone dose at the time of PET/CT, cumulative prednisone dose, flare prior to PET/CT and clinical activity at the time of PET/CT) did not alter the conclusions derived from the univariate analyses Table 1 Baseline characteristics All results represent means (SD) except otherwise indicated. PBO=placebo, TCZ=tocilizumab Table 2 Results All results represent means (SD). mSUV=maximum standardised uptake value, MDS=most diseased segment, TBR=target to background ratio Conclusions In this exploratory study, subclavian FGD-uptake was significantly reduced in GCA patients treated with TCZ plus prednisone versus prednisone monotheraphy despite lower cumulative prednisone doses. A larger, carefully designed prospective study is required to fully understand the utility of PET/CT in the longitudinal evaluation of large-vessel vasculitis associated with GCA Reference [1] Stone, et al. N Engl J Med2017. PMID28745999. Disclosure of Interest None declared

Recently, we identified baseline higher disease activity score assessing 28 joints, current smoking and no alcohol consumption as predictors of inadequate response (IR) to methotrexate (MTX), used with or without other conventional synthetic disease modifying anti-rheumatic drugs, here designated as ‘MTX+’, in new-onset rheumatoid arthritis (RA).1 For those with a predicted IR to ‘MTX+’, a more intensive treatment strategy could be initiated, if prediction would be reliable. Therefore, we investigated, within the same patient population, protein biomarkers for additive predictive value to these clinical predictors. A model was developed using data from patients with RA in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) treated with a step-up MTX strategy (n=106) and was validated in patients who received MTX therapy (n=80) in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH, ISRCTN26791028).2,3 IR to ‘MTX+’ therapy was defined as the need to initiate a biological within the first treatment year. In baseline serum, 85 proteins were analysed in 2014 using multiplex Luminex profiling; seven candidate proteins, identified by partial least square discriminant analyses, were remeasured in 2018. Clinical baseline characteristics of the patients in both studies are shown in table 1. Of the proteins identified in the development cohort, in the …

Objectives The aim of this pooled analysis of the TOZURA study programme was to evaluate the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) in patients with moderate to severe RA who had an inadequate response to csDMARD or anti-TNF agent therapy or who were MTX naïve. Methods TOZURA is a multinational, open-label, single-arm, common-framework, phase 4 study programme (11 protocols, 22 countries). Patients received TCZ-SC 162 mg each week for ⩾24 weeks, administered at the investigator’s discretion, as monotherapy or in combination with a csDMARD. Efficacy, safety and immunogenicity were evaluated; propensity score–based matching was used for between-group comparisons. Results Of 1804 patients, 353 (19.6%) received monotherapy and 1451 (80.4%) received combination therapy. The 28-joint DAS using ESR (DAS28-ESR) in both groups decreased significantly from baseline to week 24 (mean change: monotherapy −3.40, combination therapy −3.46), with no significant difference between groups (P = 0.46). The proportion of patients who achieved DAS28-ESR or Clinical Disease Activity Index remission or ACR 20/50/70/90 responses was similar between groups. Overall, 13.9% of patients withdrew—6.2% for safety reasons and 1.6% for insufficient therapeutic response; 5.8% of patients experienced one or more serious adverse events [14.6/100 patient-years (PY)]; six deaths occurred (0.64/100 PY). Conclusion In a common framework of 11 studies in 22 countries, this phase 4 study programme confirmed TCZ-SC’s known efficacy and safety profile with comparable effects as monotherapy and in combination with csDMARDs. Trial registration ClinicalTrials.gov (http://www.clinicaltrials.gov) NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603 and NCT02046616.

