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We read with great interest the correspondence of Novella-Navarro et al on our paper regarding the European League Against Rheumatism (EULAR) definition of difficult-to-treat rheumatoid arthritis (D2T RA).1 2 We appreciate their acknowledgement of the need for uniform terminology and a uniform definition to describe the concept of D2T RA. Previously, this need had also been underlined by rheumatologists participating in an international survey.3 The use of heterogeneous terminology and definitions might hamper research and management of these patients.4–9 Novella-Navarro et al compared their definition of multirefractory RA in their recently conducted retrospective study with the three criteria of the EULAR definition of D2T RA (box 1).2 10 They classified patients with RA as having ‘multirefractory’ disease after failing ≥2 biological and/or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with different mechanisms of action or ≥3 b/tsDMARDs with the same target, and as having ‘non-refractory’ disease if achieving low disease activity or remission on the first bDMARD. Noteworthy, 96% of their multirefractory patients met the EULAR definition of D2T RA (box 1),2 which supports the clinical usefulness of our definition.1 Box 1 ### EULAR definition of difficult-to-treat rheumatoid arthritis1 1. Treatment according to EULAR recommendations and failure of ≥2 b/tsDMARDs (with different mechanisms of action)* after failing csDMARD therapy (unless contraindicated)† 2. Signs suggestive of active/progressive disease, defined as ≥1 of: 1. At least moderate disease activity (according to validated composite measures including joint counts, eg, DAS28-ESR>3.2 or CDAI>10) 2. Signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease (joint related or other) 3. Inability to taper …

ObjectiveCurrent smoking reduces clinical response to several disease-modifying antirheumatic drugs. It is unknown if this is also the case for prednisone. We aimed to determine whether current smoking affects the clinical response to concomitant prednisone in a methotrexate (MTX)-based treatment strategy.MethodsIn the CAMERA-II trial (isrctn.com identifier: 70365169), patients with early rheumatoid arthritis (RA) initiated an MTX-based strategy and were randomized to concomitant prednisone (MTX + pred) or placebo (MTX + PBO) for 24 months. Linear mixed modeling was performed with Disease Activity Score assessing 28 joints (DAS28) as the dependent variable, and strategy group and current smoking status as independent variables, correcting for relevant covariates. The interaction between current smoking and strategy was tested to find out whether the effect of current smoking on clinical response was different between the strategy groups with prednisone or PBO.ResultsCurrent smoking was significantly associated with higher DAS28 over time (mean difference with nonsmokers 0.57 [95% CI 0.22–0.92, P < 0.01]). This association was not different between the strategy groups with prednisone or PBO (P = 0.73). The negative effect of current smoking on DAS28 was dose dependent.ConclusionCurrent smoking in patients with early RA significantly reduces the clinical effect of an MTX-based strategy, independent of whether concomitant prednisone is used. This effect is dose dependent.

Objectives To determine the impact of difficult-to-treat rheumatoid arthritis (D2T RA) on (costs related to) healthcare utilization, other resource use and work productivity. Methods Data regarding healthcare utilization, other resource use and work productivity of 52 D2T (according to the EULAR definition) and 100 non-D2T RA patients were collected via a questionnaire and an electronic patient record review during a study visit. Annual costs were calculated and compared between groups. Multivariable linear regression analysis was performed to assess whether having D2T RA was associated with higher costs. Results Mean (95% CI) annual total costs were €37 605 (€27 689 – €50 378) for D2T and €19 217 (€15 647 – €22 945) for non-D2T RA patients (P Conclusions The economic burden of D2T RA is significantly higher than that of non-D2T RA, indicated by higher healthcare utilization and higher annual total costs. Functional disability is a key determinant of higher costs in RA.

Objective To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. Methods In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ–Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. Results Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for Conclusion RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

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.

Resume Objectifs Identifier, par une revue systematique de la litterature, les facteurs predictifs de reponse clinique au methotrexate chez des patients atteints de polyarthrite rhumatoide, afin de faciliter la mise en place d’un traitement personnalise. Methodes Les bases de donnees PubMed et Embase ont ete consultees pour la selection des articles originaux. Les abstracts des rencontres annuelles de l’EULAR (European League Against Rheumatism) et de l’ACR (American College of Rheumatology) de ces deux dernieres annees ont egalement ete examines. Ont ete inclus les articles decrivant les facteurs predictifs de la reponse clinique au methotrexate 3 a 6 mois suivant le debut du traitement, periode qui permet de determiner l’efficacite du traitement et d’envisager une adaptation therapeutique selon les recommandations treat-to-target. Resultats 30 articles ont ete inclus, contenant un total de 102 facteurs predictifs differents et 11 modeles predictifs. 19 facteurs et 2 modeles predictifs ont ete evalues au sein de plusieurs cohortes. Le sexe feminin est apparu comme etant un facteur predictif de non-reponse au cours de deux etudes (odds ratios 0,55 et 0,54) mais ces observations n’ont pas ete retrouvees dans deux autres etudes. Dans deux etudes, le tabagisme permettait de predire la non-reponse (odds ratios ajustes 0,35 et 0,60) mais ce resultat apparaissait contradictoire pour tous les criteres de reponse evalues. La positivite du facteur rhumatoide etait un marqueur predictif de non reponse dans deux etudes (hazard ratio ajuste 0,61, odds ratio ajuste 0,4) mais cette observation n’a pas ete retrouvee dans trois autres etudes. L’heterogeneite des etudes n’a pas permis de comparer les valeurs predictives entre les etudes. Par ailleurs, un modele epigenetique valide a ete retrouve (aire sous la courbe 0,90 et 0,91). Conclusions Aucun des facteurs ne permettait de predire de maniere fiable la reponse clinique au methotrexate apres 3 a 6 mois de traitement chez les patients : ces facteurs affichaient un faible pouvoir de prediction. Cependant, un modele epigenetique prometteur a ete trouve et reste a valider.

