Obesity Impacts Swelling of Ankle and Foot Joints in Early Rheumatoid Arthritis Patients.

OBJECTIVE: The evaluation of disease activity in obese rheumatoid arthritis (RA) patients presents challenges particularly in the clinical assessment of swollen joints. This study examines the effect of obesity on the American College of Rheumatology (ACR) core set measures used in assessing RA disease activity with specific focus on the swollen joint count (SJC). METHODS: We examined a cross-sectional cohort of 323 early seropositive RA patients (symptom duration ≤15 months). Patients were biologic-naive with equal to or more than 6/44 SJC and equal to or more than 9/44 tender joint count. The ACR core set measures, components of Disease Activity Score (DAS) 44/erythrocyte sedimentation rate (ESR), DAS28/ESR4 item, Clinical Disease Activity Index (CDAI), and body mass index (BMI) were collected. Disease activity measures were compared between BMI categories. Multivariable linear regression models assessed the relationship between high BMI (≥30 kg/m) and lower-extremity (LE) SJC and SJC44 while accounting for other ACR measures. RESULTS: Disease Activity Score 44/ESR4 item, Health Assessment Questionnaire Disability Index, physician global, and SJC44 differed across BMI categories (p < 0.05). Of the SJC44, metacarpophalangeal joints and LE joints (knees, ankles, metatarsophalangeal joints) were associated with increased swelling in all BMI groups (P < 0.05). Obesity was significantly associated with LE SJC after adjusting for ACR core set measures. CONCLUSIONS: There is a direct association between increased BMI and increased swelling of LE joints in RA patients. Increases in DAS44-measured disease activity are higher in obese RA patients because of increased LE swollen joints. Disease Activity Score 28 and Clinical Disease Activity Index, which emphasize upper-extremity joint assessment, are not significantly influenced by obesity.

Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial.

OBJECTIVE: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.

Examining radiographic outcomes over time.

Statistical analysis plays a critical role in data interpretation in all fields and particularly so for clinical data where important treatment decisions are made. We provide here an in-depth and illustrative analysis to examine patterns and radiographic scores in an early disease rheumatoid arthritis cohort over a 3-year follow-up period. The total Sharp radiographic scores were interpolated from the rates at 6 months, 1, 2, and 3 years and were transformed to count data after rounding. The generalized estimating equations approach and two-part models were applied to analyze the longitudinal radiographic scores using the clinical, demographic, and therapeutic characteristics of the patients after adjusting for the pattern outcomes. Total Sharp scores were modeled, assuming that they were Poisson distributed or had a negative binomial distribution with either an AR(1) working correlation matrix or an exchangeable working correlation matrix. To account for the excessive zero counts, we used two-part models that include the zero-inflated Poisson and the zero-inflated negative binomial to fit the data. This is an innovation because two-part models have not been used in rheumatology even though they are highly appropriate for analyzing data from rheumatic studies. In addition, we analyzed data using generalized estimating equations and compared results from different models using formal statistical goodness-of-fit criteria and arrive at the best model for predicting purposes.

Older age at rheumatoid arthritis onset and comorbidities correlate with less Health Assessment Questionnaire-Disability Index and Clinical Disease Activity Index response to etanercept in the RADIUS 2 registry.

