Identify Rheumatoid Arthritis Patients Research Articles

Plasma mtDNA as a possible contributor to and biomarker of inflammation in rheumatoid arthritis

ObjectivesNeutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making.MethodsThis single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR).ResultsOne hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x108 copies/mL) compared to HC (median 5.4 x106 copies/mL, p<0.0001). Receiver operating characteristics (ROC) curve analysis of mtDNA copy numbers identified RA patients with high sensitivity (92.5%) and specificity (89.4%) with an area under the curve (AUC) of 0.97, p <0.0001 and a positive likelihood ratio of 8.7.Demographic, serological (rheumatoid factor (RF) positivity, anti-citrullinated protein antibodies (ACPA) positivity) and treatment factors were not associated with DNA concentrations. mtDNA plasma concentrations, however, correlated significantly with disease activity score-28- erythrocyte sedimentation rate (DAS28-ESR) and increased numerically with increasing DAS28-ESR and clinical disease activity index (CDAI) activity. MtDNA copy numbers also discriminated RA in remission (DAS28 <2.6) from HC (p<0.0001). Also, a correlation was observed between mtDNA and the ESR (p = 0.006, R= 0.29). Similar analyses showed no significance for nDNA.ConclusionIn contrast to nDNA, mtDNA is significantly elevated in the plasma of RA patients compared with HC. Regardless of RA activity, the abundance of circulating mtDNA is a sensitive discriminator between RA patients and HC. Further validation of the diagnostic value of mtDNA testing is required.

E054 Rituximab dose minimisation in rheumatoid arthritis, a retrospective outcome analysis

Abstract Background/Aims Rituximab was originally developed as a non-Hodgkin lymphoma treatment and rheumatology adopted the same dosing for rheumatoid arthritis(RA); two 1000mg doses two weeks apart for each maintenance cycle. UHSussex utilises self-referral for maintenance rituximab dosing once disease control lessens. Evidence demonstrates patients treated with lower dose rituximab still enjoy good disease control with less immunosuppression, reduced hospital attendance and reduction in drug expenditure. Following one two-dose cycle, stable RA patients were prescribed a single 1000mg dose from 2020 onwards. A retrospective outcome analysis was completed in August 2022; however, results were highly impacted by Covid-19 and a repeat analysis was required. Aim: to assess impact of a single 1000mg dose rituximab regime on patient sustained outcomes, dose intervals, Disease Activity Scores (DAS) and drug expenditure. Methods The pharmacy database was used to identify RA patients receiving rituximab from March 2020 to August 2023. Patients received at least one standard two-dose cycle before switching to a single infusion. Patients were excluded if lost to follow up (under care of rheumatology for less than a year following dose switching) or considered clinically unstable. Patient letters and departmental records were accessed for disease scores and treatment intervals. Results Table1: Results from the two analysis periods From the original cohort (31/59)53% remained on single dosing. Switch back tended to occur within 18 months of switching. DAS scores were not collected reliably and were omitted. Conclusion Covid-19 impacted services and attitudes during the initial study period. Many patients stopped treatment, particularly rituximab, due to the prolonged duration of effect, excluding them from analysis. The dose-interval increase during the first analysis was considered a result of the pandemic. Patients and clinicians delayed infusions; minimising immunosuppression due to perceived increased risk of Covid-19. The continued interval increase in the second analysis may identify a patient cohort in deep remission eligible for therapy review. The study highlights poor practice in collecting and recording DAS scores and appropriate patient-clinician interaction opportunities. 53% of patients remained on single infusions in August 2023 resulting in resource savings, reduced hospital attendance, immunosuppression and significant cost savings demonstrating the rationale for this option. Disclosure S. Butler: Honoraria; Abbvie, Janssen. H. Smith: Honoraria; Novartis, Abbvie.

Association between clinical, serological, functional and radiological findings and ventilatory distribution heterogeneity in patients with rheumatoid arthritis.