BackgroundIn rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes.ObjectivesTo determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy.MethodsData of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed.ResultsNo statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms.ConclusionNo effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

Objectives To identify, by a systematic literature review, predictors of clinical response to methotrexate treatment in rheumatoid arthritis patients, which would facilitate personalised treatment. Methods PubMed and Embase databases were searched for original articles. Additionally, congress abstracts of European League Against Rheumatism and American College of Rheumatology annual meetings of the past 2 years were screened. Articles describing predictors of clinical response to methotrexate after 3 to 6 months were included, since this reflects the time span used to determine treatment effectiveness and decide on treatment changes in treat-to-target recommendations. Results Thirty articles were included, containing 100 different predictors and 11 predictive models. Nineteen predictors and 2 predictive models were studied in multiple cohorts. Female gender was found to be a predictor of non-response in two studies (odds ratios 0.55 and 0.54), but these findings could not be replicated in two other studies. In two studies, smoking predicted non-response (adjusted odds ratios 0.35 and 0.60), although this was inconsistent over all response criteria assessed. Rheumatoid factor positivity predicted non-response in two studies (adjusted hazard ratio 0.61, adjusted odds ratio 0.4), but this was not found in three other studies. Heterogeneity in studies prohibited further comparison of predictive values between studies. Additionally, a validated epigenetic model was found (area under the curve 0.90 and 0.91). Conclusions No predictors were identified reliably predicting clinical response to methotrexate after 3 to 6 months in the individual patient: clinical predictors were weak. However, a promising epigenetic model was found that needs further validation.

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ObjectiveTo develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA).MethodsAn EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A–D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0–10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members.ResultsTwo overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4–9.6).ConclusionsThese PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.

In this issue of The Journal of Rheumatology , Muskens, et al describe the effect of the introduction of an etanercept (ETN) biosimilar on antirheumatic medication cost1. After a Dutch rheumatology department launched this biosimilar as a substitute for the more expensive biologic ETN, the accumulated 3-monthly antirheumatic medication cost in that hospital pertaining to in- and outpatients with rheumatoid arthritis (RA), mainly consisting of cost of biologic disease-modifying antirheumatic drugs (bDMARD), decreased, as expected. However, this financial advantage was lost within less than a year, due to an increase of the percentage of the patients with RA treated with a bDMARD. This means that the potential savings of using the biosimilar were spent on extra patients treated with a bDMARD, although the rheumatologists had not formally changed their bDMARD prescription policy. The brisk increase in percentage of patients treated with a bDMARD in this time period is not compatible with the general trend of slowly increasing bDMARD use over time. Should the reader of the paper1 thus conclude that introduction of cheaper biosimilars is not effective in reducing medication cost in the longer term? Our answer would be that interpretations of this, and of any costing study, strongly depend on what we are looking at, how we are looking, and who is looking. What we are looking at: Treatment strategy Muskens, et al 1 found no statistically significant difference in disease activity in those starting a biological before the biosimilar introduction (mean Disease Activity Score assessing 28 joints [DAS28] 4.7), versus in those starting a bDMARD after the biosimilar introduction (DAS28 4.5). Notably, the mean age of patients at the start of bDMARD after the biosimilar introduction was statistically significantly higher than that before the biosimilar introduction (58 vs 52 yrs, respectively). After the biosimilar introduction, … Address correspondence to Dr. J.W. Jacobs, Department of Rheumatology & Clinical Immunology, G02.228, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands. Email: j.w.g.jacobs-12@umcutrecht.nl.

To establish the value of a modified Disease Activity score with Optical Spectral Transmission score (DAS-OST) without joint counts but with a HandScan score, versus that of DAS28, to classify rheumatoid arthritis (RA) as active versus inactive, with as reference standard the rheumatologist's clinical classification.RA patients with at least one HandScan and DAS28 measurement performed at the same visit were included. Data was extracted from medical records, as was the clinical interpretation as active or inactive RA by the rheumatologist. Logistic regression analyses were performed to calculate areas under the receiver operating characteristics (AU-ROC) curves. The clinical interpretation was used as reference standard in all analyses, and disease activity measures were used as predictor variables. The performance of predictor variables (AU-ROCs) was compared.The data of 1505 RA patients were used for analyses. The highest AU-ROC of 0.88 (95%CI 0.85-0.90) was shown for DAS28; AU-ROC of DAS-OST was 0.78 (95%CI 0.75-0.81), difference 0.10, p0.01.Compared to DAS28, DAS-OST classified RA statistically significantly less well as active versus inactive, when using the clinical classification as reference standard. However, a DAS-modification without joint scores might have a place in strategies limiting routine outpatients' visits to the rheumatologist.

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.

Objective To establish the performance of (subsets of) the 2015 ACR/EULAR gout classification criteria in patients with unclassified arthritis, and to determine the value of dual-energy CT (DECT) herein. Reference was the MSU crystal detection result in SF at polarization microscopy. Methods We included subjects with acute, unclassified mono or oligoarthritis, who underwent SF analysis and DECT. Performance was assessed by calculating area under the receiver operating characteristic curve of (i) the clinical criteria subset, (ii) the clinical+serum urate subset and (iii) the full set (including DECT). Results Of the 89 subjects enrolled, 40 met the clinical+serum urate subset criteria, and 49 (55%) subjects did not. Of these 49, 30 had a negative microscopy result, of whom 15 had positive DECT; of these 15, 14 met the full set criteria only after adding the positive DECT result. For the clinical-only subset, the areas under the curves (AUCs) were 0.68 and 0.69 without and with DECT result, respectively, and for the clinical+serum urate subset without and with DECT, AUCs were 0.81 and 0.81, respectively (results not significant). Conclusion Adding the serum urate results to the clinical subset improves the performance, but adding the DECT result does not, neither does adding the DECT results to the clinical+serum urate subset. However, DECT seems to have an additive value in gout classification, especially when microscopy of SF is negative; 14/89 of patients (16%) only met the classification criteria with the use of DECT. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03038386.

Objectives Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. Methods Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. Results DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: −0.62 (95% CI −1.14 to −0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. Conclusions In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.

ObjectivesTo establish the value of a modified DAS (DAS-OST) without joint counts but with a HandScan score (OST), versus that of DAS28, to classify RA as active versus inactive, with as reference standard the rheumatologist's clinical classification.MethodsRA patients with at least one HandScan and DAS28 measurement performed at the same visit were included. Data was extracted from medical records, as was the clinical interpretation as active or inactive RA by the rheumatologist. Logistic regression analyses were performed to calculate areas under the receiver operating characteristics (AU-ROC) curves. The clinical interpretation was used as reference standard in all analyses, and disease activity measures were used as predictor variables. The performance of predictor variables (AU-ROCs) was compared.ResultsData of 1505 unique RA patients were used for analyses. The highest AU-ROC of 0.88 (95%CI 0.85 – 0.90) was shown for DAS28; AU-ROC of DAS-OST was 0.78 (95%CI 0.75 – 0.81), difference 0.10, pConclusionsCompared to DAS28, DAS-OST classified RA statistically significantly less well as active versus inactive, when using the clinical classification as reference standard. However, a DAS-modification without joint scores might have a place in strategies limiting routine outpatients’ visits to the rheumatologist.

To the Editor: A recent paper by Triantafyllias, et al described that optical spectral transmission (OST) scores, obtained by the HandScan, were significantly higher in male compared to female patients with rheumatoid arthritis (RA) and controls, and an association between OST score and age, BMI, and hand surface area was found.1 The difference in sex that Triantafyllias, et al showed is in line with results of studies performed at our department. We developed and validated a new disease activity index, Disease Activity Score (DAS)-OST, in which tender and swollen joint counts are replaced by the OST score. In the construction of the DAS-OST formula, sex had to be taken into account, because in this study, OST scores were higher in males than in females.2 In addition, by comparing single OST scores to the rheumatologist’s clinical classification into active or inactive RA as reference, different optimal cutoffs for males and females were calculated, again indicating a sex difference. Based on these findings, we investigated whether this difference in sex was also … Address correspondence to Dr. M.M. Verhoeven, Department of Rheumatology & Clinical Immunology G02.228, P.O. Box 85500, 3508GA Utrecht, the Netherlands. Email: m.m.a.verhoeven-15{at}umcutrecht.nl.

To develop and validate a composite rheumatoid arthritis (RA) disease activity index using optical spectral transmission (OST) scores obtained with the HandScan, replacing tender and swollen joint counts.RA patients from a single center routinely undergoing HandScan measurements with at least 1 concurrent OST score and Disease Activity Score in 28 joints (DAS28) were included. Data were extracted from medical records. Linear regression analyses with the DAS28 as the outcome were performed to create a disease activity index (DAS-OST). OST score, erythrocyte sedimentation rate (ESR), and patient global assessment (PtGA) visual analog scale (VAS), sex, age, disease duration, and rheumatoid factor status were evaluated as independent variables. Final models were derived based on the statistical significance of coefficients and model fit. Of the data, two-thirds were used for development and one-third for validation; external validation was performed in a cohort from another center. Agreement between DAS-OST and DAS28 was assessed using the Bland-Altman plot method and intraclass correlation coefficient (ICC). Diagnostic value of the DAS-OST was determined for established definitions of remission, low disease activity (LDA), and high disease activity (HDA).Data of 3,358 observations from 1,505 unique RA patients were extracted. DAS-OST was defined as: -0.44 + OST × 0.03 + male × -0.11 + LN(ESR) × 0.77 + PtGA VAS × 0.03. The ICCs between DAS-OST and DAS28 were 0.88 (95% confidence interval [95% CI] 0.87-0.90) and 0.82 (95% CI 0.75-0.86) and measurement errors were 0.58 and 0.87 in internal and external validation, respectively. Sensitivity for remission, LDA, and HDA was 79%, 91%, and 43%, respectively, and specificity was 92%, 80%, and 96% in external validation.Using the HandScan, RA disease activity can be accurately estimated if combined with ESR, PtGA VAS, and sex into a disease activity index (DAS-OST).

ObjectivesThe aims were to determine the ability of the HandScan [assessing inflammation in hand and wrist joints using optical spectral transmission (OST)] to measure RA disease activity longitudinally, compared with DAS28, and to determine whether short-term (i.e. 1 month) changes in the OST score can predict treatment response at 3 or 6 months.MethodsParticipants visited the outpatient clinic before the start of (additional) RA medication and 1, 3 and 6 months thereafter. Disease activity was monitored at each visit with the HandScan and DAS28 in parallel. A mixed effects model with DAS28 as the outcome variable with a random intercept at patient level, visit month and DAS28 one visit earlier was used to evaluate whether changes in the OST score are related to changes in DAS28. Binary logistic regression was used to test the predictive value of short-term changes in the OST score together with the baseline OST score for achievement of treatment response (EULAR or ACR criteria). All models were adjusted for RA stage (early or established).ResultsIn total, 64 RA patients were included. One unit change in OST score was found to be related to an average DAS28 change of 0.03 (95% CI: 0.01, 0.06, P = 0.03). When adding OST score as a variable in the longitudinal model, the ability of the model to estimate DAS28 (i.e. explained variance) increased by 2%, to 59%. Neither baseline OST score nor short-term change in OST score was predictive for treatment response at 3 or 6 months.ConclusionA longitudinal association of OST score with DAS28 exists, although explained variance is low. The predictive ability of short-term changes in HandScan for treatment response is limited.

