Improved outcomes in rheumatoid arthritis with obesity after a weight loss intervention: randomized trial.

OBJECTIVE: To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients. METHODS: We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28) ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000-1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05. RESULTS: The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; -0.51 [95% CI -1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 -2.0 [95% CI -7.00, 3.1], P = 0.46 between groups). CONCLUSION: Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.

Power doppler ultrasound signal predicts abnormal HDL function in patients with rheumatoid arthritis.

Active rheumatoid arthritis (RA) is associated with increased cardiovascular risk and impaired function of high-density lipoprotein (HDL). Previous work suggests that HDL may become dysfunctional through oxidative modifications within the RA joint. The current work evaluates an association of synovial power doppler ultrasound signal (PDUS) with HDL function and structure. Two open-label clinical therapeutic studies using PDUS as a disease outcome measure were included in this analysis, including a 12-month trial of subcutaneous abatacept in 24 RA patients and a 6-month trial of IV tocilizumab in 46 RA patients. Laboratory assays included assessments of HDL function and structure, HDL and total cholesterol levels, and a cytokine/chemokine panel. Patients with the highest baseline PDUS scores in both clinical studies, had worse HDL function, including suppression of paraoxonase 1 (PON1) activity as well as lower HDL-C levels. Associations between other disease assessments (DAS28 and CDAI) and HDL function/structure were noted but were generally of lesser magnitude and consistency than PDUS across the HDL profile. Treatment with tocilizumab for 6 months was associated with increases in cholesterol levels and improvements in the HDL function profile, which correlated with greater decreases in PDUS scores. Similar trends were noted following treatment with abatacept for 3 months. Higher baseline PDUS scores identified patients with worse HDL function. This data supports previous work suggesting a direct association of joint inflammation with abnormal HDL function.

Evaluation of an automated phenotyping algorithm for rheumatoid arthritis.

To better understand the challenges of generally implementing and adapting computational phenotyping approaches, the performance of a Phenotype KnowledgeBase (PheKB) algorithm for rheumatoid arthritis (RA) was evaluated on a University of California, Los Angeles (UCLA) patient population, focusing on examining its performance on ambiguous cases. The algorithm was evaluated on a cohort of 4,766 patients, along with a chart review of 300 patients by rheumatologists against accepted diagnostic guidelines. The performance revealed low sensitivity towards specific subtypes of positive RA cases, which suggests revisions in features used for phenotyping. A close examination of select cases also indicated a significant portion of patients with missing data, drawing attention to the need to consider data integrity as an integral part of phenotyping pipelines, as well as issues around the usability of various codes for distinguishing cases. We use patterns in the PheKB algorithm's errors to further demonstrate important considerations when designing a phenotyping algorithm.

Impact of Perceived Stress During the SARS-CoV-2 Pandemic on Rheumatoid Arthritis Patients' Disease Activity: An Online Survey.

INTRODUCTION/OBJECTIVES: Psychological stress worsens rheumatoid arthritis (RA) disease activity, and the COVID-19 pandemic has increased stress/anxiety in rheumatic patients. The purpose of this study was to determine if stress during the COVID-19 pandemic specifically impacts RA disease activity as reported by the patient. METHOD: This was a cross-sectional COVID-19 RA survey study. University of California, Los Angeles rheumatology clinic patients were emailed a link to a survey in July and November 2020. The 30-question survey pertained to COVID-19-related stress, RA disease activity, and demographics. For the survey responders, anti-cyclic citrullinated antibody, rheumatoid factor, and age were extracted from the electronic health record. Analyses were performed to examine the association between the 4-item Perceived Stress Scale (PSS-4) and other COVID-19-related stress measures with the Routine Assessment of Patient Index Data 3 (RAPID3). RESULTS: A total of 1138/5037 subjects completed the emailed survey (22.6% response rate). When examining responses across RAPID3 categories (near remission, low, moderate, and high disease severity), there were significant increases in PSS-4 and other stress variables. Multiple linear regression models showed that PSS-4, financial stress, age, seropositivity, disease duration, and Black race were independently associated with worsened RAPID3 scores, when controlling for other confounding factors. CONCLUSIONS: This study suggests that stress overall negatively impacts RAPID3, and Black RA patients had a higher RAPID3 scores during the COVID-19 pandemic. Despite colossal efforts to combat the pandemic, RA patients currently suffer from stress/anxiety, and methods to mitigate these psychological effects are needed.