In rheumatoid arthritis (RA), the involvement of the pulmonary interstitium can lead to structural changes in the small airways and alveoli, leading to reduced airflow and maldistribution of ventilation. The single-breath nitrogen washout (SBN2W) test is a measure of the ventilatory distribution heterogeneity and evaluates the small airways. This study aimed to find out which clinical, serological, functional and radiological findings are useful to identify RA patients with pathological values of the phase III slope (SIII) measured by the SBN2W test. This was a cross-sectional study in which RA patients were assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Clinical Disease Activity Index (CDAI) and underwent serological analysis of autoantibodies and inflammatory markers. In addition, they underwent pulmonary function tests (including the SBN2W test) and chest computed tomography (CT). Of the 60 RA patients evaluated, 39 (65%) had an SIII >120% of the predicted value. There were significant correlations between SIII and age (r = 0.56, p<0.0001), HAQ-DI (r = 0.34, p = 0.008), forced vital capacity (FVC, r = -0.67, p<0.0001), total lung capacity (r = -0.46, p = 0.0002), residual volume/total lung capacity (TLC) (r = 0.44, p = 0.0004), and diffusing capacity of the lungs for carbon monoxide (r = -0.45, p = 0.0003). On CT scans, the subgroup with moderate/severe disease had a significantly higher SIII than the normal/minimal/mild subgroup (662 (267-970) vs. 152 (88-283)% predicted, p = 0.0004). In the final multiple regression model, FVC, extent of moderate/severe involvement and age were associated with SIII, explaining 59% of its variability. In patients with RA, FVC, extent of lung involvement and age, all of which are easily obtained variables in clinical practice, identify poorly distributed ventilation. In addition, the presence of respiratory symptoms and deteriorated physical function are closely related to the distribution of ventilation in these patients.

The Fidelity of Rheumatoid Arthritis Multivariate Diagnostic Biomarkers Using Discriminant Analysis and Binary Logistic Regression.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that causes multi-articular synovitis. The illness is characterized by worsening inflammatory synovitis, which causes joint swelling and pain. Synovitis erodes articular cartilage and marginal bone, resulting in joint deterioration. This bone injury is expected to be permanent. Cytokines play a prominent role in the etiology of RA and could be useful as early diagnostic biomarkers. This research was carried out at Riyadh's King Khalid University Hospital (KKUH). Patients were enrolled from the Rheumatology unit. Seventy-eight RA patients were recruited (67 (85.9%) females and 11 (14.1%) males). Patients were selected for participation by convenience sampling. Demographic data were collected, and disease activity measurements at 28 joints were recorded using the disease activity score (DAS-28). Age- and sex-matched controls from the general population were included in the study. A panel of 27 cytokines, chemokines, and growth factors was determined in patient and control sera. Binary logistic regression (BLR) and discriminant analysis (DA) were used to analyze the data. We show that multiple cytokine biomarker profiles successfully distinguished RA patients from healthy controls. IL-17, IL-4, and RANTES were among the most predictive variables and were the only biomarkers incorporated into both BLR and DA predictive models for pooled participants (men and women). In the women-only models, the significant cytokines incorporated in the model were IL-4, IL-17, MIP-1b, and RANTES for the BLR model and IL-4, IL-1Ra, GM-CSF, IL-17, and eotaxin for the DA model. The BLR and DA men-only models contained one cytokine each, eotaxin for BLR and platelet-derived growth factor-bb (PDGF-BB) for DA. We show that BLR has a higher fidelity in identifying RA patients than DA. We also found that the use of gender-specific models marginally improves detection fidelity, indicating a possible benefit in clinical diagnosis. More research is needed to determine whether this conclusion will hold true in various and larger patient populations.

Biologic therapy is associated with malignancies among Israeli patients with rheumatoid arthritis: A population-based study.

To examine whether biologic disease-modifying anti-rheumatic drugs (bDMARDs) are associated with increased risk of malignancy among Israeli patients with rheumatoid arthritis (RA). We identified RA patients meeting specified inclusion and exclusion criteria from the Leumit healthcare services database between the years 2000 and 2017. Data were collected regarding bDMARD and conventional DMARD consumption, types of malignancies, and their temporal relation to RA diagnosis. The association between baseline variables and occurrence of malignancies was examined by Cox regression. Among 4268 eligible RA patients, 688 (16.12%) were diagnosed with any malignancy. Melanoma skin cancer (MSC) was the most prevalent malignancy (148/688, 21.5%). The proportions out of all malignancies of MSC and non-melanoma skin cancer (NMSC) were higher after than before RA diagnosis (24.7% vs 19.1%, p = .025 and 24.7% vs 13.0%, p = .021, respectively). A higher proportion of RA patients diagnosed with malignancy used bDMARDs in comparison with RA patients who were malignancy-free (40.2% vs 17.5%, p < .001). After adjusting for demographic and clinical variables, bDMARDs were associated with an increased risk of malignancy (hazard ratio 1.42, 95% confidence interval 1.10-1.78). Biologic DMARDs are associated with increased risk of malignancy among Israeli RA patients, presumably contributed by MSC and NMSC. MSC was the most prevalent type of malignancy in this cohort and may indicate a predisposition state among Israeli RA patients.