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.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia (FM) has progressed remarkably in recent years. Despite this, currents accounts of FM fail to capture the complex, dynamic and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to synthesise current knowledge on FM, explore and highlight multi-level links and pathways among different systems and build bridges between existing approaches. An extensive panel of international experts in neurophysiology and psychosocial aspects of FM discussed the collected evidence and progressively refined and conceptualized its interpretation. Fibromyalgia is a complex condition resulting from the dynamic interplay between multiple systems and processes. We provided an updated overview of the most relevant observations in FM to date as well as the potential pathways by which they exert they are related and exert their mutual influence, to produce the manifestations commonly associated with FM. This review constituted the first step towards and supported the development of a much needed model capable of integrating the main factors implicated in FM into a single, unified model that may prove valuable in understanding and managing FM.

Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. Methods In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. Discussion This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. Trial registration This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.

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.

Objective To develop an optical spectral transmission (OST) model to measure joint inflammation, and thus disease activity, as well as to evaluate (patho-)physiological findings that could lead to misclassification of inflammation. Methods Forty-six RA patients were included in this cross-sectional study, where US scores, duplicate OST measurements and 28-joint DAS (DAS28) were acquired. With US as a reference standard, the diagnostic performance of OST in detecting inflammation at the joint level was evaluated using receiver operating characteristic (ROC) curve analyses. At the patient level, correlations with US were analysed for DAS28 and OST, and at joint level for OST and tender and swollen joint counts (TJC and SJC, respectively). Joint pathology potentially influencing misclassification by OST [erosions, osteophytes, tendon (sheath) inflammation (ab)normal vasculature and chondrocalcinosis] was evaluated for significance in a multivariate nominal logistic regression model. Results Diagnostic performance of OST was good for MCP [area under the ROC curve (AUC-ROC) 0.88], PIP (AUC-ROC 0.83) and wrist (AUC-ROC 0.74) joints and for all joints together (AUC-ROC 0.85). At the patient level, DAS28 correlated very poorly (ρ = 0.06) and OST moderately (ρ = 0.54) with US. At the joint level, US correlation with OST was strong (ρ = 0.64), with SJC it was weak (ρ = 0.30) and with TJC it was very weak (ρ = -0.02). Misclassification of inflammation by OST was relatively rare (17%). Dorsal erosions [odds ratio (OR) 4.0], osteophytes (OR 2.1) and extensor tendinitis (OR 4.6) increased the risk of underestimating inflammation of MCP and PIP joints and osteophytes (OR 3.0) also increased the risk of overestimating inflammation. Conclusion OST is a sensitive, specific and objective technique to assess joints inflammation of the hands and wrists of RA patients, even though bone and tendon pathology increases the risk of misclassification.

The beneficial effects of glucocorticoids are highly regarded in the treatment of inflammatory diseases. In rheumatoid arthritis, these drugs are widely used because they effectively reduce signs and symptoms of the disease, and exert disease-modifying effects. However, both patients and physicians frequently associate glucocorticoids with a variety of adverse effects which hamper adherence. Due to this ambivalent nature of these drugs, several new glucocorticoids or glucocorticoid receptor ligands are being developed, aiming at improving their benefit-risk balance. Areas covered: Focussing on rheumatoid arthritis, we discuss current approaches to achieve this goal, including an optimized application of conventional glucocorticoids and the development of novel formulations aiming at minimizing adverse effects while keeping or even enhancing the anti-inflammatory efficacy. Expert opinion: Glucocorticoids - be it conventional or modified/delayed-release formulations - have so far been convincing in clinical practice, and their widespread use will therefore continue. They are not likely to be replaced by novel drugs in the near future although some investigational preparations are promising, and results obtained from currently ongoing clinical trials in humans are eagerly awaited. As a result of these developmental activities, a further improvement of the benefits-risk balance of glucocorticoids or glucocorticoid receptor ligands is expected.

With great interest we read the viewpoint from Professor Landewe,1 calling for more caution, research and debate regarding the risks of overdiagnosis and overtreatment in rheumatology. Strongly agreeing with the overall message, especially that ‘(…) overtreatment is hardly discussed but likely present’, we would like to contribute to this discussion by raising an issue that touches base on two paradigms listed by Professor Landewe: remission and evidence-based rheumatology. There is now ample evidence that a substantial proportion (12%–38%) of patients with rheumatoid arthritis (RA) do not achieve the status of remission according to disease activity indices, solely because of a patient global assessment (PGA) score >1 (0–10 scale, 10=worst).2 3 If the elevated score on PGA does not reflect disease activity, additional immunosuppressive agents cannot improve the status of these patients, as inflammation is already essentially abrogated. Elevated PGA, therefore, may induce the risk of overtreatment when applying disease indices or Boolean-based criteria to define the treatment aim, which is remission or at least low disease activity (LDA) according to current treatment recommendations.4 5 Naturally, patients who still report relevant disease symptoms despite the absence of significant inflammation need …