Limitations of dual-energy CT in the detection of monosodium urate deposition in dense liquid tophi and calcified tophi.

OBJECTIVE: Dual-energy CT (DECT) detection of monosodium urate (MSU) crystal deposition has demonstrated good sensitivity and specificity in patients with established gout. However, limitations have been reported with early disease and with low urate burden. We aimed to study the performance of DECT in the detection and quantification of MSU deposition in solid and liquid tophi. MATERIALS AND METHODS: Patient-derived solid and liquid tophi, suspensions of commercial synthetic, and in-house synthetic MSU crystals were prepared at varying concentrations. DECT was performed at 80 kVp and 150 kVp, and post-processed using Syngo Via gout software (Siemens) that color-coded urate and cortical bone as green and purple, respectively. DECT findings were correlated with ultrasound and microscopic findings. The protocol was reviewed by IRB and considered a non-human subject research. RESULTS: DECT did not detect urate deposition in either patient-derived liquid tophi or in-house synthetic crystals at any concentration. Lowering the post-processing minimum threshold increased the detection of in-house synthetic crystals but did not change the detection of patient-derived liquid tophi. Areas of calcium-rich purple color-coded regions, masking detection of urate, within the solid tophi and surrounding liquid tophi were noted on DECT. Histology showed co-presence of calcium along with MSU deposition in these. CONCLUSION: This study illustrates important limitations of DECT for liquid tophi due to subthreshold CT attenuation and for calcified tophi due to the obscuration of urate by calcium. Urate may be either undetectable or underestimated by DECT when these conditions are present.

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.

Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials.

OBJECTIVE: In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray. METHODS: Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses. RESULTS: Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively). CONCLUSIONS: Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

Examining the validity of the rheumatoid arthritis magnetic resonance imaging score according to the OMERACT filter-a systematic literature review.

Objective: To examine whether the RA MRI score (RAMRIS) for RA of the wrist/hand meets the OMERACT filter criteria-truth (validity), discrimination and feasibility. Methods: We conducted a systematic literature review in PubMed and Scopus, from 1970 through June 2014, focused on MRI measures of synovitis, osteitis/bone marrow oedema, erosions and/or joint space narrowing in RA randomized controlled trials and observational studies with cohort size ⩾10. Strength of evidence was assessed using the Cochrane Handbook criteria. Results: Of 634 MRI titles/abstracts, 202 met the review criteria, with 92 providing at least 1 type of validity. Four articles provided criterion validity, and 26 articles utilized RAMRIS to assess 1.5 T MRI images. Histopathology data showed inflammation corresponding to MRI of synovitis and osteitis. MRI erosions corresponded to those identified with CT. Content and construct validity for RAMRIS synovitis, osteitis and erosions were documented by correlations with clinical, laboratory and/or radiographic data. Each measure was sensitive to change and responsive to therapy. RAMRIS synovitis and osteitis were able to discriminate between the efficacy of treatments vs placebo in 12-week studies, whereas RAMRIS erosions required studies of ⩾24 weeks. Conclusion: RAMRIS synovitis, osteitis and erosions imaged with 1.5 T MRI are valid and useful for evaluating joint inflammation and damage for RA of the wrist/hand, according to the OMERACT filter.

Joint-specific assessment of swelling and power Doppler in obese rheumatoid arthritis patients.