P142 Cytomegalovirus seropositivity is associated with an increased frequency of highly differentiated T effector memory cells re-expressing CD45RA (Temra) and persistent disease refractory to anti-TNF therapy in rheumatoid arthritis

Abstract Background/Aims The role of highly differentiated T effector memory re-expressing CD45RA (Temra) in rheumatoid arthritis (RA) is unclear, including whether they can be used as a marker of persistent disease activity. Our aim was to investigate whether peripheral blood Temra frequency can be used to identify RA patients with active disease refractory to anti-TNF therapy. As cytomegalovirus (CMV) has been reported to be associated with the expansion of Temra as well as implicated in RA pathogenesis, we also explored the relationship between serum CMV immunoglobulin (IgG) status, Temra, and remission status. Methods A cross-sectional cohort of RA patients on anti-TNF therapy were recruited. Patients were stratified based on remission status. Remission was defined as no recorded DAS28-CRP≥2.4, no swollen joints, no C-reactive protein (CRP) &amp;gt;5mg/L, and on a stable DMARD dose and no reported disease flare/loss of remission in the last 6 months before recruitment. Patients on abatacept or on conventional DMARDs only were recruited as comparison groups. Peripheral blood mononuclear cells (PBMC) were analysed by flow cytometry. Serum CMV IgG was analysed by ELISA. Two-tailed Mann-Whitney U test or unpaired t-test were used to obtain unadjusted values, analysis of variance (ANOVA) of log-transformed data to obtain age-adjusted values, Spearman’s rank correlation to compare correlation between two variables, Fisher’s exact test to compare proportions. Results Thirty-six anti-TNF, 12 abatacept, and 16 patients on conventional synthetic DMARDs (csDMARDs) only were recruited. A higher proportion of CD4 and CD8 Temra (age-adjusted p = 0.004 and p = 0.0007 respectively) was observed in RA patients on anti-TNF with persistent disease compared to those in remission. This difference in Temra frequency was not observed in patients treated with csDMARDs only or abatacept. CD4 and CD8 Temra frequency correlated positively with CMV IgG levels (Spearman r = 0.8987, p &amp;lt; 0.0001 and Spearman r = 0.7211, p &amp;lt; 0.0001 respectively). There was a strikingly high proportion of anti-TNF patients with persistent disease who were CMV seropositive compared to anti-TNF patients in remission (93% versus 42%, Fisher’s exact test, p = 0.009). This difference was less marked and not significant in the other treatment groups. Conclusion The increased CMV seropositivity and Temra frequency in the context of persistent disease only in anti-TNF treated patients may provide a causal link between Temra and RA pathogenesis refractory to anti-TNF treatment. Disclosure S. Yeoh: Grants/research support; S.A.Y. has received funding for research from Versus Arthritis, Royal College of Physicians, Rosetrees Trust, University College London Hospitals NIHR BRC and UCLH charities. J. Kimpton: None. M. Shipa: Grants/research support; M.S. has received funding for research from Versus Arthritis and GSK. E. Hawkins: None. A. Akbar: Grants/research support; A.A. has received funding for research from the Medical Research Council and the Leo Skin Foundation (Denmark). M. Ehrenstein: None.

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

BackgroundThe p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53β is driving aggressive disease in RA.MethodsUsing RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53β. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software.ResultsElevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53β mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of ‘activated fibroblasts’ together with elevated levels of Δ133p53β.ConclusionsInduction of Δ133p53β in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53β could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53β could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

Baseline bony erosions and time-averaged DAS28 predict discontinuation of TNF inhibitors in rheumatoid arthritis