Chronic inflammation associated with hyperuricaemia and urate deposition may contribute to an increased risk of developing cardiovascular (CV) events (CVE) in patients with gout. The aim of this study was to explore whether urate deposition on dual-energy CT (DECT) present at the diagnosis of gout is associated with a history of CVE.Patients from a study on clinical value of DECT with mono or oligoarthritis who had gout according the 2015 EULAR/ACR classification criteria were included in this cross-sectional study. Urate volume on DECT was calculated. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors, scored with the Dutch risk prediction SCORE and the Framingham score. The data were analysed using logistic regression analyses.Sixty-eight patients were included. In the multivariable model, -next to significant associations of age (OR per year 1.1, 95% CI 1.04 to 1.02, p=0.02), HDLc per mmol/l (OR 0.04, 95% CI 0.002 to 0.8, p=0.03), and diabetes yes/no (OR 4, 95% CI 0.8 to 20.9, p=0.09)-, urate volumes at ankles/feet on DECT in the third and fourth quartile with first quartile as reference showed a trend of association (OR 4.8, 95% CI 0.6 to 42, p=0.1 and 6.4, 0.7 to 63, 0.1, respectively) with past CVE events (yes/ no). This association could be bidirectional. Almost two-third of newly classified gout patients had a high or very high CV risk.CVE history probably is associated with urate volumes already present at the time of diagnosis of gout. Our data corroborate the need of assessing and treating CV risk factors when diagnosing gout.

Chronic inflammation, as seen in gout, may contribute to an increased risk of developing cardiovascular (CV) events (CVE). The aim of the study was to explore the effect of adding gout as a chronic inflammatory disease to the Dutch SCORE, a tool predicting 10-year CV mortality and morbidity.This was a cross-sectional substudy including new patients with gout according the 2015 EULAR/ACR classification criteria who had participated in a trial on diagnostic accuracy of DECT with mono or oligoarthritis. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors with the Dutch risk prediction SCORE. Chi-square test for trends was used to test for significance reclassification of the CV risk before and after adding gout to the Dutch SCORE.Seventy-six gout patients were included. SCORE was applied in 60 patients; 16 patients had experienced a prior CVE. The 10-year risk scores without gout as risk factor were high in 29 patients (48.3%), moderate in 6 (10%) and low in 25 (41.7%); with gout, the risk of 23/60 patients (38.3%) was reclassified from low to moderate in 6 patients (10%), from low to high in 11 (18.3%) and from moderate to high in 6 (10%), p0.001 for trend.Adding gout to the risk prediction tools led to significant and clinically relevant reclassification of CV risk in new gout patients. Studies with large follow-up are warranted to validate these findings.

Background Tocilizumab (TCZ) efficacy and safety in rheumatoid arthritis (RA) have been well established by numerous phase 3 and 4 studies and observational studies. Objectives To explore the extent to which disease duration, inflammation, disease burden, and other baseline factors explain variations in outcomes in studies of RA patients treated with TCZ. Methods This was a pooled analysis of methotrexate-inadequate responding (IR)/conventional synthetic disease-modifying antirheumatic drug (csDMARD)-IR patients with RA allocated to TCZ (intravenous or subcutaneous, monotherapy + combination therapy) in phase 3 and 4 studies. End points were change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and quality of life (Health Assessment Questionnaire–Disability Index [HAQ-DI]) and week 24 ACR50 and CDAI remission (≤2.8). Using a combination of clinically informed and mathematically driven variable selection techniques, models (with study included as a random effect to account for intracorrelation of observations within each study) were built to optimize fit and explain outcome variance. Analysis of covariance and logistic regression were used for CDAI/HAQ-DI change from baseline and for ACR50/CDAI remission, respectively. Results The analyses were performed on 5462 patients from 12 studies. Analysis of baseline characteristics (before TCZ administration) revealed that patients with longer disease duration had been exposed to more csDMARDS and had worse HAQ-DI than patients with shorter disease duration. Statistical modeling of clinical outcomes showed that disease duration accounted for Conclusion In this pooled analysis of TCZ-treated RA patients, disease duration explained statistically significant but practically small variations in clinical outcomes. These findings indicate that TCZ treatment outcomes are not heavily influenced by disease duration or other baseline characteristics. Disclosure of Interests Andrea Rubbert-Roth Consultant for: Chugai, Eli Lilly, Roche, and Sanofi, Speakers bureau: AbbVie, Bristol-Myers Squibb, Chugai, Hexal/Novartis, Janssen, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi, Daniel Aletaha Grant/research support from: AbbVie, Bristol-Myers Squibb, and MSD, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB, Jenny Devenport Employee of: F. Hoffmann-La Roche, Paris N. Sidiropoulos Shareholder of: Roche, Employee of: Genentech, Yves Luder Shareholder of: F. Hoffmann-La Roche, Employee of: F. Hoffmann-La Roche, Michael Edwardes Consultant for: Roche, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche

Objectives To identify, by a systematic literature review, predictors of clinical response to methotrexate (MTX) treatment in rheumatoid arthritis (RA) patients, which would facilitate personalised treatment. Methods PubMed and Embase databases were searched for original articles. Additionally, congress abstracts of European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) annual meetings of the past 2 years were screened. Articles describing baseline predictors of clinical response to MTX after 3 to 6 months were included, since this reflects the time span used to determine treatment effectiveness and decide on treatment changes in treat-to-target recommendations. Results 30 articles were included, containing 100 different predictors and 11 predictive models, but only 19 predictors and 2 predictive models were studied in multiple similar RA cohorts. Of these 19 predictors, 4 were described in multiple articles sharing details on statistical analyses and response outcomes, allowing pooling of the predictive values of these 4 factors (Figure 1). Conflicting non-statistically significant associations between age and response were found (Figure 1a).1-4 Female gender was found to be a predictor of non-response in two studies (OR (odds ratio) 0.55 and 0.54), but these findings could not be replicated in two other studies (Figure 1b).1-4 In two studies, smoking predicted non-response (adjusted OR 0.35 and 0.60), but this was inconsistent over all response criteria assessed (Figure 1c).3,5 Higher disease activity score was a predictor of response in two studies (adjusted OR 1.12 and 2.7), conflicting and non-statistically significant predictive values were found in two other studies (Figure 1d).2-4,6 Rheumatoid factor positivity predicted non-response in two studies (adjusted hazard ratio 0.61, adjusted OR 0.4), although this was not found in three other studies.2-4,7,8 Heterogeneity between studies prohibited pooling of predictive values. Additionally, a validated epigenetic model was found: area under the receiver operating characteristic curve 0.90 in the development cohort and 0.91 in a validation cohort.9 Conclusion No predictors were identified reliably predicting clinical response to MTX after 3 to 6 months in the individual patient: clinical predictors were weak. However, a promising epigenetic model was found that needs further validation. Future studies on prediction of response to MTX should focus on combining clinical characteristics with genetic and other laboratory biomarkers and on predicting outcome after 3 to 6 months of treatment, to get closer to personalised medicine. References [1] Kavanaugh, et al. Ann Rheum Dis2017;76:822-3. [2] Ponchel, et al. Ann Rheum Dis2014;73:2047-53. [3] Saevarsdottir, et al. Ann Rheum Dis2011;70:469-75. [4] Wessels, et al. Arthritis Rheum2006;54:2830-9. [5] Saevarsdottir, et al. Arthritis Rheum2011;63:26-36. [6] Tan, et al. Int J Rheum Dis2016;19:482-9. [7] Bugatti, et al. Ann Rheum Dis2017;76:790-1. [8] Stuhlmuller, et al. Clin Immunol2016;171:50-61. [9] Carini, et al. J Transl Med2018;16:1-11. Disclosure of Interests Nadia M. T. Roodenrijs: None declared, Marlies van der Goes: None declared, Paco Welsing: None declared, Janneke Tekstra: None declared, Jacob M. van Laar Grant/research support from: Genentech, Consultant for: F. Hoffmann-La Roche, Floris Lafeber Shareholder of: ArthroSave, Grant/research support from: FOREUM; Dutch Arthritis Society, Johannes WJ 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 & Dohme, Pfizer, and UCB University Medical Center Utrecht, Utrecht University, Consultant for: SUN Pharma, Speakers bureau: Lilly, Roche, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche

Background Several trials studied initiation of therapy in early RA patients with a more intensive strategy than the standard disease modifying anti-rheumatic drug (DMARD) strategy according to current guidelines, with the aim of rapidly inducing clinical remission (remission-induction strategies). Objectives To establish in early RA patients the effectiveness of remission-induction strategies compared to standard DMARD strategies according to current guidelines. Methods A systematic literature review was performed, searching Embase and Medline October 2018 for RCTs and other comparative studies in early RA patients, published the past 5 years. Induction therapy was defined as initiating treatment with a biological (b)DMARD or a targeted small molecule (ts)DMARD, both with or without a conventional synthetic (cs)DMARD, or initiating a csDMARD with moderately-high dosed glucocorticoids (GCs), with delayed tapering (not ‘bridging therapy’) or starting ≥2 csDMARDs. Standard DMARD strategy was defined as starting monotherapy with a csDMARD, with or without GCs as bridging therapy. The outcome was remission according to a validated disease activity index or the Boolean definition.1 Numbers of patients were extracted from all studies and relative risks (RR) for achieving remission with 95% confidence intervals (95%CI) per study were calculated. Subgroup analyses were performed for different definitions of remission, the use of a b/tsDMARD as part of the induction therapy strategy (yes/no) and the use of concomitant GC bridging therapy (yes/no) in standard DMARD strategies. Results Included were 22 clinical studies, involving 4435 patients in induction strategies and 3314 in standard DMARD strategies. For remission, 17 studies applied the criterion of DAS28 In the figure we provide results for studies applying the DAS28 remission definition. Of those studies, 13/17 (76%) showed a statistically significant effect in favour of induction therapy. The pooled RR of achieving remission for strategies initiating bDMARDs was 1.73 [95%CI 1.59 to 1.88] versus the standard DMARD strategy without GC bridging, and it was 1.20 [95%CI 1.03 to 1.40] for induction strategies without bDMARD versus standard DMARD strategies without GC bridging. No superior effect of any induction strategy was found compared to that of standard DMARD strategies with GC bridging (pooled RR 1.06, 95%CI 0.83 to 1.35). When using other remission definitions, all induction strategy studies with Boolean/CDAI/SDAI outcomes applied a b/tsDMARD, and 63%, 100% and 78%, respectively found a statistically significantly superior effect compared to standard DMARD strategies without GC bridging; however, compared to standard DMARD strategies with GC bridging, only trends in the same direction were found. Conclusion Induction therapy strategies initiated in early RA patients are more effective in achieving remission compared to standard DMARD strategies. However, their benefit compared to that of a standard DMARD strategy with GC bridging seems to be limited. References [1] Felson DT, et al. Arthritis Res Ther. 2011;63;573-586 Disclosure of Interests Maxime Verhoeven: None declared, Paco Welsing: None declared, Johannes WJ 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 & Dohme, Pfizer, and UCB University Medical Center Utrecht, Utrecht University, Consultant for: SUN Pharma, Speakers bureau: Lilly, Roche, Jacob M. van Laar Grant/research support from: Genentech, Consultant for: F. Hoffmann-La Roche, Floris Lafeber Shareholder of: ArthroSave, Grant/research support from: FOREUM; Dutch Arthritis Society, Janneke Tekstra: None declared, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche

Background Several studies have shown that treatment with tocilizumab (TCZ) may reduce radiograph progression compared to treatment with methotrexate (MTX) in rheumatoid arthritis (RA). However, individual studies were not powered to detect differences in the incidence of progression. By combining several studies, a more precise estimate can be obtained. Furthermore, by using individual patient data (IPD), outcome definitions and methods can be harmonized for a valid combined analysis. Objectives To determine the effectiveness of treatment with TCZ on radiographic progression compared to MTX in RA patients over two years. Methods Randomized controlled trials in RA patients using TCZ as one of the treatment arms with radiographic damage assessed on radiographs at baseline and after two years were identified and IPD obtained. The primary endpoint was defined as any radiographic progression over two years. Secondary endpoint was the amount of joint damage progression (points per time unit, expressed as incidence rate). Analyses were performed on total scores and for erosions and joint space narrowing (JSN) separately. TCZ strategies were compared with the control strategies. Within the TCZ strategies, a comparison between monotherapy and the combination with MTX was made. A two-step IPD meta-analysis was performed. In the first step, data of the individual trials were analysed using logistic regression and zero-inflated Poisson models. In the second step association measures (odds ratio’s (OR) and incidence rate ratio’s (IRR)) of individual trials were pooled using random effect models in Review Manager1. A subgroup analysis was performed on early versus established RA. All analyses were adjusted for baseline DAS28 and Sharp van der Heijde (SvdH) score to provide a more precise treatment effect estimate. Results Five trials were identified, one trial2 using a tight-control treat-to-target approach, and the four other RCTs3-6 allowed the control group to start TCZ after 6 months or 1 year when the treatment target was not reached. Two trials were performed in early RA1–2. The dose of TCZ was tapered down in two studies2,6. IPD of 4 trials could be obtained and were included (n=2439 randomized to TCZ arm and n=791 to control arm, MTX in all cases)2–5. The radiographs, performed at baseline and after two years, were all assessed with the SvdH method. Due to missing radiographic data, 1766 patients were evaluated in the TCZ arms and 543 patients in MTX arms. Patient characteristics are shown in Table 1. The occurrence of any radiographic progression was statically significantly less in the TCZ arms compared to MTX arms (pooled OR 0.76 [95%CI 0.67 to 0.86]). The effect for erosions (OR 0.77 [95%CI 0.67 to 0.88]) was stronger than for JSN (OR 0.88 [95%CI 0.78 to 0.98]) with both being in favour of TCZ. No clear differences between early and established RA were observed for any progression. Any radiographic progression did not occur statistically significantly more often in the TCZ monotherapy group compared to the combination group. No statistically significant difference were observed for the amount of radiographic progression. Conclusion Based on this individual patient data meta-analysis, radiographic progression was less common in TCZ-treated patients compared to MTX-treated patients in RCTs, possibly more for progression of erosions. No difference was observed between TCZ used as monotherapy or in combination with MTX. Reference [1] Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Disclosure of Interests Maxime Verhoeven: None declared, Janneke Tekstra: None declared, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche, Jacob M. van Laar Grant/research support from: Genentech, Consultant for: F. Hoffmann-La Roche, Johannes WJ 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 & Dohme, Pfizer, and UCB University Medical Center Utrecht, Utrecht University, Consultant for: SUN Pharma, Speakers bureau: Lilly, Roche, Attila Pethoe-Schramm Shareholder of: F. Hoffmann-La Roche, Employee of: F. Hoffmann-La Roche, Michelle Borm Employee of: An employee of Roche Nederland BV, Floris Lafeber Shareholder of: ArthroSave, Grant/research support from: FOREUM; Dutch Arthritis Society, Paco Welsing: None declared

Background: The latest diagnostic technique to visualize monosodium uric acid (MSU) depositions is Dual Energy CT scan (DECT).1 Objectives: To assess the additive value and accuracy of DECT in diagnosing gout in a prospective study in subjects with unclassified arthritis. Methods: We included 100 consecutive patients with acute unclassified mono or oligo arthritis who presented to the outpatient clinic of the Department of Rheumatology of Meander Medical Centre, Amersfoort, the Netherlands, ClinicalTrials.gov NCT03038386. Eleven patients dropped out, see Figure. Patients underwent aspiration of the arthritic joint (see Table) and a DECT scan of hands and wrists, knees, ankles and feet bilaterally. The 2015 EULAR/ACR gout classification criteria were used to score the subjects, with and without DECT result, to determine the additive value of DECT. Sensitivity and specificity of DECT for diagnosing gout were calculated separately for at the joint and at individual persons’ level, using as reference standards microscopy of synovial fluid (SF) and the gout classification criteria. Results: For demographic and clinical characteristics of the patients see Table 1, and for study data and outcomes see Figure and Table 2. Sixty-eight of 89 patients (76.4%) fulfilled the 2015 EULAR/ACR criteria for gout. Of the 98 patients with SF aspiration, 55 (56%) were positive for MSU; of these, 89 subjects underwent DECT, of whom 38 had a negative microscopy result. Of these 38 subjects, 14 (37%) met the gout classification criteria only after a positive DECT result. Conclusion: Our findings suggested that DECT could have an additive value to clinical algorithms in subjects with undifferentiated arthritis when microscopy of SF fails to demonstrate the presence of MSU crystals. References: [1] Choi HK, et al. Dual energy CT in gout: a prospectieve validation study. Ann Rheum Dis2012; 71:1466-71. Disclosure of Interests: Mihaela Gamala: None declared, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche, Suzanne Linn-Rasker: None declared, Maarten Nix: None declared, Ben Heggelman: None declared, Pieternel Pasker: None declared, Jacob M. van Laar Grant/research support from: Genentech, Consultant for: F. Hoffmann-La Roche, Ruth Klaasen: None declared