BACKGROUND: Controversy exists in understanding the effects of age at onset and comorbidities in predicting rheumatoid arthritis (RA) response to biologic therapy. OBJECTIVE: The objective of this study was to investigate the influence of age at onset and number of comorbidities on Health Assessment Questionnaire-Disability Index (HAQ-DI) and Clinical Disease Activity Index (CDAI) responses in active RA patients after 6 months of treatment with etanercept. METHODS: One thousand eight hundred ninety-nine RA patients were assessed after 6 months of etanercept therapy. Patients met the following inclusion criteria: initiated etanercept, continued therapy for at least 6 months, and were not in CDAI low disease activity (LDA) at baseline (CDAI ≤10.0). Changes in HAQ-DI and CDAI scores over 6 months were analyzed across age of onset quintiles. Multivariate regression models evaluated the independent association between both age at onset and number of comorbidities with change in HAQ-DI/CDAI scores or achieving LDA, while accounting for other covariates. RESULTS: Significant improvements in HAQ-DI and CDAI scores were observed in all age-onset groups, although HAQ-DI improvements were less in older-onset patients. Results of multiple linear regression demonstrated that younger age at onset, higher baseline HAQ-DI/CDAI score, rheumatoid factor positivity, shorter disease duration, and fewer comorbidities at baseline were independently associated with improvement in both HAQ-DI and CDAI scores. Similarly, achieving CDAI LDA after 6 or more months of etanercept was associated with younger age at onset, higher baseline CDAI, shorter disease duration, and fewer comorbidities. CONCLUSIONS: These patients with older-onset RA and more comorbidities clinically improved with etanercept, but had lower odds of achieving CDAI LDA. Age of onset and number of comorbidities may be important in determining RA tumor necrosis factor inhibitor response.

Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy ≥ 3 months, CDAI ≥ 2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no). RESULTS: Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001). CONCLUSION: In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat-to-target recommendations and aid in understanding achievable RA therapeutic goals.

A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial.

OBJECTIVE: To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥ 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. METHODS: The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥ 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. RESULTS: At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047). CONCLUSION: There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy.

Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis.

OBJECTIVES: Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls. METHODS: HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDL's antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay. RESULTS: Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2% ± 11.1%) and controls (39.5% ± 8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=-0.39, p=0.01) and erythrocyte sedimentation rate, (r=-0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDL's ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=-0.34, p=0.03). CONCLUSIONS: The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDL's antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.

An association study of disease activity score components and patient satisfaction with overall health for early RA patients on non-biologic DMARD therapy.

Patient overall satisfaction with health (PSH) was measured by a subset of questions from the Arthritis Impact Measurement Scales II. Based on longitudinal observations for 267 early rheumatoid arthritis (RA) patients of the United States Western Consortium (WC) cohort receiving first non-biologic DMARD treatment, we estimated the 1-year change in PSH (Δ PSH). Logistic regression analysis was used to estimate the association of improvement in Δ PSH with the core set of clinical and patient-reported components of disease activity scores (DAS). Most patients were more satisfied with health after 1 year of treatment (80%); few achieved DAS28-ESR minimal disease activity (27%) or remission (7%). Laboratory and joint count measures were not associated with improved 12-month PSH. Patients with greater HAQ-DI (P = 0.0473) and self-reported stiffness (P = 0.0669) were more likely to have a perceived overall health benefit from treatment. Regardless of objective disease status, patients are generally satisfied with first-line treatment, which could present a challenge to implementing DAS-guided treatment change. Patients with greater self-reported functional limitations might have lower expectations for treatment benefit and be less willing to modify their current therapy; subjective assessments of function and stiffness could be particularly useful in identifying these patients.

A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis.

OBJECTIVE: We previously observed the association of the co-occurrence of the HLA-DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)-positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs. METHODS: SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription-PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay. RESULTS: A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti-cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5. CONCLUSION: The RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.

Remission in rheumatoid arthritis.

With advancing therapeutic options, achieving a state of remission has become the treatment goal in rheumatoid arthritis. Agreeing on what constitutes remission and what measures should be used to assess disease activity has remained a challenge. Multiple remission criteria have been devised and modified, all with different strengths and limitations. A consensus definition of remission will need to be achieved if we are to be able to evaluate outcomes of clinical trials and establish treatment targets for practice. Remission defined as the complete absence of disease currently may not be a realistic therapeutic goal.

Comparison of composite measures of disease activity in an early seropositive rheumatoid arthritis cohort.

OBJECTIVE: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort. METHODS: Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients. RESULTS: Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index. CONCLUSION: The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.

Classifying radiographic progression status in early rheumatoid arthritis patients using propensity scores to adjust for baseline differences.