The present study evaluated the predictive role of baseline radiographic change and disease activity on drug retention and clinical response in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitor (TNFi). Korean Observational Study Network for Arthritis (KORONA) registry was evaluated to identify RA patients treated with a TNFi. Disease activity score-28 (DAS28) was evaluated at baseline and 1 year after TNFi initiation or at termination of TNFi due to inefficacy (within 1 year). The retention rate of TNFi was compared in patients with and without bony erosions. The hazard ratio (HR) for drug retention was evaluated by Cox regression analysis, as was the odds ratio (OR) for achieving remission (DAS28 < 2.6). This study included 109 RA patients, including 97 (89%) women and 30 (27.5%) with erosions, who were treated with a TNFi. Higher baseline DAS28 was negatively associated with achievement of remission (OR = 0.56, 95% CI 0.35–0.88). The TNFi retention rate was significantly lower in RA patients with than in those without erosions (p = 0.04). Factors significantly associated with drug discontinuation included the presence of erosions (HR = 2.45, 95% CI 1.08–5.51) and higher time-averaged DAS28 (HR = 2.17, 95% CI 1.47–3.20), whereas concomitant methotrexate was associated with lack of drug discontinuation (HR = 0.40, 95% CI 0.17–0.95). The presence of erosions and high time-averaged disease activity could predict poor retention of TNFi by RA patients. Higher baseline DAS28 was associated with a reduced clinical response in patients with RA.Trial registration Clinical Research Information Service of South Korea https://cris.nih.go.kr: KCT0000086, registered May 26, 2009.

Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis.

To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA). Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted. Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P=0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P=0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P=0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P=0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients. Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

Efficacy of Abatacept Versus Tumor Necrosis Factor Inhibitors in Anti-citrullinated Protein Antibody-Positive Patients with Rheumatoid Arthritis: Results from a Korean Nationwide Biologics Registry.

Introduction To compare the efficacy of abatacept and tumor necrosis factor inhibitor (TNFi) in patients with anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) and identify those who benefit most from abatacept over TNFi.MethodsThis observational study identified RA patients who were ACPA-positive and initiated abatacept or TNFi from the Korean College of Rheumatology Biologics and Targeted therapy registry. Propensity score (PS) matching was performed to balance baseline confounding in abatacept- or TNFi-treated patients. The major endpoints were changes in Clinical Disease Activity Index (CDAI) and achievement of CDAI remission/low disease activity after 1 year of treatment. Subgroup analysis was mainly performed stratified by prior biologics use.ResultsA total of 291 PS-matched, ACPA-positive RA patients who initiated abatacept (n = 97) and TNFi (n = 194) were included. From baseline CDAI scores of 26.52 in the abatacept group and 26.38 in the TNFi group, the mean changes after 1 year were − 16.78 and − 13.61, respectively (difference − 3.17, p = 0.020). The proportion of patients achieving CDAI remission/low disease activity was 68.0% with abatacept and 52.6% with TNFi (p = 0.013). In the subgroup analysis, patients that were biologics-naïve had better improvement in CDAI after treatment with abatacept than TNFi (difference − 3.35, p = 0.021).ConclusionsThis real-world study suggests that abatacept may have better clinical response compared to TNFi in patients with established ACPA-positive RA, especially in those that were biologics-naïve.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00467-4.

Increased Risk of COVID-19 in Patients With Rheumatoid Arthritis: A General Population-Based Cohort Study.

ObjectivePatients with rheumatoid arthritis (RA) are at an increased risk of acquiring infections owing to immunologic dysfunction and use of potent immunomodulatory medications; however, few data are available on their risk of COVID‐19. We estimated the rate of COVID‐19 among RA participants and compared it with that of the general population.MethodsUsing the Health Improvement Network, we identified RA patients before February 2020 and followed them to September 2020. We calculated the rate of COVID‐19 among participants with RA and compared it with that of the general population using a Cox proportional hazards model, adjusting for potential confounders using overlap weighting of exposure score. We repeated the same analysis among participants with osteoarthritis, a nonautoimmune rheumatic disease, as a negative control exposure.ResultsWe identified 225 cases of suspected and confirmed COVID‐19 among 17,268 RA patients, and 14,234 cases among 1,616,600 participants in the general population (1.4 versus 0.9/1,000 person‐months), with the adjusted hazard ratio (HRadj) being 1.19 (95% confidence interval [95% CI] 1.04–1.36). Confirmed COVID‐19 cases developed in 46 RA participants and in 2,249 in the general population (0.3 versus 0.1/1,000 person‐months), with the HRadj being 1.42 (95% CI 1.01–1.95). No statistically significant difference was observed for suspected and confirmed (HR 1.00 [95% CI 0.93–1.07]) or confirmed (HR 1.08 [95% CI 0.92–1.27]) COVID‐19 rates between participants with osteoarthritis and the general population.ConclusionRA, but not osteoarthritis, was associated with an increased risk of COVID‐19. Our findings provide timely evidence to support recommendations that booster vaccines and priority access to anti–SARS–CoV‐2 monoclonal antibody treatments should be encouraged for RA patients.