Background Predictive markers of treatment response in rheumatoid arthritis (RA) are necessary to stratify patients to devise personalised treatment strategies. The U-Act-Early trial [1], in which disease-modifying antirheumatic drugs (DMARD) naive early RA patients initiated either methotrexate (MTX) or tocilizumab (TCZ) in monotherapy or in combination, offers a unique opportunity to assess the capacity of many baseline –omics markers (i.e. genomics, transcriptomics, proteomics, metabolomics, auto-antibodies) to predict clinical outcomes. Objectives To identify predictive markers of treatment response by developing a statistical machine learning methodology for correlating baseline clinical and –omics variables with clinical response data over time. Methods We developed a multi-omics approach that combines longitudinal statistical modelling of clinical data with Bayesian machine learning variable selection to identify the most predictive markers of treatment response. The time course of clinical outcomes was fit using a non-linear mixed longitudinal model, that characterise each patient of the U-Act-Early trial (n=317) by three parameters: a baseline value, an asymptotic value and a velocity (describing the speed at which the asymptote is reached). Supervised machine learning methods (such as Bayesian sparse regression as well as tree-based algorithms) were subsequently employed to find predictive markers for each of the longitudinal model parameters. We specifically focused on 85 auto-inflammatory proteins and 450 auto-antibodies markers, including 41 citrullinated-peptides antigens. The analysis was repeated for the three treatment-arms since DAS28-subscores response markers may vary across treatment strategies and clinical outcomes. We finally investigated whether predictions are enhanced by incorporating known networks of protein-protein interactions, rather than considering the predictive power of each protein independently. Results Preliminary results are that some proteins (e.g. sCD14, VEGF) were moderately predictive of the disease status at baseline. Specifically, the available inflammatory proteins predicted baseline DAS28, swollen and tender joints and ESR with R2 values of 0.25, 0.32, 0.16 and 0 respectively. Surprisingly, these proteins did not improve the prediction of treatment-response (i.e. the velocity and asymptotic parameters) after controlling for the baseline disease status. Protein networks marginally improved prediction when compared to prediction of individual proteins. Citrullinated peptide antigens did not appear predictive of the baseline disease status nor the treatment response. Conclusion In our initial investigation inflammatory proteins, especially when considered as part of interaction networks, appear to be predictive of the baseline status of the disease but not of treatment-response. The most predictive marker of treatment response appears to be disease activity at baseline. References [1] Bijlsma JWJ, et al. Lancet. 2016;388:343-55. Acknowledgement This study was funded by F. Hoffmann-LaRoche Disclosure of Interests Francesco Brizzi Employee of: F. Hoffmann-La Roche, Suleiman A. Khan: None declared, Marco Prunotto Employee of: F. Hoffmann-La Roche, Jenny Devenport Employee of: F. Hoffmann-La Roche, Attila Pethoe-Schramm Shareholder of: F. Hoffmann-La Roche, Employee of: F. Hoffmann-La Roche, Michelle Borm Employee of: An employee of Roche Nederland BV, Johannes WJ 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 & Dohme, Pfizer, and UCB University Medical Center Utrecht, Utrecht University, Consultant for: SUN Pharma, Speakers bureau: Lilly, Roche, Johannes W. G. Jacobs Grant/research support from: Roche, Consultant for: Roche, Floris Lafeber Shareholder of: ArthroSave, Grant/research support from: FOREUM; Dutch Arthritis Society, Paco Welsing: None declared, Tero Aittokallio: None declared, Antoine Soubret Employee of: F. Hoffmann-La Roche

An array of new and expensive drugs recently entered the market for psoriatic arthritis (PsA), and several soon will follow, joining the already rich armamentarium [1,2]. As a consequence, clinicia...

Purpose of review This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. Recent findings In early rheumatoid arthritis, treatment regimens with a disease-modifying drug and initially medium-dose glucocorticoids (>7.5 but ≤30 mg prednisone equivalent) are noninferior compared with regimens with disease-modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. Summary Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium-dose glucocorticoids are noninferior compared with regimens with initially high-dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing.

Objective This study aimed to assess the utility of dual energy CT (DECT) for diagnosing gout. Methods A systematic literature search was performed in PubMed, EMBASE and Cochrane Library. Studies evaluating the utility of DECT for diagnosing gout were included. Reference standards were detection of monosodium urate crystals at SF assessment or a validated set of criteria. The methodological quality of studies was evaluated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 criteria. Data from person-based and joint-/localization-based evaluations were pooled separately, and subgroup analyses for disease stage/duration and reference standard were performed. Results Ten studies were included; in person-based evaluations, the pooled (95% CI) sensitivity and specificity were 0.81 (0.77, 0.86) and 0.91 (0.85, 0.95), respectively. In joint-based evaluations, they were 0.83 (0.79, 0.86) and 0.88 (0.83, 0.92), respectively. At short disease duration (⩽6 weeks), the pooled (95% CI) sensitivity and specificity at the joint level were 0.55 (0.46, 0.64) and 0.89 (0.84, 0.94), respectively. Conclusion DECT has a high diagnostic accuracy in established gout, but its diagnostic sensitivity is low in subjects with recent onset gout.

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

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.