Comprehensive exploratory autoantibody profiling in patients with early rheumatoid arthritis treated with methotrexate or tocilizumab.

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.

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis.

OBJECTIVES: To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). METHODS: A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. RESULTS: 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. CONCLUSION: This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.

OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

Is prediction of clinical response to methotrexate in individual rheumatoid arthritis patients possible? A systematic literature review.

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.

International Consortium for Health Outcome Measurement Set of Outcomes That Matter to People Living With Inflammatory Arthritis: Consensus From an International Working Group.

OBJECTIVE: The implementation of value-based health care in inflammatory arthritis requires a standardized set of modifiable outcomes and risk-adjustment variables that is feasible to implement worldwide. METHODS: The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary working group that consisted of 24 experts from 6 continents, including 6 patient representatives, to develop a standard set of outcomes for inflammatory arthritis. The process followed a structured approach, using a modified Delphi process to reach consensus on the following decision areas: conditions covered by the set, outcome domains, outcome measures, and risk-adjustment variables. Consensus in areas 2 to 4 were supported by systematic literature reviews and consultation of experts. RESULTS: The ICHOM Inflammatory Arthritis Standard Set covers patients with rheumatoid arthritis (RA), axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA). We recommend that outcomes regarding pain, fatigue, activity limitations, overall physical and mental health impact, work/school/housework ability and productivity, disease activity, and serious adverse events be collected at least annually. Validated measures for patient-reported outcomes were endorsed and linked to common reporting metrics. Age, sex at birth, education level, smoking status, comorbidities, time since diagnosis, and rheumatoid factor and anti-citrullinated protein antibody lab testing for RA and JIA should be collected as risk-adjustment variables. CONCLUSION: We present the ICHOM inflammatory arthritis Standard Set of outcomes, which enables health care providers to implement the value-based health care framework and compare outcomes that are important to patients with inflammatory arthritis.

RNA sequencing to predict response to TNF-α inhibitors reveals possible mechanism for nonresponse in smokers.

BACKGROUND: Several studies have employed microarray-based profiling to predict response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid arthritis (RA); yet efforts to validate these targets have failed to show predictive abilities acceptable for clinical practice. METHODS: The eighty most extreme responders and nonresponders to TNFi therapy were selected from the observational BiOCURA cohort. RNA sequencing was performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected before initiation of treatment. The expression of pathways as well as individual gene transcripts between responders and nonresponders was investigated. Promising targets were technically replicated and validated in n = 40 new patients using qPCR assays. RESULTS: Before therapy initiation, nonresponders had lower expression of pathways related to interferon and cytokine signaling, while also showing higher levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be validated, however, additional analyses revealed that GPR15 and SEMA6B did not independently predict response, but were rather dose-dependent markers of smoking (p < 0.0001). CONCLUSIONS: The study did not identify new transcripts ready to use in clinical practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers for the reduced treatment success in RA smokers.

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.

Managing rheumatic and musculoskeletal diseases - past, present and future.

Progress in rheumatology has been remarkable in the past 70 years, favourably affecting quality of life for people with rheumatic and musculoskeletal diseases. Therapeutics have advanced considerably in this period, from early developments such as the introduction of glucocorticoid therapy to the general use of methotrexate and other disease-modifying agents, followed by the advent of biologic DMARDs and, most recently, small-molecule signalling inhibitors. Novel strategies for the use of such agents have also transformed outcomes, as have multidisciplinary nonpharmacological approaches to the management of rheumatic musculoskeletal disease including surgery, physical therapy and occupational therapy. Breakthroughs in our understanding of disease pathogenesis, diagnostics and the use of 'big data' continue to drive the field forward. Critically, the patient is now at the centre of management strategies as well as the future research agenda.

Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis.

OBJECTIVES: To develop a Glucocorticoid Toxicity Index (GTI) to assess glucocorticoid (GC)-related morbidity and GC-sparing ability of other therapies. METHODS: Nineteen experts on GC use and outcome measures from 11 subspecialties participated. Ten experts were from the USA; nine from Canada, Europe or Australia. Group consensus methods and multicriteria decision analysis (MCDA) were used. A Composite GTI and Specific List comprise the overall GTI. The Composite GTI reflects toxicity likely to change during a clinical trial. The Composite GTI toxicities occur commonly, vary with GC exposure, and are weighted and scored. Relative weights for items in the Composite GTI were derived by group consensus and MCDA. The Specific List is designed to capture GC toxicity not included in the Composite GTI. The Composite GTI was evaluated by application to paper cases by the investigators and an external group of 17 subspecialists. RESULTS: Thirty-one toxicity items were included in the Composite GTI and 23 in the Specific List. Composite GTI evaluation showed high inter-rater agreement (investigators κ 0.88, external raters κ 0.90). To assess the degree to which the Composite GTI corresponds to expert clinical judgement, participants ranked 15 cases by clinical judgement in order of highest to lowest GC toxicity. Expert rankings were then compared with case ranking by the Composite GTI, yielding excellent agreement (investigators weighted κ 0.87, external raters weighted κ 0.77). CONCLUSIONS: We describe the development and initial evaluation of a comprehensive instrument for the assessment of GC toxicity.