Therapeutic response to leflunomide in combo therapy and monotherapy is associated to serum teriflunomide (A77 1726) levels

There is a significant rate of therapeutic failure in rheumatoid arthritis (RA) patients treated with leflunomide (LEF). This study investigates the utility values of teriflunomide levels (A77 1726) in identifying RA patients who remained with moderate or severe disease activity after the treatment with LEF. In this cross-sectional study, we compared: (a) RA patients who achieved a DAS28-ESR ≤ 3.2, and (b) RA patients who maintained a DAS28-ESR > 3.2 after treatment. ROC curves determined the cut-off of A77 1726 with the better performance to identify patients achieving a DAS28-ESR ≤ 3.2. Of the 115 patients treated with LEF, 69 (60%) remained with moderate/severe disease activity and 46 (40%) achieved low disease activity/remission. Higher A77 1726 levels showed a negative correlation with DAS28-ESR (r = − 0.42, p < 0.001) and other parameters of disease activity. We obtained the following utility values with the cut-off of A77 1726 > 10 µg/mL to identify RA patients who achieved a DAS28-ESR ≤ 3.2: sensitivity of 91.31%; specificity of 73.91%; positive predictive value of 70.00%; and negative predictive value of 92.73%. Serum A77 1726 discriminated between RA patients who remained with moderate/severe disease activity despite the treatment with LEF both as monotherapy and LEF as combo therapy.

SCORE2 Assessment in the Calculation of Cardiovascular Risk in Patients with Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the risk of CVD in patients with RA. In this sense, the use of noninvasive tools, such as the carotid ultrasound, has made it possible to identify RA patients at high risk of CVD who had subclinical atherosclerosis disease and who had been included in the low or moderate CVD risk categories when the SCORE risk tables were applied. The 2003 SCORE calculator was recently updated to a new prediction model: SCORE2. This new algorithm improves the identification of individuals from the general population at high risk of developing CVD in Europe. Our objective was to compare the predictive capacity between the original SCORE and the new SCORE2 to identify RA patients with subclinical atherosclerosis and, consequently, high risk of CVD. 1168 non-diabetic patients with RA and age > 40 years were recruited. Subclinical atherosclerosis was searched for by carotid ultrasound. The presence of carotid plaque and the carotid intima media wall thickness (cIMT) were evaluated. SCORE and SCORE2 were also calculated. The relationships of SCORE and SCORE2 to each other and to the presence of subclinical carotid atherosclerosis were studied. The correlation between SCORE and SCORE2 was found to be high in patients with RA (Spearman’s Rho = 0.961, p < 0.001). Both SCORE (Spearman’s Rho = 0.524) and SCORE2 (Spearman’s Rho = 0.521) were similarly correlated with cIMT (p = 0.92). Likewise, both calculators showed significant and comparable discriminations for the presence of carotid plaque: SCORE AUC 0.781 (95%CI 0.755–0.807) and SCORE2 AUC 0.774 (95%CI 0.748–0.801). Using SCORE, 80% and 20% of the patients were in the low or moderate and high or very high CVD risk categories, respectively. However, when the same categories were evaluated using SCORE2, the percentages were different (58% and 42%, respectively). Consequently, the number of RA patients included in the high or very high CVD risk categories was significantly higher with SCORE2 compared to the original SCORE. (p < 0.001). In conclusion, although predictive capacity for the presence of carotid plaque is equivalent between SCORE and SCORE2, SCORE2 identifies a significantly higher proportion of patients with RA who are at high or very high risk of CVD.

Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interstitial Lung Disease in Rheumatoid Arthritis.