Various methods are used to measure radiographic joint damage in patients with rheumatoid arthritis (RA), but determining proportions of responsive patients is difficult. A key problem in observational studies when assessing damage outcomes is incorporating time to treatment initialization and adjusting for observed baseline differences. We examined five different definitions to select an appropriate index to classify radiographic damage in RA patients as progressive or nonprogressive. In addition, we compared different times from symptom onset to treatment and their effects on patient radiographic categorization. Propensity scores to adjust for baseline differences, including time since symptom onset, were used to match those treated early with those treated later using the stratification, radius, nearest neighbor and kernel methods. The mean effect of treatment on the treated was computed for each matching method. Observational data were analyzed for 185 early RA patients from the Western Consortium study followed six to sixty months (mean thirty-one months). For the selected index, 75 patients were categorized as nonprogressors; they had significantly lower disease activity, more clinical improvement and were treated earlier than the progressors. Of those treated within three months of symptom onset, 57% were classified as radiographically progressive versus 35% of those treated later (P = 0.0058). However, after propensity score adjustment for baseline differences, we noticed nonsignificant (P > 0.05) nonprogression in patients given earlier treatment. We conclude that propensity score analysis reduced but did not remove all bias.

Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial.

OBJECTIVE: Abnormal function of high-density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL-associated proteins over 2 years of follow-up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. METHODS: The antioxidant capacity of HDL, paraoxonase 1 (PON-1) activity, and levels of HDL-associated haptoglobin (Hp), HDL-associated apolipoprotein A-I (Apo A-I), and myeloperoxidase (MPO) were measured in 550 TEAR participants at 4 time points (time 0 [pretreatment] and at 24, 48, and 102 weeks of treatment). Repeated-measures analysis using mixed-effects linear models with an autoregressive covariate structure was performed to model the within-subject covariance over time. RESULTS: Mixed-effects models, which were controlled for traditional CV risk factors, treatment regimen, prednisone use, and statin use, demonstrated significant associations between RA disease activity, measured using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, or C-reactive protein level, and the profile of HDL function over time. Specifically, decreases in RA disease activity over time were associated with increases in PON-1 activity and levels of HDL-associated Apo A-I, and decreases in the HDL inflammatory index and levels of MPO and HDL-associated Hp. CONCLUSION: Reduced disease activity in patients with early RA treated with MTX monotherapy, MTX + ETN combination therapy, or MTX + SSZ + HCQ triple therapy in the TEAR trial was associated with improvements in the HDL function profile. Additional studies are warranted to evaluate abnormal HDL function as a potential mechanism and therapeutic target for CV risk in patients with RA.

Real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry.

OBJECTIVE: To evaluate the effectiveness of select biologics, methotrexate (MTX), and other disease-modifying anti-rheumatic drugs (DMARDs) in the management of adult rheumatoid arthritis (RA) in routine clinical practice. RESEARCH DESIGN AND METHODS: RADIUS (Rheumatoid Arthritis DMARD Intervention and Utilization Study) comprises two prospective, 5-year, observational registries of over 10 000 patients. Over 4600 patients who initiated MTX or a biologic regimen (etanercept [ETN], infliximab [INF], ETN + MTX, and INF + MTX) and who had at least one on-regimen, follow-up evaluation, were included in this analysis. Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation. Other common DMARD regimens (N = 762) were also compared with MTX. Patients who initiated less commonly used regimens, such as anakinra or cyclosporine, and those who did not have at least one on-regimen, follow-up evaluation, were not eligible for this analysis. Because ESR/CRP measurements were often not available, a modified ACR20 response (mACR20), defined as three out of four response criteria excluding ESR/CRP, was used to assess response at 12 months. Logistic regression analysis was performed to control for baseline covariates that may affect outcomes. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry. RESULTS: After adjusting for baseline covariates, patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.09-1.52; p < 0.01 and OR 1.23, 95% CI 1.02-1.47; p < 0.05, respectively). Conversely, patients treated with MTX + leflunomide (LEF) were less likely to achieve a mACR20 response than those receiving MTX alone (OR 0.68, 95% CI 0.48-0.96; p < 0.05). Significant differences were not observed between patients receiving MTX alone and either INF + MTX, MTX + hydroxychloroquine, MTX + hydroxychloroquine + sulfasalazine, INF monotherapy, or LEF monotherapy. CONCLUSION: These data from routine rheumatology clinical practice settings highlight the effectiveness of common biologic and DMARD therapies, and provide additional data beyond those of randomized, controlled trials.