OBJECTIVE Using the UK Clinical Practice Research Datalink, we examined the incidence of glucocorticoid (GC)-related serious adverse events (SAEs) in rheumatoid arthritis (RA) and non-RA patients and quantified the risk of SAEs in patients with RA. METHODS We matched incident patients with RA to an age- and sex-matched, non-RA comparison group of equal size. In a cohort analysis, we estimated incidence rates (IRs) and IR ratios (IRRs) for GC-related AEs (i.e., diabetes mellitus [DM], osteoporosis, fractures, glaucoma, hypertension, gastrointestinal [GI] perforation or bleeding, thrombotic stroke or myocardial infarction [MI], or death), stratified by GC use. We conducted a series of nested case-control analyses among patients with RA, evaluating the effects of increasing cumulative and average daily GC dose. Cases of each outcome were matched to controls for age, sex, and general practice. We calculated adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) for each outcome. RESULTS Patients with RA had a higher incidence for all investigated SAEs except glaucoma, compared to non-RA patients. IRRs were greater in those patients prescribed a GC than in those without. In patients with RA, GCs were associated with an elevated risk of DM (adjusted OR 1.33 [95% CI 1.14-1.56]), osteoporosis (adjusted OR 1.41 [95% CI 1.25-1.59]), thrombotic stroke or MI (adjusted OR 1.28 [95% CI 1.07-1.52]), serious infection (adjusted OR 1.28 [95% CI 1.11-1.48]), and death (adjusted OR 1.33 [95% CI 1.19-1.48]). There was a trend of increasing risk with increasing cumulative and average daily GC dose for all outcomes other than glaucoma, hypertension, and GI perforations or bleeding (P < 0.05). CONCLUSION Patients with RA had an increased incidence of GC-related AEs. Increasing cumulative and average daily GC doses were found to be associated with an increasing risk of developing an AE.

Objective To evaluate the effect of initiation of tocilizumab, with or without MTX, compared with MTX alone on patient-reported outcomes (PROs), in DMARD-naive patients with early RA. Methods In U-Act-Early, patients initiated treat-to-target step-up MTX, tocilizumab or tocilizumab plus MTX therapy. PROs assessed included the Functional Assessment of Chronic Illness Therapy-Fatigue, 36-item Short Form (SF-36), five dimensional EuroQol (EQ-5D) and the Revised Illness Perception Questionnaire. Differences between strategy groups over time and proportions of patients exceeding minimum clinically important differences (MCID) were evaluated. Results During the 2-year study period, significant improvements were found in the tocilizumab strategies in the SF-36 physical component score (tocilizumab, P = 0.012; tocilizumab plus MTX, P = 0.044) and EQ-5D score (tocilizumab plus MTX, P = 0.020) when compared with the MTX strategy. No significant differences were noted in other PROs (P ⩾ 0.052, except for the domain 'identity' in the Illness Perception Questionnaire; tocilizumab vs MTX, P = 0.048). The proportions of patients achieving MCID in SF-36 physical component score were significantly higher at 12 and 52 weeks (P ⩽ 0.049) in the tocilizumab arms when compared with the MTX arm. At week 24, the proportion achieving MCID in EQ-5D was significantly higher in the tocilizumab plus MTX arm vs the MTX arm (P = 0.045). Conclusion Initiation of treat-to-target tocilizumab therapy resulted in significantly improved PROs, especially within the first 24 weeks, when compared with initiation of MTX therapy. Also on the patients' level, initiating tocilizumab may be considered as a valuable strategy in DMARD-naive patients with early RA. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01034137.

Background Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy. Methods Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (≥3 months in drug-free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4+) and CD14+ cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses. Results Network analyses within CD4+ cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p ≤ 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14+ cells. Conclusions Within networks of co-expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR. Trial registration Clinicaltrials.gov, NCT01034137. Registered on 16 December 2009. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1378-x) contains supplementary material, which is available to authorized users.