Objective: Human epididymis protein 4 (HE4) have been implicated in the pulmonary involvements. We aimed to investigate the clinical utility of HE4 in clinical stratification in patients with rheumatoid arthritis (RA).Methods: This study included a discovery cohort comprising 70 RA patients and 64 healthy controls (HCs), and a validation cohort comprising 98 RA patients and 75 HCs. Human epididymis protein 4 were determined by electrochemical luminescence analyzer.Results: The levels of HE4 were significantly elevated in patients with RA compared to HCs. The positive rates of HE4 in patients with RA and HCs were 50.0% and 0, respectively, in the discovery cohort and 53.1 and 1.3%, respectively, in the validation cohort. When RA patients were subgrouped according to HE4 status, HE4-positive group displayed higher prevalence of interstitial lung disease (ILD) compared to HE4-negative group (28.6 vs. 11.4% in discovery cohort and 57.7 vs. 8.7% in the validation cohort). A positive correlation between the levels of HE4 with the degree of lung impairment was identified. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.3 pmol/L in HE4 for distinguishing RA-ILD from RA-non ILD with the areas under the curve (AUC) of 0.790. Multivariate logistic regression analysis illustrated that high levels of HE4 independently identified patients with RA-ILD (OR, 9.080, p < 0.001).Conclusion: Our findings showed a novel role of HE4 in RA risk stratification, suggest that introducing HE4 to the current RA test panel may serve as an indicator in identifying RA patients for further RA-ILD workups, such as high-resolution computed tomography (HRCT).

Risk of venous thromboembolism associated with methotrexate versus hydroxychloroquine for rheumatoid arthritis: A propensity score-matched cohort study

AimsPatients with rheumatoid arthritis (RA) have an increased risk of venous thromboembolism (VTE), likely related to underlying inflammation. We examined VTE risk associated with two commonly used immunomodulators in RA patients, methotrexate and hydroxychloroquine. Methods and resultsUsing U.S. Medicare claims data (2008–2017), we identified RA patients (≥65 years) who initiated methotrexate or hydroxychloroquine without prior use of any immunomodulators. The primary outcome was VTE, a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes included PE, DVT, and all-cause mortality. After 1:1 propensity score matching for confounding control, we identified 26,534 pairs of methotrexate and hydroxychloroquine initiators (mean (SD) age 74 (7) years; 79% female). During a total of 56,686 person-years of follow-up, 208 methotrexate and 83 hydroxychloroquine initiators developed VTE. The incidence rate of VTE was higher among methotrexate initiators (6.94/1,000 person-years) than hydroxychloroquine initiators (3.11/1,000 person-years) with a hazard ratio (HR) of 2.26 (95% CI 1.75, 2.91). Methotrexate initiators had a greater risk of PE (HR 3.30, 95% CI 2.28, 4.77) and DVT (HR 1.53, 95% CI 1.07, 2.19) than hydroxychloroquine initiators. All-cause mortality was similar between the two groups (HR 0.91, 95% CI 0.83, 1.00). ConclusionIn this large real-world cohort of older RA patients, treatment with methotrexate was associated with a 2-fold increased risk of VTE relative to hydroxychloroquine, although all-cause mortality was similar. Future experimental studies with non-user control groups are needed to determine the causal relationships between the study drugs and VTE and whether methotrexate elevates or hydroxychloroquine reduces the risk of VTE.

Association between sarcopenia, physical performance and falls in patients with rheumatoid arthritis: a 1-year prospective study

BackgroundPatients with rheumatoid arthritis (RA) are at increased risk of falls and fractures. Sarcopenia occurs more frequently in RA patients due to the inflammatory processes. Early diagnosis and prevention programmes are essential to avoid serious complications. The present study aims to identify risk factors for falls related to sarcopenia and physical performance.MethodsIn a 1-year prospective study, a total of 289 patients with RA, ages 24–85 years, were followed using quarterly fall diaries to report falls. At the baseline, medical data such as RA disease duration and Disease Activity Score (DAS28CRP) were collected. Self-reported disability was assessed using the Health Assessment Questionnaire (HAQ). Appendicular skeletal mass was determined by Dual X-ray-Absorptiometry (DXA). Physical performance was evaluated by handgrip strength, gait speed, chair rise test, Short Physical Performance Battery, and FICSIT-4. Muscle mechanography was measured with the Leonardo Mechanograph®. Sarcopenia was assessed according to established definitions by the European Working Group on Sarcopenia in Older People (EWGSOP2) and The Foundation for the National Institutes of Health (FNIH). Univariate and multiple logistic regression analysis were used to explore associations with falling. Receiver-operating characteristics (ROC) were performed, and the area under the curve is reported.ResultsA total of 238 subjects with RA completed the 1-year follow-up, 48 (20.2%) experienced at least one fall during the observational period. No association was found between sarcopenia and prospective falls. Age (OR = 1.04, CI 1.01–1.07), HAQ (OR = 1.62, 1.1–2.38), and low FICSIT-4 score (OR = 2.38, 1.13–5.0) showed significant associations with falls.ConclusionsIn clinical practice, a fall assessment including age, self-reported activities of daily life and a physical performance measure can identify RA patients at risk of falling.Trial registrationThe study has been registered at the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform (ICTRP) since 16 March 2017 (DRKS00011873).