Real-world utilization of DMARDs and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) study.

OBJECTIVE: Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice. RESEARCH DESIGN AND METHODS: Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study. Two separate patient cohorts were enrolled; RADIUS 1 patients initiated any new therapy at entry, and RADIUS 2 patients initiated etanercept at entry. Patient demographics and disease activity measures were collected at study entry, and baseline characteristics were summarized for various subgroups. Effectiveness, safety, and patterns of use will be tracked for therapies utilized during the 5-year study. RESULTS: RADIUS 1 enrolled 4959 patients, and RADIUS 2 enrolled 5102 patients, mostly at community private practices (88%). In RADIUS 1, most patients initiated methotrexate (MTX) monotherapy, followed by MTX in combination with a biologic (e.g. infliximab plus MTX) or other DMARD. In RADIUS 2, most patients initiated etanercept in combination with MTX, followed by etanercept monotherapy. When a new therapy was required, physicians tended to add another therapy versus switching therapies. Patients initiating a biologic had a longer duration of RA and more severe disease compared with patients initiating non-biologic therapy. CONCLUSIONS: These real-world data provide evidence of the prescribing practices of rheumatologists in 2001-2003. Future analyses will allow evidence-based comparisons of the long-term safety and effectiveness of DMARDs, biologics, and combination therapies to assist physicians in clinical decision-making.

Using Dermal Temperature to Identify Rheumatoid Arthritis Patients With Radiologic Progressive Disease in Less Than One Minute.

OBJECTIVE: To explore development of a screening test for rheumatoid arthritis (RA) patients most likely to develop radiographic damage in the next year. The test is a simple, objective measurement of elevated dermal temperature over an inflamed joint in this observational, prospective cohort study. METHODS: Seropositive RA patients were sequentially enrolled into cohorts with hot or cool joints, as determined by a dermal thermometer. Patients naive to biologic therapy were maintained on a stable dosage of methotrexate (20-25 mg/week). The hot-joint cohort had a joint skin temperature greater than their body temperature on vital signs. Hand/wrist radiographs obtained at baseline and 1 year later were read and scored using modified Sharp/van der Heijde scores (SHS) by a single reader without sequence order or identifiers. RESULTS: Each cohort consisted of 104 patients enrolled into observation between 2009 and 2014. Patients in the cohort with hot joints had a mean ± SD joint temperature of 1.06 ± 0.69°F above central body temperature and a nearly 4-fold higher risk of new radiographic damage than those with cool joints (SHS score 8.7 ± 6.2 versus 2.5 ± 1.4; P < 0.001). Sensitivity and specificity for joint temperature to predict radiographic damage in the next year were 92% and 78%, respectively, in the hot-joint cohort. As expected, this cohort at baseline was younger, had more recent onset RA, and had higher Westergren erythrocyte sedimentation rate levels than the cool-joint cohort (P < 0.001 for each). CONCLUSION: Dermal joint temperature may become a screening test to quickly and accurately identify individual RA patients at high risk for radiographic damage and those who may benefit most from biologic therapy.

Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial.

OBJECTIVE: To evaluate long-term changes in cholesterol levels in patients with early rheumatoid arthritis (RA) who were randomized to begin treatment with methotrexate (MTX) monotherapy, MTX plus etanercept, or triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. METHODS: Levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed in 416 patients participating in the TEAR trial, during 102 weeks of followup. Associations of cholesterol changes with disease activity and drug treatment were evaluated using repeated-measures analysis with mixed-effect linear models to model within-subject covariance over time. RESULTS: Mixed-effect models controlling for traditional cardiovascular (CV) risk factors, TEAR treatment, and baseline prednisone and statin use demonstrated significant inverse associations of RA disease activity with changes in cholesterol over time. Decreases in the 28-joint Disease Activity Score, the C-reactive protein level, or the erythrocyte sedimentation rate were associated with increases in levels of HDL cholesterol, LDL cholesterol, and total cholesterol in all treatment groups (P < 0.001-0.035). Triple therapy was strongly associated with higher levels of HDL cholesterol, lower levels of LDL cholesterol, and higher ratios of total cholesterol:HDL cholesterol (P < 0.001 for all) compared to MTX monotherapy or MTX plus etanercept therapy over the 2-year followup. CONCLUSION: Decreases in RA disease activity over long-term followup were associated with increases in cholesterol levels in patients with early RA treated with either biologic or nonbiologic therapies. The use of triple therapy during 2 years of followup was associated with higher HDL cholesterol levels, lower LDL cholesterol levels, and lower total cholesterol:HDL cholesterol ratios compared to those observed in patients who received MTX monotherapy or MTX plus etanercept combination therapy. Additional studies are needed to assess the effects of these cholesterol changes on CV events in patients with RA.