Necessity of TNF-alpha inhibitor discontinuation in rheumatoid arthritis is predicted by smoking and number of previously used biological DMARDs.

OBJECTIVES: Despite the success of TNF-alpha inhibitor (TNFi) treatment in rheumatoid arthritis (RA), a substantial number of patients necessitate discontinuation. Prediction thereof would be clinically relevant and guide the decision whether to start TNFi treatment. METHODS: Data were used from the observational BiOCURA cohort, in which patients initiating biological treatment were enrolled and followed up for one year. In the model development cohort (n=192), a model predicting TNFi discontinuation was built using Cox-regression with backward selection (p<0.05). The parameters of the model were tested again in a model refinement cohort (n=60), for significance (p<0.05) and consistency of effect. In addition, we performed a systematic review to put our study results into perspective. RESULTS: Of the 252 patients who initiated TNFi treatment, 103 (41%) had to discontinue treatment. Discontinuation was predicted at baseline by female gender, current smoking, high visual analogue scale of general health, and higher number of previously used biological disease-modifying anti-rheumatic drugs (bDMARDs). At refinement, smoking status and number of previously used bDMARDs remained with re-estimated hazard ratios (HRs) in the total cohort of 1.74 (95%-CI 1.15-2.63, p<0.01) and 1.40 (95%-CI 1.1-1.68, p<0.01), respectively. Using these two predictors, we developed a simple score predicting discontinuation (PPV=72.3%). From literature, predictors were pack years of smoking, number of previously used bDMARDs, lack of any concomitant DMARD therapy and in particular lack of concomitant methotrexate (MTX). CONCLUSIONS: TNFi discontinuation is predicted by current smoking and number of previously used bDMARDs, as well as by pack years of smoking and lack of any concomitant DMARD/MTX therapy.

Exploring the Inflammatory Metabolomic Profile to Predict Response to TNF-α Inhibitors in Rheumatoid Arthritis.

In clinical practice, approximately one-third of patients with rheumatoid arthritis (RA) respond insufficiently to TNF-α inhibitors (TNFis). The aim of the study was to explore the use of a metabolomics to identify predictors for the outcome of TNFi therapy, and study the metabolomic fingerprint in active RA irrespective of patients' response. In the metabolomic profiling, lipids, oxylipins, and amines were measured in serum samples of RA patients from the observational BiOCURA cohort, before start of biological treatment. Multivariable logistic regression models were established to identify predictors for good- and non-response in patients receiving TNFi (n = 124). The added value of metabolites over prediction using clinical parameters only was determined by comparing the area under receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, positive- and negative predictive value and by the net reclassification index (NRI). The models were further validated by 10-fold cross validation and tested on the complete TNFi treatment cohort including moderate responders. Additionally, metabolites were identified that cross-sectionally associated with the RA disease activity score based on a 28-joint count (DAS28), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Out of 139 metabolites, the best-performing predictors were sn1-LPC(18:3-ω3/ω6), sn1-LPC(15:0), ethanolamine, and lysine. The model that combined the selected metabolites with clinical parameters showed a significant larger AUC-ROC than that of the model containing only clinical parameters (p = 0.01). The combined model was able to discriminate good- and non-responders with good accuracy and to reclassify non-responders with an improvement of 30% (total NRI = 0.23) and showed a prediction error of 0.27. For the complete TNFi cohort, the NRI was 0.22. In addition, 88 metabolites were associated with DAS28, ESR or CRP (p<0.05). Our study established an accurate prediction model for response to TNFi therapy, containing metabolites and clinical parameters. Associations between metabolites and disease activity may help elucidate additional pathologic mechanisms behind RA.

Can baseline serum microRNAs predict response to TNF-alpha inhibitors in rheumatoid arthritis?