Factors associated with drug survival on first biologic therapy in patients with rheumatoid arthritis: a population-based cohort study.

Lack of sufficient head-to-head trials comparing biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA), makes the choice of the first bDMARD a matter of rheumatologist's preference. Longer drug survival on the first bDMARD usually correlates with early remission. We aimed to identify factors associated with longer drug survival. We conducted a population-based retrospective longitudinal cohort study. We identified RA patients using the relevant International Classification of Disease 9th codes. "True" RA patients were defined as patients fulfilling, additionally, at least one of the following: receiving conventional DMARDs (cDMARDs), being positive for rheumatoid factor or anti-cyclic citrullinated peptide, or being diagnosed by a rheumatologist. We compared drug survival times and identified factors associated with longer drug survival. We identified 4268 true RA patients between the years of 2000-2017. 820 patients (19.2%) received at least one bDMARD. The most commonly prescribed bDMARDs were etanercept (352, 42.9%), adalimumab (143, 17.4%), infliximab (142, 17.3%) and tocilizumab (58, 7.1%). Infliximab was associated with the longest drug survival (47.1months ± 46.3) while golimumab was associated with the shortest drug survival (14.9months ± 15.1). Male gender [hazard ratio (HR) = 0.76, 95% confidence interval (CI), 0.63-0.86, p = 0.001], concurrent conventional DMARDs use (HR = 0.79, 95% CI 0.68 - 0.98, p = .031) and initiating bDMARD therapy in earlier calendric years (HR = 1.12, 95% CI 1.10 -1.18, p = 0.0001) were associated with longer drug survival. Male gender, concomitant cDMARDs and initiating biologic therapy at earlier calendric years are associated with longer drug survival.

Disease activity influences the reclassification of rheumatoid arthritis into very high cardiovascular risk

BackgroundPrevious studies have shown that risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the actual cardiovascular (CV) risk of patients with rheumatoid arthritis (RA). In contrast, carotid ultrasound was found to be useful to identify RA patients at high CV. In the present study, we aimed to determine if specific disease features influence the CV risk reclassification of RA patients assessed by SCORE risk charts and carotid ultrasound.Methods1279 RA patients without previous CV events, diabetes, or chronic kidney disease were studied. Disease characteristics including disease activity scores, CV comorbidity, SCORE calculation, and the presence of carotid plaque by carotid ultrasound were assessed. A multivariable regression analysis was performed to evaluate if the reclassification into very high CV risk category was independently associated with specific features of the disease including disease activity. Additionally, a prediction model for reclassification was constructed in RA patients.ResultsAfter carotid ultrasound assessments, 54% of the patients had carotid plaque and consequently fulfilled definition for very high CV risk. Disease activity was statistically significantly associated with reclassification after fully multivariable analysis. A predictive model containing the presence of dyslipidemia and hypertension, an age exceeding 54 years, and a DAS28-ESR score equal or higher than 2.6 yielded the highest discrimination for reclassification.ConclusionReclassification into very high CV risk after carotid ultrasound assessment occurs in more than the half of patients with RA. This reclassification can be independently explained by the activity of the disease.

AB0787 RECEIVER OPERATING CHARACTERISTIC ANALYSIS OF JOINT INFLAMMATION IN RELATION TO DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS ASSESSED USING A NOVEL COMBINED THERMAL AND ULTRASOUND IMAGING