Background Tocilizumab (TCZ), a humanized interleukin-6 receptor inhibitor, has been shown effective in suppressing symptoms of rheumatoid arthritis (RA). In U-Act-Early, a significantly greater proportion of patients with early RA who initiated TCZ (84%) or TCZ plus MTX therapy (86%) achieved sustained remission (Disease Activity Score assessing 28 joints (DAS28) Objectives To determine the effect of treat-to-target TCZ therapy, with or without MTX, on health-related quality of life (HRQoL) in disease modifying anti-rheumatic drugs (DMARD)-naive patients with early RA. Methods Patients (n=317) were randomized to initiate TZC, TCZ+MTX or MTX therapy and treated according to a step-up strategy. TCZ was given (8 mg/kg) every 4 weeks and MTX (oral) was started at 10 mg/week and increased with steps of 5 mg steps 4 weekly up to 30 mg/week (or maximum tolerable dose) until remission. If after 20 weeks remission was not achieved, hydroxychloroquine was added and discontinued 12 weeks thereafter if the target still was not achieved. Patients who originally initiated monotherapy then switched to TCZ+MTX therapy and those already on this combination therapy switched to a tumour necrosis factor inhibitor. To evaluate the effect of TCZ on HRQoL, we used the 36-item Short-Form (SF-36), which can be summarized into a physical (PCS) and mental (MCS) component score. HRQoL was measured at baseline and after 12, 24, 52, and 104 weeks. A linear mixed effect model with a random intercept was used to evaluate differences between treatment strategies over time with visit (time), strategy, baseline SF-36 score, baseline DAS28 level (i.e., DAS28 Results We found significantly greater improvements over time in the SF-36 PCS in patients initiating treatment with TCZ (TCZ vs MTX; p=0.041, TCZ+MTX vs MTX; p=0.011, Fig. 1). For the SF-36 MCS, no significant differences over time were noted between the treatment arms (p≥0.11). A significantly higher proportion of patients initiating treatment with TCZ (76%; p=0.016, 89%; p=0.030) or TCZ+MTX (73%; p=0.049, 89%; p=0.027) achieved MCID in the SF-36 PCS at week 12 and week 52, when compared to those initiating treatment with MTX (59% and 73%, respectively). Although the proportions of patients achieving MCID in the SF-36 MCS were numerically higher in the TCZ arms, no significant differences were found (p≥0.06). Conclusions Initiation of TCZ, with or without MTX, at start of therapy resulted in statistically significant and clinically relevant improvements in the HRQoL when compared to initiation of MTX alone and may be considered as a valuable treatment strategy in DMARD-naive patients with early RA. References Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016; 388:343–55. Disclosure of Interest X. Teitsma: None declared, J. Jacobs: None declared, P. Welsing: None declared, A. Petho-Schramm Employee of: Employee of F.Hoffmann-La Roche, M. Borm Employee of: Roche Nederland B.V., J. van Laar Consultant for: Received fees from MSD, Pfizer, Roche, Eli Lilly and BMS, F. Lafeber: None declared, J. Bijlsma Grant/research support from: Received research grants (to his department) and consultancy fees from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun and UCB

Background Tocilizumab administered subcutaneously (TCZ-SC) has been approved for the treatment of rheumatoid arthritis (RA) both as mono- and combination therapy. Objectives To evaluate the efficacy and safety of TCZ-SC 162 mg once weekly (qw) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 24 weeks in adult patients (pts) with moderate to severe RA. Methods TOZURA is a multinational, open-label, single-arm umbrella program comprising 7 single-country and 4 regional multicountry protocols (total 22 countries). Pts enrolled were inadequate responders to DMARD, and previous biologic DMARDs were allowed in 8 of 11 protocols. Pts received TCZ-SC 162 mg qw for 24 weeks administered at the investigator9s discretion as monotherapy or in combination with a csDMARD. Stable oral NSAIDs and corticosteroids (CS), ≤10 mg/day prednisone or equivalent, were allowed. Efficacy and safety were evaluated at weeks 1, 2, 4 and every 4 weeks for 24 weeks (plus 8 weeks for safety). Propensity score-based matching was used for between-group tests. Results Of 1804 pts treated, 353 (19.6%) received monotherapy (mono) and 1451 (80.4%) combination therapy (combo); 349 pts (19.3%) had received a prior biologic DMARD. Background characteristics: 81.6% female; mean age, 54.1 years; mean RA duration, 7.7 years; and 82.7% seropositive –similar between treatment groups. Baseline CS was less frequent in the mono vs combo group (41.1% vs 51.2%); however, the mean prednisone equivalent daily dose was similar (6.6 vs 6.5 mg/day, respectively). Pts who continued TCZ to week 24 based on Kaplan-Meier estimates (95% CI) were 79.3% (74.7%>83.2%) for mono and 85.6% (83.7%>87.3%) for combo. DAS28 scores decreased comparably from baseline to week 24 in both groups (mean change: mono −3.40 and combo −3.46), with no significant difference between groups ( P =0.61). Results were similar for the Clinical Disease Activity Index (CDAI, mean change by week 24: −23.5 and −23.8, with no significant difference between groups: P =0.42). The proportion of pts who achieved DAS28 or CDAI-based remission, low disease activity or ACR20/50/70/90 responses was similar between groups (Figure 1). In all, 18.2% of pts withdrew; 6.4% did so for safety reasons (mono 9.1%, combo 5.8%). AE rates were similar between groups (Table). Serious AE (SAE) rates were 14.6/100 PY (mono: 22.8/100 PY, combo: 12.8/100 PY). Serious infection and infestation rates were 3.6/100 PY (mono: 4.0/100 PY, combo: 3.5/100 PY) – similar between groups. Six deaths occurred (0.64/100 PY), 1 in the monotherapy group (0.57/100 PY) and 5 in the combination (0.65/100 PY) group. Conclusions TCZ-SC demonstrated convincing and comparable efficacy as mono- and combination therapy in pts with RA as was previously observed with TCZ-IV. The safety profile of TCZ-SC is consistent with the known safety profile of TCZ as monotherapy and in combination with csDMARDs. Acknowledgements Funded by F. Hoffmann-La. Roche, Ltd. Disclosure of Interest E. Choy Grant/research support from: F. Hoffmann-La Roche, Chugai Pharmaceutical, Consultant for: F. Hoffmann-La Roche, Chugai Pharmaceutical, Speakers bureau: F. Hoffmann-La Roche, Chugai Pharmaceutical, R. Caporali Consultant for: AbbVie, Bristol-Myers Squibb, F. Hoffmann-La Roche, UCB and MSD Pharmaceuticals, R. Xavier Consultant for: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceuticals, AbbVie, Eli Lilly and Company, Speakers bureau: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceuticals, Abbvie, Eli Lilly and Company, B. Fautrel: None declared, R. Sanmarti: None declared, C. Bernasconi Employee of: F. Hoffmann-La Roche (contractor), A. Petho-Schramm Employee of: F. Hoffmann-La Roche

Background Rapidly reducing disease activity is of major importance in the management of newly diagnosed rheumatoid arthritis (RA) patients as early response strongly correlates with long-term clinical outcomes. To select patients for whom it would be favourable to initiate a biological drug from start of therapy, it is crucial to study biological pathways and biomarkers involved in treatment response. Objectives To identify biological networks and signature genes among disease modifying anti-rheumatic drug (DMARD)-naive early RA patients achieving sustained drug-free remission (sDFR) after initiating treatment with tocilizumab (TCZ). Methods Data was used from DMARD-naive early RA patients in the U-Act-Early trial who had been randomized to initiate TCZ therapy. The study design and details have previously been described.[1] Briefly, TCZ (8 mg/kg) was given every 4 weeks and if remission was not achieved, methotrexate (oral) was added. When the target was achieved, therapy was tapered and subsequently discontinued provided remission persisted. sDFR was reached when patients remained ≥3 months in remission while being drug-free until the end of the two-year study period. Before the first dose of medication, whole blood samples were collected and RNA was isolated from CD4 cells and analyzed using RNA sequencing. The DESeq2 package was used to identify differentially expressed genes (DEGs) between responders (achieving sDFR, n=13) and non-responders (not able to taper medication, n=11). Subsequently, weighted gene co-expression network analysis (WGCNA) was used to study clusters (modules) within the 1000 most relevant DEGs. Results In total, eight modules with varying sizes (10–470 genes) were identified. The module best correlated (Pearson correlation coefficient 0.52, p=0.009) with achieving sDFR included 26 genes and was used for further functional analysis. Within this module, we found three significantly enriched pathways in the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database. These were calcium signalling pathway (p=5.81E-04), carbohydrate digestion & absorption (p=4.46E-02), and neuroactive ligand-receptor interaction (p=2.61E-02). In addition, we identified 83 overrepresented Gene Ontology (GO) terms of which granulocyte migration (p=2.70E-04), myeloid leukocyte migration (p=8.95E-04) and G-protein coupled amine receptor activity (p=1.25E-03) were most significant. The genes in the module of interest showing the highest connectivity were the upregulated testis expressed 22 (TEX22), doublecortin lie kinase 2 (DCLK2), and the downregulated Williams Beuren syndrome chromosome region 27 (WBSCR27) gene (Fig. 1). Conclusions When performing network analyses of the DEGs between responders and non-responders, TEX22 and DCLK2 were identified as signature genes for treatment response to TCZ therapy. WBSCR27 was found to be associated with less chance of achieving sDFR. References Bijlsma JW, Welsing PM, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016; 388:343–55. Disclosure of Interest X. Teitsma: None declared, J. Jacobs: None declared, M. Mokry: None declared, A. Petho-Schramm Employee of: F. Hoffmann-La Roche, M. Borm Employee of: Roche Nederland B.V., J. van Laar Consultant for: Received fees from MSD, Pfizer, Roche, Eli Lilly and BMS, J. Bijlsma Grant/research support from: Received research grants (to his department) and consultancy fees from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun and UCB, F. Lafeber: None declared

To evaluate the progression of erosions and joint space narrowing (JSN) in feet and hands in the U-Act-Early trial.In this trial, 317 newly diagnosed DMARD-naïve RA patients initiated randomly tocilizumab, or step-up MTX or a combination of the two. Radiographs were scored at baseline and after 52 and 104 weeks using the Sharp-van der Heijde erosion and JSN score. Between the strategy arms, changes from baseline and the proportions of patients without radiographic progression (change from baseline ≤0) were compared.Mean changes from baseline in erosion and JSN scores for the whole study population were after 52 weeks 0.59 and 0.18 and after 104 weeks 0.70 and 0.50, respectively. For JSN, at both time points no differences in progression were found between strategies (P ⩾ 0.09). For erosions, the progression was significantly lower at week 104 in both tocilizumab arms when compared with the MTX arm ((p≤0.023). Less progression of erosions in the feet was found after 104 weeks in both tocilizumab arms (P ⩽ 0.046); this was not significant for the hands (P ⩾ 0.11). The proportion of patients without progression in erosions was higher in the tocilizumab arms at week 52 (tocilizumab plus MTX: 87%, P = 0.038; tocilizumab: 81%, P = 0.29) and 104 (tocilizumab plus MTX: 85%, P = 0.001; tocilizumab: 77%, P = 0.028), compared with the MTX arm (74 and 60%, respectively).In DMARD-naïve early RA patients, initiating a tocilizumab-based treat-to-target strategy inhibits the progression of erosions, especially in the feet, more compared with initiation of a step-up MTX strategy.ClinicalTrials.gov, https://clinicaltrials.gov, NCT01034137.

Background The U-ACT EARLY study is a 2-year, randomized placebo-controlled, double blind study in which disease modifying antirheumatic disease (DMARD)-naive early RA patients were randomized to initiate tocilizumab (TCZ, n=103), methotrexate (MTX, n=108)) or their combination (n=106), and treated according to a step-up strategy. The primary endpoint, sustained remission (SR, defined as DAS28 24 weeks), was achieved by significantly more patients in the TCZ+MTX (86%) and TCZ (84%) groups, compared to MTX (44%). Here we report a post hoc analysis of sustained drug free remission (sDFR). Objectives To compare the number of patients achieving sDFR between the three treatment strategies. Methods We analyzed data of all 317 patients included in the study. TCZ was given intravenously (8 mg/kg 4 weekly) and MTX was increased over 3 months from 10 to 30 mg/week (or maximum tolerated dose) until remission. If remission was not reached after 20 weeks, hydroxychloroquine was added. Twelve weeks thereafter, if the target was not achieved, the placebo was substituted by TCZ/MTX. If SR was achieved, medication was tapered stepwise and stopped provided remission persisted. Differences in prevalence, time-to, and duration of sDFR (drug-free for >3 months with remission) were analyzed. To identify predictive factors for achieving sDFR, baseline data were analyzed using a backward selection procedure (p≤0.10). Results Table 1 shows baseline characteristics. The proportion of patients achieving sDFR was significantly higher in the TCZ+MTX (35%, p Conclusions Early RA patients initiating tight-control TCZ treatment achieve sDFR more often and earlier, compared to MTX. Predictors of sDFR include TCZ treatment itself, as well as baseline HAQ and being seronegative. Disclosure of Interest X. Teitsma: None declared, J. Jacobs: None declared, P. Welsing: None declared, T. Woodworth Employee of: Roche, A. Petho-Schramm Employee of: Roche, M. Borm Employee of: Roche, C. Bernasconi Employee of: Roche, F. Lafeber: None declared, J. Bijlsma Grant/research support from: received research grants (to his department) from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun, UCB./, Consultant for: received consultancy fees from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun, UCB.