BACKGROUND: In rheumatoid arthritis, prediction of response to TNF-alpha inhibitor (TNFi) treatment would be of clinical value. This study aims to discover miRNAs that predict response and aims to replicate results of two previous studies addressing this topic. METHODS: From the observational BiOCURA cohort, 40 adalimumab- (ADA) and 40 etanercept- (ETN) treated patients were selected to enter the discovery cohort and baseline serum profiling on 758 miRNAs was performed. The added value of univariately selected miRNAs (p < 0.05) over clinical parameters in prediction of response was determined by means of the area under the receiver operating characteristic curve (AUC-ROC). Validation was performed by TaqMan single qPCR assays in 40 new patients. RESULTS: Expression of miR-99a and miR-143 predicted response to ADA, and miR-23a and miR-197 predicted response to ETN. The addition of miRNAs increased the AUC-ROC of a model containing only clinical parameters for ADA (0.75 to 0.97) and ETN (0.68 to 0.78). In validation, none of the selected miRNAs significantly predicted response. miR-23a was the only overlapping miRNA compared to the two previous studies, however inversely related with response in one of these studies. The reasons for the inability to replicate previously proposed miRNAs predicting response to TNFi and replicate those from the discovery cohort were investigated and discussed. CONCLUSIONS: To date, no miRNA consistently predicting response to TNFi therapy in RA has been identified. Future studies on this topic should meet a minimum of standards in design that are addressed in this study, in order to increase the reproducibility.

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.

Does disease activity add to functional disability in estimation of utility for rheumatoid arthritis patients on biologic treatment?

OBJECTIVE: Treatment in general is mostly directly aimed at disease activity, and measures such as the DAS28 might therefore present important additional information. Our aim was to develop and validate a model that uses a combination of disease activity (DAS28) and HAQs to estimate EuroQoL 5-dimension scale (EQ5D) utilities. METHODS: Longitudinal data from a cohort study in RA patients from the Utrecht Rheumatoid Arthritis Cohort study Group (Stichting Reumaonderzoek Utrecht) who started treatment with a biologic drug were used for mapping and validation. All 702 observations, including DAS28, HAQ and EQ5D assessed at the same time points, were used. The observations were randomly divided into a subset for development of the model (n = 428 observations) and a subset for validation (n = 274). A stepwise multivariable regression analysis was used to test the association of DAS28 (components) and HAQ (domains) with EQ5D. Model performance was assessed using the explained variance (R(2)) and root mean square errors. Observed and predicted utility scores were compared to check for under- or overestimation of the scores. Finally, the performance of the model was compared with published mapping models. RESULTS: Lower DAS28 score and HAQ items dressing and grooming, arising, eating, walking and activities were associated with higher EQ5D scores. The final model had an explained variance of 0.35 and a lower root mean square error as compared with other models tested. The agreement between predicted and observed scores was fair. CONCLUSION: HAQ components estimate EQ5D better than total HAQ. Adding DAS28 to HAQ components does not result in better utility estimations.

Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability.

OBJECTIVES: To review studies that address prediction of response to biologic treatment in RA and to explore the clinical utility of the studied (bio)markers. METHODS: A search for relevant articles was performed in PubMed, Embase and Cochrane databases. Studies that presented predictive values or in which these could be calculated were selected. The added value was determined by the added value on prior probability for each (bio)marker. Only an increase/decrease in chance of response ⩾15% was considered clinically relevant, whereas in oncology values >25% are common. RESULTS: Of the 57 eligible studies, 14 (bio)markers were studied in more than one cohort and an overview of the added predictive value of each marker is presented. Of the replicated predictors, none consistently showed an increase/decrease in probability of response ⩾15%. However, positivity of RF and ACPA in case of rituximab and the presence of the TNF-α promoter 308 GG genotype for TNF inhibitor therapy were consistently predictive, yet low in added predictive value. Besides these, 65 (bio)markers studied once showed remarkably high (but not validated) predictive values. CONCLUSION: We were unable to address clinically useful baseline (bio)markers for use in individually tailored treatment. Some predictors are consistently predictive, yet low in added predictive value, while several others are promising but await replication. The challenge now is to design studies to validate all explored and promising findings individually and in combination to make these (bio)markers relevant to clinical practice.

Ultrasonographic predictors for clinical and radiological progression in knee osteoarthritis after 2 years of follow-up.