BACKGROUND: Clinical swollen joint examination of the obese rheumatoid arthritis (RA) patient can be difficult. Musculoskeletal Ultrasound (MSUS) has higher sensitivity than physical examination for swollen joints (SJ). The purpose of this study was to determine the joint-specific association between power Doppler (PDUS) and clinical SJ in RA across body mass index (BMI) categories. METHODS: Cross-sectional clinical and laboratory data were collected on 43 RA patients. PDUS was performed on 9 joints (wrist, metacarpalphalangeal 2-5, proximal interphalgeal 2/3 and metatarsalphalangeal 2/5). DAS28 and clinical disease activity index (CDAI) were calculated. Patients were categorized by BMI: <25, 25-30, and >30. Demographic and clinical characteristics were compared across BMI groups with Kruskal-Wallis test and chi-square tests. Joint-level associations between PDUS and clinically SJ were evaluated with mixed effects logistic regression models. RESULTS: While demographics and clinically-determined disease activity were similar among BMI groups, PDUS scores significantly differed (p = 0.02). Using PDUS activity as the reference standard for synovitis and clinically SJ as the test, the positive predictive value of SJ was significantly lower in higher BMI groups (0.71 in BMI < 25, 0.58 in BMI 25-30 and 0.44 in BMI < 30) (p = 0.02). The logistic model demonstrated that increased BMI category resulted in decreased likelihood of PDUS positivity (OR 0.52, p = 0.03). CONCLUSIONS: This study suggests that in an obese RA patient, a clinically assessed SJ is less likely to represent true synovitis (as measured by PDUS). Disease activity in obese RA patients may be overestimated by CDAI/DAS28 calculations and clinicians when considering change in therapy.

Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial.

OBJECTIVE: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. METHODS: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2. RESULTS: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. CONCLUSION: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.

Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis.

OBJECTIVE: To investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). METHODS: The relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients. RESULTS: Paraoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05). CONCLUSION: The current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA.

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.

Effects of subcutaneous and intravenous golimumab on inflammatory biomarkers in patients with rheumatoid arthritis: results of a phase 1, randomized, open-label trial.

OBJECTIVE: To evaluate the effects of the anti-TNF-α monoclonal antibody golimumab, administered by s.c. injection or i.v. infusion, on markers of inflammation in patients with RA. METHODS: In this phase 1, open-label study, patients with active RA were randomized to receive s.c. golimumab 100 mg at baseline and every 4 weeks through week 20 (n = 33; group 1) or i.v. golimumab 2 mg/kg at baseline and week 12 (n = 16; group 2). Serum levels of CRP, IL-6, serum amyloid A (SAA), TNF receptor II (TNFRII), MMP-3, hyaluronic acid, haptoglobin, ferritin and haemoglobin and serum/urine hepcidin were measured at various time points. Associations between the biomarkers were assessed with Spearman's correlations. RESULTS: In both groups 1 and 2, decreases in mean serum levels of CRP, IL-6, SAA, TNFRII, MMP-3, haptoglobin, ferritin and hepcidin, and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8. Decreases in concentrations of serum CRP, IL-6, SAA, MMP-3, hepcidin, ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1, but began to reverse after week 8 in group 2. Among all patients, decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin. CONCLUSION: Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with golimumab, and most of these improvements were sustained through week 24 in group 1.

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.

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.

Optimizing Reliability of Real-Time Sonographic Examination and Scoring of Joint Synovitis in Rheumatoid Arthritis.

