Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD): A Report of an International Research Collaboration Network.

Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.

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.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To 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. METHODS: Data 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. RESULTS: No 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. CONCLUSION: No 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.

Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials.

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.

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

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

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.

Explorative analyses of protein biomarkers in patients with early rheumatoid arthritis achieving sustained drug-free remission after treatment with tocilizumab- or methotrexate-based strategies: from transcriptomics to proteomics.

OBJECTIVES: Previously, we identified networks of co-expressed genes related to achieving sustained drug-free remission (sDFR). The aim of the present exploratory analysis was to identify inflammatory proteins associated with achieving sDFR and their enriched biological pathways, and compare these pathways with those found in the previous transcriptomic analyses. METHODS: Serum samples were used from 60 patients who participated in the U-Act-Early trial and were treated-to-target with tocilizumab plus methotrexate, or tocilizumab or methotrexate; 37 achieved sDFR (≥3 months drug-free) and 23 did not (controls). Luminex® multi-analyte profiling (xMAP)® was used to measure 85 proteins. Partial least square discriminant analyses (PLSDA) identified proteins associated with achieving sDFR within each strategy arm, which were thereafter used for pathway analyses. RESULTS: PLSDA identified 9, 14 and 13 relevant proteins in the tocilizumab plus methotrexate, tocilizumab and methotrexate arm, respectively and pathway analyses thereafter identified respectively 49, 88 and 117 significantly enriched gene ontology (GO) terms. When comparing these terms with those previously found in the transcriptomic analyses, corresponding pathways were related in the tocilizumab arm to activity of leukocytes; in the methotrexate arm to response of stimuli and regulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. In the tocilizumab plus methotrexate arm, no corresponding enriched pathways were found. CONCLUSIONS: Multiple proteins were associated with achieving sDFR and several biological pathways corresponded, mainly in the methotrexate arm, with our previous transcriptomic findings potentially providing further insights into gene expression and protein translation in newly diagnosed RA patients.

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

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

Patient-reported outcomes in newly diagnosed early rheumatoid arthritis patients treated to target with a tocilizumab- or methotrexate-based strategy.

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

Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy.

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

Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials.

BACKGROUND: Previous studies in patients with rheumatoid arthritis (RA) have shown that switching to tocilizumab (TCZ) monotherapy (TCZMONO) or combination therapy (TCZCOMBI) with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) is efficacious in reducing disease activity in patients with inadequate response to csDMARDs. However, hitherto there is no consensus on whether TCZMONO is as effective as TCZCOMBI. The objective of this study was therefore to evaluate the efficacy and safety of TCZMONO versus add-on TCZCOMBI and both TCZ therapies versus continuing the current csDMARD therapy, by performing a systematic review and meta-analyses. METHOD: The MEDLINE, EMBASE and CENTRAL databases were searched until February 2016 for relevant randomized controlled trials (RCTs). We performed meta-analyses of Disease Activity Score in 28 joints (DAS28 < 2.6), American College of Rheumatology (ACR) 20/50/70 responses, adverse events (AEs) and serious AEs (SAEs) to compare the three different strategies, whereas a random-effect model was used for pooling relative risks (RR) and 95 % confidence intervals (CI). In addition, sensitivity analyses were performed for evaluating differences in study duration. RESULTS: In total, 13 RCTs were included in the meta-analysis, involving 6679 patients. When comparing both TCZ strategies, a marginally greater proportion of patients achieving DAS28 < 2.6 (RR 1.21; 95 % CI 1.09, 1.36) and ACR50 response (RR 1.14; 95 % CI 1.03, 1.26) was found in favor of the TCZCOMBI strategy. However, the risk of SAEs was also significantly higher using this strategy (RR 1.40; 95 % CI 1.03, 1.92, p = 0.03). Pooled effect estimates showed statistical superiority of switching to either TCZ strategy compared to continuing csDMARD therapy. CONCLUSIONS: In the management of active RA, almost similar efficacy can be expected in patients unable to tolerate csDMARDs, who switch to TCZMONO compared to inadequate responders switching to add-on TCZCOMBI. Although TCZCOMBI is marginally superior to TCZMONO in achieving DAS28 < 2.6 and ACR50 response, this is at the cost of an increased risk of SAEs.

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.

Impact of Patient Sex on Clinical Outcomes: Data From an Anterior Cruciate Ligament Reconstruction Registry, 2008-2013.

BACKGROUND: The Combined Quality Care Anterior Cruciate Ligament registry provides data for clinical research regarding primary anterior cruciate ligament (ACL) surgery. PURPOSE: To explore the data with regard to the clinical outcomes between sexes after ACL reconstruction in a Dutch population. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data involving patients diagnosed with an ACL tear and eligible for surgery were recorded. Isokinetic muscle strength, functional muscle performance, and anterior-posterior translation of the knee joint were documented preoperatively and at 3, 6, 9, and 12 months postoperatively. Patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm, and Tegner rating scales during each examination using a web-based questionnaire. RESULTS: Approximately 90% of ACL injuries occurred during sport activities. The mean (SD) age at surgery was 28 (11) years for both men and women, and the majority of patients were treated with hamstring tendon autografts (94%). Four percent received bone-patellar tendon-bone autografts, and 2% of the patients received other grafts. Preoperatively, the KOOS, Lysholm, and Tegner scores were significantly higher in males. Twelve months postoperatively, both sexes showed comparable isokinetic strength (P = .336), knee laxity (P = .680), and hop test for distance (P = .122) when comparing the injured with the uninjured side. Self-reported knee function was comparable between sexes as assessed by the KOOS (P = .202), Lysholm (P = .872), and Tegner (P = .767) questionnaires during the 12-month follow-up. CONCLUSION: One year after ACL surgery, all patients had improved greatly, showing only minor differences between sexes. The male group showed slightly better results when evaluating self-reported knee questionnaires. Comparable outcomes and knee function between sexes can therefore be presumed with patients who are treated with hamstring tendon autografts in a Dutch population. CLINICAL RELEVANCE: These results can be used during the clinical evaluation of patients who are eligible for ACL reconstruction.

Prevalence of modic changes in active duty military men with lumbar disk herniation who were scheduled for surgery.

OBJECTIVE: The purpose of this study was to report on the prevalence of Modic changes (MCs) in a group of Netherlands military men who were scheduled for surgery (lumbar discectomy). METHODS: This was a retrospective observational study of health records. From 133 patients in active military service seen from January 2004 to March, 77 case files were selected. For all subjects who met inclusion criteria, the health records and T1- and T2-weighted magnetic resonance imaging files of lumbar levels L4/L5 and L5-S1 were assessed. Data including age, sex, rank in military, level of lumbar herniation, and level of MC including their types were evaluated. RESULTS: Nineteen subjects (24.7%) showed presence of MC at the level of disk herniation, 5 subjects (6.5%) showed MC at a different level, and 10 subjects (13%) showed MC at both levels. In total, 154 segments were analyzed on magnetic resonance imaging for present MC of which 44 levels (28.6%) showed MC type I (31.8%), type II (65.9%), or type III (2.3%). Higher age showed to be significant (P ≤ .001) on developing MC, but no significance was found for physical workload in relation to these changes. CONCLUSIONS: For the subjects in this study, MCs were most common at the lower lumbar spine segments, with a predominance of type II. In this study, the presence of a disk herniation and MC at the same level was 37.7%; however, a significant association was not demonstrable.