OBJECTIVE: The aim of this study was to investigate the association between a set of US features and radiographic and clinical progression of knee OA after 2 years of follow-up. METHODS: A total of 125 patients fulfilling ACR clinical criteria for knee OA underwent US examination of the most symptomatic knee. The US protocol included assessment of synovial hypertrophy, joint effusion, infrapatellar bursitis, Baker's cyst, medial meniscus protrusion and cartilage thickness. Clinical progression was defined using the inverse Osteoarthritis Research Society International responder criteria or progression to total knee replacement. Radiological progression was defined as a ≥2 point increase in Altman score or progression to total knee replacement. Regression analyses were performed with baseline ultrasonographic features as independent variables and progression (two separate models for clinical progression and radiographic progression) as the dependent variable. RESULTS: A total of 31 (25%) patients fulfilled the criteria of clinical progression and 60 (48%) patients fulfilled the criteria of radiological progression. The presence of Baker's cyst showed a statistically significant association with clinical [odds ratio (OR) 3.07 (95% CI 1.21, 7.78)] as well as radiological [OR 2.84 (95% CI 1.17, 6.90)] progression. Synovial hypertrophy showed a weaker but consistent association with clinical as well as radiological progression [OR 2.11 (95% CI 0.80, 5.57)]. CONCLUSION: We demonstrated a longitudinal association between Baker's cyst (and to a lesser extent synovial hypertrophy) at baseline and radiological and clinical progression after 2 years.

Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.

OBJECTIVE: To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. DESIGN: Randomised controlled, open label, non-inferiority strategy trial. SETTING: Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. PARTICIPANTS: 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. INTERVENTIONS: Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. MAIN OUTCOME MEASURES: Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. RESULTS: Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval -12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. CONCLUSIONS: A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.

Are ultrasonographic signs of inflammation predictors for response to intra-articular glucocorticoids in knee osteoarthritis?

OBJECTIVES: To investigate the predictive value of ultrasound (US) characteristics for the effect of intra-articular glucocorticoids in knee osteoarthritis (OA). METHODS: In this prospective cohort study, 62 patients with symptomatic knee OA (clinical knee OA criteria, pain>4 on a Numerical Rating Scale (NRS; 0-10)) received an intra-articular glucocorticoid injection (40 mg triamcinolone acetonide). Patients with NRS pain ≤4 at 4 weeks were defined as responders. On inclusion, demographics, clinical data (body mass index, local swelling) knee x-rays and knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire were collected. Six US features were assessed including: effusion, synovial hypertrophy, Baker's cyst, infrapatellar bursitis, meniscal protrusion and cartilage thickness. Stepwise multiple logistic regression analyses with forward selection were conducted to identify possible predictors. RESULTS: At 4 weeks, 42% of the study participants reached a NRS ≤4; an effect comparable to existing literature. Regression analyses showed that patients who used analgesics at baseline were less likely to have a good response. The small proportion of patients with infrapatellar bursitis was more likely to respond to the injection. CONCLUSIONS: No patient, disease or US characteristic of inflammation, turned out to be a reliable and clinically meaningful predictor for the effect of intra-articular glucocorticoids after four weeks in knee OA.

Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

BACKGROUND: Anti-tumor necrosis factor (TNF) agents are effective in treating patients with rheumatoid arthritis (RA), but they are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation or disease activity guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) on disease activity, functioning, costs, safety and radiographic damage compared with usual care in patients with RA and low disease activity. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 8, 2013; Ovid MEDLINE (1946 to 8 September 2013); EMBASE (1947 to 8 September 2013); Science Citation Index (Web of Science); and conference proceedings of the American College of Rheumatology (2005 to 2012) and European League against Rheumatism (2005 to 2013). We contacted authors of the seven included studies to ask for additional information on their study; five responded. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in patients with RA and a low disease activity state. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. MAIN RESULTS: Six RCTs and one CCT (total 1203 participants), reporting anti-TNF down-titration, were included. Three studies (559 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Five studies (732 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (two studies assessed both anti-TNF discontinuation and dose reduction), and one study assessed disease activity-guided anti-TNF dose tapering (137 participants). These studies include only adalimumab and etanercept; controlled data on other anti-TNF agents are absent. Two studies were available in full text; one was assessed as having low risk of bias and the other high risk. Five studies were available only as one or more abstracts. Because data provided in these abstracts were limited, risk of bias was unclear. Clinical heterogeneity between the trials was high.Dose reduction of anti-TNF (etanercept data only) showed no statistically significant or clinical relevant difference in disease activity score in 28 joints (DAS28) (mean difference (MD) 0.10, 95% confidence interval (CI) -0.11 to 0.31) (scale 0.9 to 8; higher score indicates worse disease activity). The proportion of participants who maintained low disease activity was slightly lower among participants given reduced doses of the anti-TNF agent (risk ratio (RR) 0.87, 95% CI 0.78 to 0.98, absolute risk difference (ARD) 9%). Radiographic outcome was slightly worse, but this was not clinically meaningful, compared with continuation of anti-TNF (MD 0.11, 95% CI 0.08 to 0.14) (scale 0 to 448; higher score indicates greater joint damage). Function was not statistically different between anti-TNF dose reduction and continuation (MD 0.10, 95% CI 0.00 to 0.20) (scale 0 to 3; higher score indicates worse functioning). Reinstalment of anti-TNF after failure of dose reduction showed a 5% risk of persistent flare. Data on numbers of serious adverse events (SAEs) (RR 0.58, 95% CI 0.23 to 1.45, ARD -2%) and withdrawals due to adverse events (AEs) (RR 0.57, 95% CI 0.17 to 1,92, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.Participants who discontinued anti-TNF (adalimumab and etanercept data) had higher mean DAS28 (DAS28-erythrocyte sedimentation rate (ESR): MD 1.10, 95% CI 0.86 to 1.34) and DAS28-C-reactive protein (CRP): MD 0.57 95% CI -0.09 to 1.23) and were less likely to maintain a low disease activity state (RR 0.43, 95% CI 0.27 to 0.68, ARD 40%). Also, radiographic and functional outcomes are worse after anti-TNF discontinuation (MD 0.66, 95% CI 0.63 to 0.69, and MD 0.30, 95% CI 0.19 to 0.41, respectively). Data on numbers of SAEs (RR 1.26, 95% CI 0.61 to 2.63, ARD 2%) and withdrawals due to AEs (RR 0.72, 95% CI 0.23 to 2.24, ARD -1%) were inconclusive. Most outcomes were based on moderate quality evidence.The one study comparing disease activity-guided anti-TNF dose tapering (adalimumab and etanercept data) reported no statistically significant differences in functional outcomes (MD 0.20, 95% CI -0.02 to 0.42). Significantly higher mean disease activity was found among participants with tapered anti-TNF at study end (MD 0.50, 95% CI 0.11 to 0.89). No full text of this trial was available for this review. No other major outcomes were reported. All outcomes were based on low quality evidence. AUTHORS' CONCLUSIONS: We can conclude, mostly based on moderate quality evidence, that non-disease activity guided dose reduction of etanercept 50 mg weekly to 25 mg weekly, after at least three to 12 months of low disease activity, seems as effective as continuing the standard dose with respect to disease activity and functional outcomes, although dose reduction significantly induces minimal and not clinically meaningful differences in radiological progression. Discontinuation (also without disease activity-guided adaptation) of adalimumab and etanercept is inferior to continuation of treatment with respect to disease activity and radiological outcomes and function. Disease activity-guided dose tapering of adalimumab and etanercept seems slightly inferior to continuation of treatment with respect to disease activity, with no difference in function. However the only study investigating this comparison included lower than projected numbers of participants.Caveats of this review are that available data are limited. Also, the heterogeneity between studies and the suboptimal design choices (including absence of disease activity-guided dose reduction and discontinuation and use of superiority designs) limit definitive conclusions. None of the included studies assessed long-term safety and costs, although these factors are specific reasons why clinicians consider lowering the dose or stopping the administration of anti-TNF agents.Future research should include other anti-TNF agents; assessment of disease activity, function and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness and predictors for successful down-titration. Also use of a validated flare criterion, non-inferiority designs and disease activity-guided instead of fixed-dose tapering or stopping would allow researchers to better interpret study findings and generalise the information to clinical practice.

Mortality in British hip fracture patients, 2000-2010: a population-based retrospective cohort study.

BACKGROUND: Data on recent trends in mortality after hip fracture are scarce. Aims were therefore to examine secular trends in all-cause and cause-specific mortality post hip fracture and to compare this to the general population from 2000 to 2010. METHODS: Population-based cohort study within the United Kingdom Clinical Practice Research Datalink and linked to cause of death data for 57.7% of patients. Patients with a first hip fracture (n=31,495) were matched to up to four controls by age, sex, index date, and practice. All subjects were followed for death, and lifestyle, disease and medication history adjusted hazard ratios (HRs) were calculated. RESULTS: One-year all-cause mortality after hip fracture declined from 2009 and was 14% lower after, compared with before 2009 (22.3% to 20.5%, adj. HR 0.86, 95% CI: 0.81-0.92). The decline was observed for males (≥75years) and females (≥85years). Significant contributors to the decline in mortality post hip fracture were respiratory infections in females as were malignant diseases in males. However, one-year all-cause mortality remained unaltered over the decade when compared to controls with a 3.5-fold and 2.4-fold increased risk in males and females respectively. No significant changes were observed in the relative risks for one-year cause-specific mortality for both genders. CONCLUSIONS: One-year mortality after hip fracture has declined over the last decade in the UK. However, the difference in one-year mortality between hip fracture patients and the general population remained unaltered. These observations highlight the need for the continued implementation of evidence-based standards for good hip fracture care.