OBJECTIVE: Musculoskeletal ultrasound real-time image acquisition and scoring are complex, and many factors affect reliability. Static image reliability does not guarantee real-time scoring. This study aimed to identify factors and solutions to improve real-time scoring reliability for the grey scale and power Doppler evaluation of synovitis. We also report on using a novel musculoskeletal ultrasound synovitis rule-based scoring atlas. METHODS: In four stages, we evaluated inter- and intra-reader reliability among three ultrasonographers (US1-3). Intra- and inter-reader reliability was calculated using weighted-kappa, intraclass correlation coefficient, and Spearman correlation. Reliability statistics were compared between stages using permutation tests to compute empirical distributions for differences in those statistics. At each stage, factors that diminished reliability were identified and addressed. After intensive reliability exercises, a RA MSUS atlas with in-depth scoring rules was generated to improve interpretive reliability. RESULTS: The three ultrasonographers had good to excellent intra-reader reliability for real-time acquisition scoring over 2432 views (weighted kappa 0.52-0.80, intraclass correlation coefficient 0.59-0.86, and Spearman correlation 0.64-0.86). Inter-reader reliability was good to excellent between US1/US2 and US1/US3 (weighted kappa 0.51-0.66, intraclass correlation coefficient 0.66-0.75, Spearman correlation 0.59-0.73). US1 achieved significant improvement in intra-reader reliability from stage 1 to stage 2 (p<0.05, weighted-kappa 0.63 to 0.80, intraclass correlation coefficient 0.71 to 0.86, Spearman 0.67 to 0.86) with use of the atlas.  Conclusion: This rheumatoid arthritis musculoskeletal ultrasound study addressed complex factors affecting musculoskeletal ultrasound acquisition-scoring reliability. Systematic identification and amelioration of many factors and using a novel rule-based scoring atlas significantly improved intra-reader reliability.

Adaptation of American College of Rheumatology Rheumatoid Arthritis Disease Activity and Functional Status Measures for Telehealth Visits.

OBJECTIVE: To provide guidance on the implementation of recommended American College of Rheumatology (ACR) rheumatoid arthritis (RA) disease activity and functional status assessment measures in telehealth settings. METHODS: An expert panel was assembled from the recently convened ACR RA disease activity and functional status measures working groups to summarize strategies for implementation of ACR-recommended RA disease activity (the Clinical Disease Activity Index [CDAI], Disease Activity Score in 28 joints using the erythrocyte sedimentation rate or the C-reactive protein level [DAS28-ESR/CRP], Patient Activity Scale II [PAS-II], Simplified Disease Activity Index [SDAI], and Routine Assessment of Patient Index Data 3 [RAPID3]) and functional status (the Health Assessment Questionnaire II [HAQ-II], Multidimensional Health Assessment Questionnaire [MDHAQ], and PROMIS physical function 10-item short form [PROMIS PF-10]) measures in telehealth settings. RESULTS: Measures composed of patient-reported items (disease activity: PAS-II, RAPID3; functional status: HAQ-II, MDHAQ, PROMIS PF-10) require minimal modification for use in telehealth settings. Measures requiring formal joint counts (the CDAI, DAS28-ESR/CRP, and SDAI) can be calculated using patient-reported swollen and tender joint counts. When the feasibility of laboratory testing is limited, the CDAI can be used in place of the SDAI, and scoring modifications of the DAS28-ESR/CRP without the acute-phase reactant are available. Assessment of the validity of these modifications is limited. Implementation of these measures can be facilitated by electronic health record collection, mobile applications, and provider/staff administration during telehealth visits. CONCLUSION: The ACR-recommended RA disease activity and functional status measures can be adapted for use in telehealth settings to support high-quality clinical care. Research is needed to better understand how telehealth settings may impact the validity of these measures.

Sentinel joint scoring in rheumatoid arthritis: an individualized power Doppler assessment strategy.