Background International guidelines for treatment-to-target in rheumatoid arthritis (RA) recommend methotrexate (MTX) as first line therapy because of its favorable benefit/risk ratio and long-term safety. However, about 50% of patients fail to achieve remission and require other treatment. Identification and application of predictors of inadequate response to MTX may improve clinical outcome by enabling timely step-up treatment in those who need it. Objectives To evaluate the added predictive value of protein biomarkers compared to use of clinical variables alone, to identify early RA patients failing a MTX step-up strategy, including hydroxychloroquine (HCQ). Methods In the treat-to-target U-ACT-EARLY trial, 108 DMARD-naive RA patients initiated MTX step-up therapy (10 mg to 30 mg or maximum tolerable dose) until remission (DAS28 Results Within 1 year, 56 (52%) of the 108 patients failed the strategy for various reasons: adverse events (n=4), added TCZ according to treatment protocol (n=42), withdrawal from study because of inefficacy (n=10). Multiple logistic regression identified baseline DAS28, current smoking and alcohol consumption as clinical predictors ( model 1 , AUC-ROC 0.75, 95%>CI 0.66–0.84) and in addition MCP1, IL6, IL33, sCD14 and PD1 ( model 2 , AUC-ROC 0.87, 95%>CI 0.80–0.94) as significant protein biomarkers (Table 1). The LLR test showed a better fit of model 2 (59.83, p 80% as cut off, model 1 correctly predicted 24/51 patients not failing the strategy and model 2 predicted 15 (29% improvement) extra patients not failing the strategy (Table 2). In those failing the strategy, 50/56 patients were correctly predicted by model 1 and 4 (-7%) patients less was correctly predicted by model 2 . Conclusions Adding protein biomarkers to clinical predictors increases the predictive accuracy of identifying patients at baseline who will need other treatment after initiating a MTX step-up strategy. These findings could contribute too more personalized treatment in early RA patients to optimize long-term outcomes. Disclosure of Interest X. Teitsma: None declared, J. Jacobs: None declared, P. Welsing: None declared, T. Woodworth Employee of: Roche, A. Petho-Schramm Employee of: Roche, M. Borm Employee of: Roche, C. Bernasconi Employee of: Roche, J. van Laar Consultant for: received fees from MSD, Pfizer, Roche, Eli Lilly and BMS, J. Bijlsma Grant/research support from: received research grants (to his department) from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun and UCB, Consultant for: received consulting fees from AbbVie, BMS, Crescendo, MSD, Mundipharma, Pfizer, Roche, Sun and UCB, F. Lafeber: None declared

Background Rheumatoid arthritis (RA) is a chronic, erosive form of inflammatory arthritis characterized by a distinctive pattern of bone and joint destruction. Along with disease-modifying antirheumatic drugs and newer biologic therapy, treatment can include oral corticosteroids (oCS), predominantly prednisolone or prednisone. CS are associated with a variety of adverse effects. 1 Objectives Using data from the UK9s Clinical Practice Research Datalink, we estimated the incidence rates (IRs) and incidence rate ratios (IRRs) of known oCS-related serious adverse events (SAEs) of interest in an RA cohort and in a non-RA general population (GP) comparison group matched on age, sex, and time. We also explored the role of oCS use on the risk for SAEs of interest by comparing RA patients of varying exposure levels of oCS. Methods Patients with a first-time diagnosis of RA who were ≥18 years of age were identified and matched to patients in a non-RA GP comparison group of equal size. Group IRs and IRRs were estimated for diabetes, osteoporosis, fractures, glaucoma, hypertension, thrombotic stroke or myocardial infarction (MI), gastrointestinal (GI) perforation or bleeding, and death for the RA group and the GP group. We then performed a series of nested case-control analyses examining the effect of oCS use on the risk for SAEs of interest. We used conditional logistic regression to calculate the unadjusted and multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the association between oCS use