Xavier M. Teitsma

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early) : a multicentre, randomised, double-blind, double-dummy, strategy trial

BACKGROUND For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING Roche Nederland BV.

Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies

Objective To evaluate the progression of erosions and joint space narrowing (JSN) in feet and hands in the U-Act-Early trial. Methods 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. Results 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). Conclusion 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. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT01034137.

Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors

Objective To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). Methods In 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) <2.6 with four or less swollen joints for ≥24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, ‘MTX+’) and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to ‘MTX+’. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. Results Within 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. Conclusion Higher 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 registration NCT01034137; Post-results, ISRCTN26791028; Post-results.

Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology

BackgroundWe 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.MethodsSerum 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.ResultsIn 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 < 0.001); in the tocilizumab strategy it was “arachidonic acid metabolism” (p = 0.018); and in the methotrexate strategy it was “arginine and proline metabolism” (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate.ConclusionIn early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated.Trial registrationClinicalTrials.gov, NCT01034137. Registered on January 2010

Adding baseline protein biomarkers to clinical predictors does not enhance prediction of treatment response to a methotrexate strategy in early rheumatoid arthritis

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 …

SAT0218 Effect of tocilizumab in DMARD-NAÏVE early rheumatoid arthritis patients on health-related quality of life: results of the U-ACT-EARLY trial

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) <2.6 with ≤4 swollen joints for ≥24 weeks), when compared to those initiating MTX (44%).[1] 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)-naïve 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 <5.1 or ≥5.1) and centre as fixed effects. The proportions of patients exceeding the minimum clinically important differences (MCID, ≥2.5-point increase from baseline) were tested for significance using the two-sided Pearsons chi-squared test. 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-naïve 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. Pethö-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

OP0293 Weighted gene co-expression network analysis of DMARD-NAÏVE early ra patients achieving sustained drug-free remission after initiating tocilizumab therapy

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)-naïve early RA patients achieving sustained drug-free remission (sDFR) after initiating treatment with tocilizumab (TCZ). Methods Data was used from DMARD-naïve 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. Pethö-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

FRI0203 Sustained Drug Free Remission in Early Ra Patients Treated To Target with Tocilizumab, Methotrexate or Their Combination

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 <2.6 and <4 swollen joints for >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<0.01) and TCZ (27% p<0.01) strategy, compared to MTX (11%, Fig. 1). In patients achieving it, the median time (IQR) to achieve sDFR was shorter in the TCZ+MTX (48 (44–56) weeks; p=0.09) and TCZ strategy (52 (44–67) weeks; p=0.18) when compared to MTX (60 (52–76) weeks). The median duration (IQR) of sDFR within the study period was 44 (16–56), 32 (20–48) and 28 (20–44) weeks (p=0.15) in the TCZ+MTX, TCZ and MTX group, respectively. Baseline HAQ (OR 0.2 (95% CI: 0.1–0.4), any (RF and/or anti-CCP) seropositivity (OR 0.5 (95% CI: 0.2–0.8) and initiation with TCZ+MTX (OR 3.9 (95% CI: 1.9–8.3) or TCZ (OR 3.4 (95% CI: 1.5–7.3) were significant predictors for achieving sDFR. The Area Under the Curve (AUC-ROC) of the multivariable model was 0.73 (95% CI: 0.67–0.80), indicating fair discriminative ability. In our sample, a classifier with 84% sensitivity and 53% specificity correctly predicted achievement of sDFR in 66% of patients.Table 1. Characteristics of the 317 patients with early rheumatoid arthritis Mean (SD) age, years 53 (13) Female gender, n (%) 212 (67) Mean (SD) BMI, kg/m2 26 (4) Current smoker, n (%) 90 (28) Median (IQR) alcohol consumption, unit per week 1 (0–6) Median (IQR) symptom duration, days 26 (16–43) Any seropositivity*, n (%) 251 (79) Mean (SD) DAS28 5.2 (1.1) Median (IQR) CDAI 25 (19–34) Median (IQR) VAS pain 60 (40–70) Median (IQR) HAQ 1.1 (0.6–1.6) *RF and/or anti-CCP positive. 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. Pethö-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.

FRI0040 Protein Biomarkers Improves The Prediction of Clinical Response To Methotrexate Step-Up Strategy in Early RA Patients

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-naïve RA patients initiated MTX step-up therapy (10 mg to 30 mg or maximum tolerable dose) until remission (DAS28 <2.6 with SJC ≤4) was achieved. If no remission after 20 weeks, HCQ was added, which after 12 weeks was replaced by tocilizumab (TCZ) if remission still was not achieved. Clinical assessments at baseline were analyzed and missing values were imputed using multiple imputations (n=20). Additionally, serum was collected before treatment and analyzed for 85 inflammatory proteins using Luminex® xMAP technology. Predictors for failing the MTX step-up strategy (MTX+HCQ) were selected using univariate preselection (p≤0.15) followed by multivariate backward selection (p≤0.10). A model including only clinical predictors was developed and subsequently, a second model in which protein biomarkers was added. The Area Under the Receiver Operator Curve (AUC-ROC), Net Reclassification Index (NRI, quantifies the improvement in prediction between two models) and Likelihood-ratio (LLR) test were used to assess both models. 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<0.001). When using a risk of non-response >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. Pethö-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