Background:A novel combined thermal and ultrasound (CTUS) imaging approach in rheumatoid arthritis (RA) was recently shown to be superior to either imaging modality alone in terms of correlation with the 28-joint disease activity score (DAS28).Objectives:To determine the performance of CTUS imaging in identifying RA patients with at least moderate disease activity (DAS28 &gt; 3.2).Methods:Bilateral hand (22 joints) thermal and ultrasound (US) imaging was performed. Thermal imaging provides the surface temperature readings at the joints with MAX, AVG and MIN derived per patient by summing the temperature differences with a control temperature, for the respective maximum (Tmax), average (Tavg) and minimum (Tmin) temperatures at each joint. US imaging assesses joint inflammation by summing up the power Doppler (PD) and grey-scale (GS) joint inflammation scores (graded 0-3 at each joint recess) at each joint to obtain the respective total PD and total GS scores per patient. CTUS imaging utilizes data from both thermal and US imaging to derive the MAX (PD), AVG (PD) and MIN (PD) by multiplying MAX, AVG and MIN by a factor of 2 when a patient’s Total PD &gt; median score, which otherwise remained the same as the MAX, AVG and MIN. The results of the imaging parameters were compared between patients with DAS28 ≤ 3.2 and those with DAS28 &gt; 3.2. Sensitivity (Sn), specificity (Sp) and receiver operating characteristic (ROC) curve analysis was performed to determine if the use of CTUS imaging can help identify patients with DAS28 &gt; 3.2.Results:In this cross-sectional study, 814 joints from 37 RA patients (75.7% female; 75.7% Chinese; baseline mean disease duration, 30.9 months; baseline mean DAS28, 4.43) were imaged. The mean (SD) values for the CTUS—but not single modality—imaging parameters (Table 1) were all significantly greater among patients with DAS28 &gt; 3.2 versus those with DAS28 ≤ 3.2 (P-values were all &lt;0.01). Based on cut-off levels of (a) MAX (PD) ≥ 94.5, (b) MIN (PD) ≥ 42.3 and (c) AVG (PD) ≥ 64.6 in identifying patients with DAS28 &gt; 3.2, the respective area under the ROC curves (AUCs) (95%CIs) were (a) 0.731 (0.541, 0.921) with Sn = 58.1%; Sp = 100.0%; negative predictive value (NPV) = 31.6%; positive predictive value (PPV) = 100.0%; accuracy = 64.9%, (b) 0.758 (0.591, 0.925) with Sn = 61.3%; Sp = 100.0%; NPV = 33.3%; PPV = 100.0%; accuracy = 67.6% and (c) 0.763 (0.596, 0.931) with Sn = 61.3%; Sp = 100.0%; NPV = 33.3%; PPV = 100.0%; accuracy = 67.6%.Conclusion:The severity of joint inflammation as detected by CTUS—but not single modality—imaging parameters were significantly greater among patients with DAS28 &gt; 3.2 versus those with DAS28 ≤ 3.2. For the first time ever, by applying ROC analysis, this has helped to determine cut-off MAX (PD), MIN (PD) and AVG (PD) levels for identifying patients with DAS28 &gt; 3.2; the usefulness of these cut-off levels will require further validation in independent RA cohorts.Table 1.Comparison of imaging parameters between patient groups.Imaging ParameterDAS28 Mean (95% CI)Difference (95% CI)P-valueDAS28 ≤ 3.2DAS28 &gt; 3.2MAX (PD)75.25 (58.8, 91.7)119.5 (101.12, 137.87)-44.25 (-70.49, -18.01)0.0022**MIN (PD)33.72 (25.82, 41.61)57.51 (47.63, 67.39)-23.79 (-37.13, -10.45)0.0012**AVG (PD)50.72 (39.45, 61.98)85.39 (71.89, 98.88)-34.67 (-53.27, -16.07)0.0008***MAX67.38 (50.75, 84.02)82.23 (74.71, 89.75)-14.85 (-34.11, 4.42)0.1268MIN30.27 (22.06, 38.47)40.02 (35.02, 45.03)-9.75 (-22.18, 2.66)0.1198AVG45.45 (33.94, 56.96)59.11 (52.99, 65.23)-13.66 (-29.04, 1.72)0.0801Total PD2.83 (-0.23, 5.9)3.65 (2.71, 4.58)-0.82 (-3.39, 1.77)0.5269Total GS6.67 (1.31, 12.02)6.58 (4.12, 9.04)0.09 (-6.21, 6.38)0.9780Statistically significant: **P&lt;0.01, ***P&lt;0.001.Disclosure of Interests:None declared

Circulating Dickkof-1 as a potential biomarker associated with the prognosis of patients with rheumatoid arthritis-associated interstitial lung disease.

Circulating Dickkof-1 as a potential biomarker associated with the prognosis of patients with rheumatoid arthritis-associated interstitial lung disease.