and the risk for each separate outcome of interest. We stratified the analyses according to increasing cumulative and average daily oCS use. Results The cohort consisted of 34,047 RA patients and 34,047 matched non-RA GP patients. Mean follow-up time was ∼8 years. The incidence for most SAEs was greater in the RA group than in the GP group. IRRs (95% CIs) for SAEs of interest were diabetes (1.21; 1.13–1.31), osteoporosis (2.11; 1.96–2.27), fractures (1.16; 1.08–1.24), glaucoma (1.08; 0.94–1.22), hypertension (1.13; 1.09–1.18), thrombotic stroke or MI (1.22; 1.11–1.34), GI perforation or bleeding (1.3; 1.15–1.47), and death (1.17; 1.11–1.22). In multivariate analyses, increasing risks for diabetes, osteoporosis, fractures, thrombotic stroke or MI, and death were observed with increasing cumulative oCS use ( p 7.5 mg/day had an increased adjusted OR (95% CI) for diabetes (1.49; 1.21–1.84), osteoporosis (1.41; 1.20–1.66), fractures (1.22; 1.03–1.45), thrombotic stroke or MI (1.61; 1.27–2.04), and death (1.49; 1.27–1.74). Conclusions Patients with RA experienced an increased incidence of diabetes, osteoporosis, fractures, hypertension, thrombotic stroke or MI, GI perforation or bleeding, and death compared with age- and sex-matched controls. Increasing cumulative oCS doses and average daily oCS doses were associated with increased odds of diabetes, osteoporosis, fractures, thrombotic stroke or MI, and death. References Venables PJW. Rheumatoid arthritis treatment (beyond the basics). UpToDate, Inc. 2016. http://www.uptodate.com/contents/rheumatoid-arthritis-treatment-beyond-the-basics.Accessed January 21, 2016. Disclosure of Interest J. Wilson: None declared, K. Sarsour Shareholder of: Roche, Employee of: Roche, S. Gale Shareholder of: Roche, Employee of: Roche, A. Petho-Schramm Employee of: F. Hoffmann-La Roche, S. Jick: None declared, C. Meier Shareholder of: Hoffmann-La Roche, Grant/research support from: Hoffmann-La Roche

Background Tocilizumab (TCZ), administered as intravenous (TCZ-IV) and subcutaneous (TCZ-SC) formulations, has been approved for treatment of patients (pts) with rheumatoid arthritis (RA) both as mono- and combination therapy. Objectives To evaluate the efficacy and safety of TCZ-SC 162 mg once weekly (qw) as monotherapy and in combination with conventional synthetic DMARDs (csDMARDs) over 24 weeks in adult pts with moderate to severe RA. Methods TOZURA is a multinational, open-label, single-arm umbrella study comprising 7 single-country and 4 regional multicountry protocols. It aimed to enroll $≈ $ 1,850 pts who were biological DMARD inadequate responders (IR; 8/11 protocols) and/or csDMARD-IR (11/11 protocols). Pts received TCZ-SC 162 mg qw for 24 weeks, administered at the investigator9s discretion as monotherapy or in combination with a csDMARD. Stable oral NSAIDs and corticosteroids (CCS), ≤10 mg/day prednisone or equivalent, were allowed. Efficacy and safety were evaluated at weeks 1, 2, 4 and every 4 weeks thereafter. Results In this interim analysis, 1246 pts were included by end of 2014; 283 pts received monotherapy, 963 combination; 25% of pts were biologic DAMRD-IR (monotherapy: 36%, combination: 22%). Background characteristics: 80.5% female, mean age 54.5 years, mean RA disease duration 7.7 years and 81.4% seropositive – similar between treatment groups. Baseline oral CCS use was less frequent in the mono- group (42.8%) than in the combination group (51.2%); however, their mean dose was similar (6.673 vs 6.505 mg/day, respectively). Pts continuation of TCZ at week 24 based on Kaplan-Meier estimates (95% CI) were 0.784 (0.732, 0.828) for mono- and 0.855 (0.831, 0.875) for combination therapy. All pts had significant reductions in mean 28-joint Disease Activity (DAS28) scores by week 24 (mean decrease: monotherapy 3.41 and combination 3.44; P P =0.788). Results were similar for the Clinical Disease Activity Index (CDAI), which does not include acute phase reactants (mean change by week 24: 24.03 and 23.28, P P =0.629). The proportion of pts who achieved DAS28 or CDAI-based remission and low disease activity and ACR20/50/70/90 responses was similar between the treatment groups (Figs 