OBJECTIVE: Musculoskeletal ultrasound quantifies the total synovial inflammatory burden in rheumatoid arthritis (RA) but is time consuming when scanning numerous joints. This study evaluated a novel patient-centered method for constructing a longitudinal ultrasound score in RA patients. METHODS: Fifty-four RA patients starting intravenous tocilizumab were evaluated with power Doppler ultrasound (PDUS) of 34 joints and DAS28-ESR was assessed at baseline and weeks 4, 12, 16, and 24. The sentinel joint score (SJS) was derived from the reduced subset of joints with PDUS ≥ 1 at baseline. Total PDUS (tPDUS) score and US7 were also calculated. Changes in tPDUS and SJS were correlated. Effect sizes were calculated for tPDUS, SJS, and US7. The proportion of "flipped" joints without baseline PDUS signal that later developed PDUS signal was estimated. RESULTS: At baseline, 1236/1829 joints scanned (67.5%) did not have PDUS signal. The proportion of "flipped" joints at 24 weeks was 5.6% for ≥ 1, 2.9% for ≥ 2, and 1.0% for = 3 PD. tPDUS and SJS scores were highly correlated (r = 0.91 to 0.97). Overall the effect sizes for tPDUS, SJS, and US7 increased over 24 weeks, where SJS was the highest (SJS 1.00 4-week, 1.07 12-week, 1.26 24-week) and tPDUS and US7 were comparable (tPDUS 0.32 4-week, 0.52 12-week, 0.84 24-week; US7 0.23 4-week, 0.52 12-week, 0.74 24-week). CONCLUSION: In RA patients starting a biologic, scanning only joints with baseline PDUS signal can substantially reduce the number of joints requiring follow-up scanning by 67.5% and improves feasibility. "Flipped" joints are infrequently seen after starting therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01717859 Key messages • Only a small percent of joints develop power Doppler signal after baseline scanning. • Changes in the SJS correlate well with changes in clinical activity measured by DAS28-ESR over time. • The SJS effect size is higher than total PDUS and US7 scores, and may improve examination feasibility.

Doppler ultrasound impacts response to intravenous tocilizumab in rheumatoid arthritis patients.

OBJECTIVE: Within rheumatoid arthritis (RA) patients treated with intravenous tocilizumab (IV-TCZ), it is unclear if power Doppler ultrasonography (PDUS) can predict future clinical response. This study sought to determine if baseline PDUS or its early changes can predict 12-week and 24-week disease activity outcomes, and quantify the need for dose escalation (4 to 8 mg/kg). METHODS: Fifty-four RA patients starting IV-TCZ were evaluated at baseline, 4, 6, 12, 16, and 24 weeks using 34-joint PDUS (US34-PDUS), clinical disease activity index (CDAI), 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR), ACR 20/50/70, health assessment questionnaire-disability index (HAQ-DI), and PDUS 20/50/70, a novel measure. Logistic regression models evaluated the predictive utility of US34-PDUS of DAS28-ESR response after adjusting for covariates. RESULTS: Ninety-four percent of patients required dose escalation to 8 mg/kg. US34-PDUS, CDAI, and DAS28-ESR improved significantly over 24 weeks (p < 0.001). Baseline PDUS and 12-week PDUS change correlated with CDAI at 24 weeks (p < 0.05). Logistic regression demonstrated baseline US34-PDUS was independently associated with DAS28-ESR ≥ 1.2 response, even after adjusting for baseline DAS28-ESR (p = 0.03). CDAI, DAS28-ESR, and their components increased across PDUS 20/50/70 categories; however, HAQ-DI did not. CONCLUSION: RA patients treated with IV-TCZ for 24 weeks demonstrated significant improvement, and baseline/early changes in PDUS were predictive of later clinical response. The PDUS 20/50/70 measure is a novel metric of response. This study suggests that IV-TCZ 4 mg/kg may not be sufficient to attain low RA disease activity at 12 weeks, in RA patients with moderate to severe disease (DAS28 ≥ 4.4 and US34-PDUS ≥ 10). TRIAL REGISTRATION: ClinicalTrials.gov NCT01717859 Key Points • Over 90% of RA patients with baseline DAS28-ESR ≥ 4.4 and PDUS34 ≥ 10 required intravenous tocilizumab dose escalation from 4 to 8 mg/kg at 12 weeks. • Reduction in power Doppler ultrasonography (US34-PDUS) scores correlate with DAS28-ESR and CDAI over 24 weeks in rheumatoid arthritis patients with moderate to severe disease activity. • Baseline US34-PDUS predicts future improvements in clinical disease activity outcomes, independent of baseline DAS28-ESR. • Clinical response measures, DAS28-ESR and CDAI, improved across US34-PDUS 20/50/70 categories, while patient-reported outcomes did not.