ObjectivesTo compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis.MethodsIn a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression.Results281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively −2.39 (95% CI −4.77 to −0.00) and −1.67 (95% CI −3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM.ConclusionsTreatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used.Trial registration numberISRCTN26791028.

Triple DMARD induction therapy is better than MTX monotherapy in early RA. Furthermore, no differences were seen in medication adjustments due to adverse events after stratification for drug. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used.

Objective. To optimize use of the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA) by adding the "squeeze test" of forefeet.Methods. The squeeze test is used to examine bilateral compression pain (BCP) across the metatarsophalangeal (MTP) joints. For this study, data for patients participating in the Treatment in the Rotterdam Early Arthritis Cohort study, an ongoing clinical trial that evaluates different induction therapies in patients with early RA, were randomly divided into 2 subsets. In subset 1 (149 patients and 819 disease activity assessments), the mathematical function of the DAS28-squeeze was constructed using a linear regression model with the DAS as the dependent variable and the DAS28 and squeeze test as the independent variables. A DAS28-BCP disease state was also constructed, in which DAS28 disease state categorizations were upgraded one state if the result of the squeeze test was positive. In subset 2 (153 patients and 754 assessments), concordance in disease states between the DAS28, DAS28-squeeze, and DAS28-BCP disease states was compared, using both the DAS and Boolean-defined remission criteria as reference.Results. Agreement between the DAS and the DAS28-squeeze (82%) was significantly higher than agreement between the DAS and the DAS28 (76%). When we assessed the group of patients who had arthritis of the forefeet only (22 patients and 46 assessments), overall agreement between the DAS and the DAS28 was 40%, while agreement between the DAS and the DAS28-squeeze was 59% and that between the DAS and the DAS28-BCP disease state was 65%. Furthermore, the specificities of the DAS28-squeeze and the DAS28-BCP (80% and 81%, respectively) were higher than that of the DAS28 (76%), while the sensitivities of the DAS28, DAS28-squeeze, and DAS28-BCP to identify true remission according to the Boolean criteria were 88%, 87%, and 81%, respectively.Conclusion. Adding the squeeze test of forefeet to the DAS28 has value for dependably classifying the disease state in patients with early RA.

Background Recent research has shown that response to glucocorticoids (GC) predicts the effectiveness of DMARD induction therapy including methotrexate (MTX).[1] Moreover, GC use has been associated with higher intracellular concentrations of methotrexate-polyglutamates (MTX-PG),[2] and higher MTX-PG concentrations were associated with lower disease activity in rheumatoid arthritis (RA).[3] If GC use is associated with higher MTX-PG concentrations, the association between MTX-PG concentrations and non-response may be modified by GC use. Objectives The objectives were to investigate whether MTX concentrations are associated with response and whether this association is modified by CG use. Methods This study included combined data of RA patients treated with MTX from 2 longitudinal cohorts: 285 from the tREACH study and 102 from the MTX-R study. We measured MTX with a tail of 1,2,3,4 and 5 glutamates in erythrocytes after 3 months of therapy using an LC-MS/MS assay. GC use was defined as use of oral or intramuscular GC therapy at start of treatment. As outcome measure for MTX response we defined disease activity score (DAS) 28 at 3 months. GC use, MTX-PG concentrations and their interaction terms (CGuse*MTX-PG concentrations) were tested for associations with DAS28 with an ANCOVA analysis. The analysis was corrected for gender, age, MTX-dose, baseline DAS28, and other DMARD use. Results Mean DAS28 decreased from 4.76 (SD=1.26) to 3.07 (SD=1.20) after 3 months. 49% of patients used glucocorticosteroids at baseline and the median total MTX-PG was 54 nmol/l (IR=42-70). MTX-PG1 (p=0.012), MTX-PG2 (p=0.001), MTX-PG3 (p=0.006) and total MTX-PG were negatively associated with DAS28. GC use was not associated with DAS28 (p=0.450). Patients with GC use had higher concentrations of MTX-PG3 (p=0.005), MTX-PG4 (p<0.001) and MTX-PG5 (P<0.001) than patients without GC treatment. The interactions between GC use and total MTX-PG was significantly associated with DAS28 (p=0.049). When data were stratified by CG use lower MTX-PG1 (p=0.004), MTX-PG2 (p=0.005) and total MTX-PG (p=0.008) were associated with non-response only in patients who did not use corticosteroids at baseline. In persons who used CGs no association was shown. Conclusions This study shows that MTX-PG concentrations were related to a lower DAS28. Furthermore we showed that GC use increases the accumulation speed of MTX-PG concentrations and thereby possibly potentiating the efficacy of MTX, resulting in a lower DAS28. The association between MTX-PGs and DAS28 depends on CG use. References de Jong PH, et al. Ann Rheum Dis. 2012 Oct 31; Stamp LK, et al. Arthritis Rheum. 2009 Aug;60(8):2248-56; Dervieux T, et al. Ann Rheum Dis. 2005 Aug;64(8):1180-5. Acknowledgements tREACH: Unrestricted grant from Pfizer bv. (0881-102217). RDJ: Dutch Arthritis Association (06-02-402 and 09-1-402). Disclosure of Interest None Declared