1A, 1B). Of the 231 pts (18.5%) who withdrew, 92 (7.4%) did so for safety reasons (29 [10.2%] monotherapy, 63 [6.5%] combination). Serious AEs (SAEs) occurred in 78 pts (6.3%; 11.5/100 PY) and rates of AEs and SAEs were similar between groups (Table 1). Serious infections and infestations occurred in 18 pts (1.4%; 2.2/100 PY), with similar rates between groups. Five deaths occurred, 1 in the monotherapy group (coronary artery disease) and 4 in the combination group (intestinal ischemia, myocardial infarction, pneumonia, septic shock). Conclusions TCZ-SC demonstrated convincing and comparable efficacy in mono- and combination therapy in pts with RA as previously observed with TCZ-IV. The safety profile of TCZ-SC is consistent with the known safety profile of TCZ as monotherapy and in combination with csDMARDs. Disclosure of Interest E. Choy Grant/research support from: F. Hoffmann-La Roche and Chugai Pharmaceutical, Consultant for: F. Hoffmann-La Roche and Chugai Pharmaceutical, Speakers bureau: F. Hoffmann-La Roche and Chugai Pharmaceutical, R. Caporali Consultant for: Abbvie, Bristol-Myers Squibb, F. Hoffmann-La Roche, UCB and MSD Pharmaceuticals, R. Xavier Consultant for: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceutica, Abbvie, Eli Lilly and Company, Speakers bureau: F. Hoffmann-La Roche, Pfizer, Janssen Pharmaceutica, Abbvie, Eli Lilly and Company, B. Fautrel: None declared, R. Sanmarti: None declared, C. Bernasconi Employee of: F. Hoffmann-La Roche, A. Petho-Schramm Employee of: F. Hoffmann-La Roche

Background Anemia, a common complication of RA, has a negative impact on RA symptoms and QOL and is associated with a more severe form of RA. Roles of biologic DMARDs (BDMARDs), including the IL-6 pathway–inhibiting biologic tocilizumab (TCZ), in the pathophysiology of anemia have not been well explored at the population level. Objectives Evaluate the impact of treatment (Tx) with nonbiologic (NB) and BDMARDs on hemoglobin (Hb) and hematocrit (Hct) in a real-world setting. Methods Using the GE EMR database, a longitudinal cohort study was conducted on 153,672 adult RA pts in the US who had ≥6-mo follow-up. 4 mutually exclusive DMARDTx groups (TxGs) were identified: TCZ, tofacitinib (TOFA), other BDMARDs (OBDMARD), and other NBDMARDs (ONBDMARD). To evaluate changes in Hb and Hct at 6 and 12 mo from index date (ID) in different TxGs, unadjusted and adjusted mean (95% CI) changes were obtained, adjusting for age, sex, smoking status, RA duration, concomitant medications, CRP, and other covariates. Separate analyses were conducted for pts with Hb Results Demographics of the cohort were: 55 y mean age, 76% female, 59% white, 57% current or ex-smokers, 44% obese (mean BMI 30 kg/m 2 ). 2% of pts had ischemic heart disease, 2% renal disease, and 7% diabetes. Mean Hb and Hct levels at ID across TxGs were 13.3 g/dL and 40%. Average CRP (1.6 mg/dL) and ESR (23 mm/h) were clinically similar across TxGs at ID. Adjusting for covariates, increases in Hb and Hct levels at 6 and 12 mo were significantly higher in the TCZ group vs the other TxGs (Table). Among anemic pts at ID, increases in Hb and Hct at 6 mo were significantly higher in the TCZ group vs the other TxGs. Significantly greater reductions in ESR and CRP levels over all follow-up periods were observed in the TCZ group vs the other TxGs. Conclusions This study suggests significant increases in Hb and Hct levels after TCZ therapy vs other nonbiologic and biologic therapies in RA pts with anemia, in line with the potential role of IL-6 in RA pts with anemia. Further study is needed to better evaluate the role of IL-6–based OBDMARDs as a Tx option for RA pts with anemia. Disclosure of Interest S. Paul Grant/research support from: Genentech, AstraZeneca, Novo Nordisk, Consultant for: GI Dynamics, Speakers bureau: AstraZeneca, GI Dynamics, Novo Nordisk, K. Klein Grant/research support from: Genentech, AstraZeneca, Novo Nordisk, Consultant for: GI Dynamics, J. Best Shareholder of: Roche, Employee of: Genentech, S. Gale Shareholder of: Roche, Employee of: Roche, A. Petho-Schramm Employee of: F. Hoffmann-La Roche, K. Sarsour Shareholder of: Roche, Employee of: Roche