Comprehensive appraisal of magnetic resonance imaging findings in sustained rheumatoid arthritis remission: a substudy.

OBJECTIVE: To evaluate the effect of sustained American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission on residual joint inflammation assessed by magnetic resonance imaging (MRI) and to secondarily evaluate other clinical definitions of remission, within an early seropositive rheumatoid arthritis (RA) cohort. METHODS: A subcohort of 118 RA patients was enrolled from patients who completed the 2-year, double-blind randomized Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. Patients received a single contrast-enhanced 1.5T MRI of their most involved wrist. Two readers scored MRIs for synovitis, osteitis, tenosynovitis, and erosions. Clinical assessments were performed every 3 months during the trial and at time of MRI. RESULTS: The subcohort was 92% seropositive with mean age 51 years, duration 4.1 months, and Disease Activity Score in 28 joints using the erythrocyte sedimentation rate 5.8 at TEAR entry. Total MRI inflammatory scores (tenosynovitis + synovitis + osteitis) were lower among patients in clinical remission. Lower MRI scores were correlated with longer duration of Clinical Disease Activity Index (CDAI) remission (ρ = 0.22, P = 0.03). At the time of MRI, 89 patients had no wrist pain/tenderness/swelling; however, all 118 patients had MRI evidence of residual joint inflammation after 2 years. No statistically significant differences in damage or MRI inflammatory scores were observed across treatment groups. CONCLUSION: This is the first detailed appraisal describing the relationship between clinical remission cut points and MRI inflammatory scores within an RA randomized controlled trial. The most stringent remission criteria (2011 ACR/EULAR and CDAI) best differentiate the total MRI inflammatory scores. These results document that 2 years of triple therapy or tumor necrosis factor plus methotrexate treatment in early RA does not eliminate MRI evidence of joint inflammation.

Case finding for population-based studies of rheumatoid arthritis: comparison of patient self-reported ACR criteria-based algorithms to physician-implicit review for diagnosis of rheumatoid arthritis.

OBJECTIVE: To evaluate the interrater reliability of rheumatologist diagnosis of rheumatoid arthritis (RA) and the concordance between rheumatologist and computer algorithms for assessing the accuracy of a diagnosis of RA. METHODS: Self-reported data regarding symptoms and signs for a diagnosis of RA were considered by a panel of rheumatologists and by computer algorithms to assess the probability of a diagnosis of RA for 90 patients. The rheumatologists' review was validated through medical record. RESULTS: The interrater reliability among rheumatologists regarding a diagnosis of RA was 84%; the chance-corrected agreement (kappa) was 0.66. Agreement between the rheumatologists' rating and the best-performing algorithm was 95%. Using rheumatologist's review as a standard, the sensitivity of the algorithm was 100%, specificity was 88%, and the positive predictive value was 91%. The validation of rheumatologist's review by medical record showed 81% sensitivity, 60% specificity, and 78% positive predictive value. CONCLUSION: Reliability of rheumatologists' assignment of a diagnosis of RA by using self-report data is good. Algorithms defining symptoms as either joint swelling or tenderness with symptom duration >or=4 weeks have a better agreement with rheumatologist's diagnosis than do ones relying on a longer symptom duration. RELEVANCE: These findings have important implications for health services research and quality improvement interventions pertinent to case finding for RA through self-report data.