BackgroundIn 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.ObjectivesTo identify and validate clinical baseline predictors associated with inadequate response (IR) to MTX therapy in disease modifying anti-rheumatic drug (DMARD)-naïve early RA patients.MethodsFor 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).ResultsIn 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<0.001; current smoking, ORadj 3.0, 95% CI 1.1–8.0; p=0.027; and alcohol consumption, ORadj 0.3, 95% CI 0.1–0.9; p=0.021. A risk matrix, categorised by these predictors, shows nearly a twelve and a halve fold risk difference in predicted probabilities (figure 1). The area under the receiver operating characteristic curve (AUROC) of the model is 0.75 (95% CI 0.66–0.84); no statistically significant difference (p=0.96) was found between the observed and predicted probabilities (i.e. calibration). When using a negative predictive value (NPV), i.e. predicted chance of not failing “MTX+” therapy, of >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).Abstract FRI0040 – Figure 1Risk matrix of predicted probability (%) of IR to “MTX+” therapy.Conc...

No abstract

BackgroundWhat is the optimal glucocorticoid (GC) bridging therapy with MTX monotherapy in early arthritis?ObjectivesTo compare short term clinical efficacy of high and low dose GC tapering schedules with MTX monotherapy in 2 clinical trials in early rheumatoid arthritis (RA) and undifferentiated arthritis (UA) patients.MethodsIn tREACH, early RA and UA (arthritis in ≥1 joint(s),<1 year symptoms) patients were randomised to 3 different treatment arms. For this analysis we only use the data of arm C: oral GCs (prednisone) (15 mg/day, tapered to 0 in 10 weeks) with MTX monotherapy (25 mg/week); low dose GC tapering schedule (LDGC).In IMPROVED RA and UA (arthritis in ≥1 joint and ≥1 other painful joint,<2 years symptoms) patients were treated with prednisone (60 mg/day, tapered in 7 weeks to 7.5 mg/day, continued to 4 months)+MTX monotherapy (25 mg/week); high dose GC tapering schedule (HDGC). We compared%DAS-remission (<1.6) and low disease activity (≤2.4) at first evaluation (3 months tREACH, 4 months IMPROVED) and DAS and HAQ over time. After multivariate normal imputation we applied generalised estimating equations (GEE) for linear outcomes and logistic regression models for binary outcomes, adjusted for potential baseline confounders (figure 1). Adverse events were compared between treatment arms using χ2-square tests.ResultsPatients with a HDGC (n=610) had shorter symptom duration and higher HAQ, were less often seropositive (ACPA positive 56.0% vs 77.3%, RF positive 58.1% vs 65%) and more often had UA (20.3% vs 2.1%) than patients with a LDGC (n=97). Baseline DAS was comparable.At the first evaluation time point (median 3.06 (IQR 2.99–3.22) months in LDGC, 4.01. (3.8–4.17) in HDGC) DAS and HAQ had decreased significantly less after 3 months LDGC: DAS β (95% CI) 0.500 (0.276; 0.725), and HAQ 0.330 (0.189; 0.470) than after 4 months HDGC (figure 1).Compared to the HDGC patients, patients with the LDGC had a significantly lower chance of achieving DAS-remission 63.4% vs 28.9% (OR (95% CI) 0.215 (0.124; 0.373) and low disease activity 80.6% vs 55.7% ((OR (95% CI) 0.249 (0.143; 0.435)). Presence of ACPA was positively associated with achieving DAS-remission in the HDGC group, but not in the LDGC group. Per 100 patient years, 7.98 serious adverse events were reported in the HDGC and 23.4 in the LDGC (p=0.004). Hypertension, hyperglycemia (>7.8 mmol/L), gastrointestinal complaints and liverenzymes above normal were reported in similar frequencies across all groups. In patients with a LDGC more headaches, skin rashes, creatinine above normal range and any decrease in haematology blood counts were reported (data not shown).Abstract OP0030 – Figure 1 A:Predicted DAS over time, B: PRedicted HAQ over time. All predictions are from multiple imputed models, adjusted for age, gender body mass index, presence of ACPA, presence of rheumatoid factor, symptom duration, effect over time (in GEE) and baseline DAS (for binary out-comes). DAS, Disease Activity Score; HAQ Health Assessment Questionnarie; HD GC, high dose glucocortico...

ackground: Randomised controlled trials (RCTs) are the gold standard to estimate treatment effects. When patients receive effective treatment over time they may reach the limit of a certain measurement scale. This phenomenon is known as censoring and lead to skewed distributions of the outcome variable with an excess of either low (floor effect) or high values (ceiling effect). Applying traditional methods such as linear mixed models to analyse this kind of longitudinal RCT data may result in bias of the regression parameters. To deal with floor effects due to censoring,  a tobit mixed model can be used. The objective of this study was to compare the results of longitudinal linear mixed model analyses with longitudinal tobit mixed model analyses.Methods: First, a simulation study was performed in which several situations of RCTs with floor effects were simulated. Second, data from an empirical RCT was analysed with both methods.Results: Although all analyses underestimated the intervention effects, the tobit mixed model performed much better than the linear mixed model in handling floor effects. However, with an increasing number of follow-up measurements in combination with a strong floor effect estimates from the tobit mixed model were also not accurate.Conclusion: tobit mixed model analysis should be used to estimate treatments effects in longitudinal RCTs with floor effects due to censoring.