Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.

Patterns of Involvement of the Hand Joints in Classical Rheumatoid Arthritis.

BACKGROUND: Symmetrical involvement of the hand joints is described as characteristic of rheumatoid arthritis (RA). Quantitative data on specific patterns of involvement are lacking. OBJECTIVE: The Brigham Rheumatoid Arthritis Sequential Study was created for observational studies of patients with RA and afforded a unique opportunity to answer these questions. METHODS: Of 1598 subjects in the Brigham Rheumatoid Arthritis Sequential Study cohort, 535 met the following criteria: (1) disease duration of 7 years or greater, (2) seropositive, and (3) hand radiographs available. Patterns in specific hand joints based on physical examination and radiographic findings obtained at entry were identified. The level of symmetry of involvement of the metacarpophalangeal (MCP) and wrist joints was determined, as was the correlation between findings on physical examination and radiographic changes in the hand joints. RESULTS: The prevalence of joint space narrowing and/or erosions in each proximal interphalangeal (PIP) joints ranged between 11% and 18%. Joint space narrowing and/or erosions in the MCPs increased radially from the fifth to the second finger. Swelling and tenderness on physical examination of both the PIPs and MCPs also increased radially although the positive predictive value of physical examination as an indicator of joint damage decreased radially. The wrist was the most common joint involved both by physical examination (67%) and radiographically (70%). The right side was more involved radiographically. Analysis of radiographic changes in individual patients revealed that symmetrical findings in the wrists and MCPs occurred in only 67% of patients. CONCLUSIONS: The study describes the pattern of involvement of the hand joints in patients with long standing RA. Findings of interest include symmetrical involvement in only 67% of patients and a discordancy between physical findings and radiographic changes most marked in the more radial PIP joints.

Serum proteomic profiling of rheumatoid arthritis-interstitial lung disease with a comparison to idiopathic pulmonary fibrosis.

Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets.

Screening for preclinical parenchymal lung disease in rheumatoid arthritis.

OBJECTIVES: Pulmonary disease is a common extraarticular manifestation of RA associated with increased morbidity and mortality. No current strategies exist for screening this at-risk population for parenchymal lung disease, including emphysema and interstitial lung disease (ILD). METHODS: RA patients without a diagnosis of ILD or chronic obstructive pulmonary disease underwent prospective and comprehensive clinical, laboratory, functional and radiological evaluations. High resolution CT (HRCT) scans were scored for preclinical emphysema and preclinical ILD and evaluated for other abnormalities. RESULTS: Pulmonary imaging and/or functional abnormalities were identified in 78 (74%) of 106 subjects; 45% had preclinical parenchymal lung disease. These individuals were older with lower diffusion capacity but had similar smoking histories compared with no disease. Preclinical emphysema (36%), the most commonly detected abnormality, was associated with older age, higher anti-cyclic citrullinated peptide antibody titres and diffusion abnormalities. A significant proportion of preclinical emphysema occurred among never smokers (47%) with a predominantly panlobular pattern. Preclinical ILD (15%) was not associated with clinical, laboratory or functional measures. CONCLUSION: We identified a high prevalence of undiagnosed preclinical parenchymal lung disease in RA driven primarily by isolated emphysema, suggesting that it may be a prevalent and previously unrecognized pulmonary manifestation of RA, even among never smokers. As clinical, laboratory and functional evaluations did not adequately identify preclinical parenchymal abnormalities, HRCT may be the most effective screening modality currently available for patients with RA.

Geometric Features Associated with Middle Cerebral Artery Bifurcation Aneurysm Formation: A Matched Case-Control Study.

OBJECTIVES: The pathogenesis of intracranial aneurysms is multifactorial and includes genetic, environmental, and anatomic influences. We aimed to identify image-based morphological parameters that were associated with middle cerebral artery (MCA) bifurcation aneurysms. MATERIALS AND METHODS: We evaluated three-dimensional morphological parameters obtained from CT angiography (CTA) or digital subtraction angiography (DSA) from 317 patients with unilateral MCA bifurcation aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We chose the contralateral unaffected MCA bifurcation as the control group, in order to control for genetic and environmental risk factors. Diameters and angles of surrounding parent and daughter vessels of 634 MCAs were examined. RESULTS: Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with smaller (≤ 3 mm) aneurysms only and with angles excluded, were also performed. In a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 0.0004, 95% CI 0.0001-0.15), larger daughter-daughter angles (OR 1.08, 95% CI 1.06-1.11) and larger parent-daughter angle ratios (OR 4.24, 95% CI 1.77-10.16) were significantly associated with MCA aneurysm presence after correcting for other variables. In order to account for possible changes to the vasculature by the aneurysm, a subgroup analysis of small aneurysms (≤ 3 mm) was performed and showed that the results were similar. CONCLUSIONS: Easily measurable morphological parameters of the surrounding vasculature of the MCA may provide objective metrics to assess MCA aneurysm formation risk in high-risk patients.

Satisfaction With a Virtual Learning Collaborative Aimed at Implementing Treat-to-Target in Rheumatoid Arthritis.

OBJECTIVE: Limited information is available concerning experiences of participants in a virtual learning collaborative (LC), and little qualitative data or participant feedback on how this format can be improved. One prior in-person LC in rheumatology successfully improved adherence with treat-to-target (TTT) for RA. We conducted a virtual LC on TTT and herein report on participant satisfaction. METHODS: We conducted a virtual LC with 18 rheumatology practices from across the United States during 2020 to 2021. The LC included a virtual kickoff meeting and monthly videoconferences, accompanied by data submission and feedback. At the conclusion of the LC, we surveyed the 45 LC participants concerning individual experience and satisfaction. RESULTS: All sites and 78% of participants responded to the surveys. The LC included small and large practices, 14 academic and 4 nonacademic, and respondents ranged in their roles: 24 physicians, 5 nurses or nurse practitioners, 3 administrators, and 3 other roles. Overall, 94% of respondents indicated they were either somewhat or very satisfied with the LC, and 94% said they would recommend a similar LC to a colleague. Aspects of the LC described as "very useful" included a kickoff meeting, intersite discussion, and monthly speakers; however, digital tools such as the Web site and meeting recordings were not found useful. CONCLUSIONS: Virtual LCs are feasible, and participants reported strong satisfaction. Virtual LCs were highly valued by rheumatologists, trainees, and their practice staffs. Potential topics were identified for future LCs that could improve the quality of care delivered to rheumatology patients.

Adjustment of the multi-biomarker disease activity score to account for age, sex and adiposity in patients with rheumatoid arthritis.

OBJECTIVE: To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. METHODS: Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). RESULTS: Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. CONCLUSION: Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

Elevated International Normalized Ratio Is Associated With Ruptured Aneurysms.

Background and Purpose- The effects of anticoagulation therapy and elevated international normalized ratio (INR) values on the risk of aneurysmal subarachnoid hemorrhage are unknown. We aimed to investigate the association between anticoagulation therapy, elevated INR values, and rupture of intracranial aneurysms. Methods- We conducted a case-control study of 4696 patients with 6403 intracranial aneurysms, including 1198 prospective patients, diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 who were on no anticoagulant therapy or on warfarin for anticoagulation. Patients were divided into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to evaluate the association of anticoagulation therapy, INR values, and presentation with a ruptured intracranial aneurysm, taking into account the interaction between anticoagulant use and INR. Inverse probability weighting using propensity scores was used to minimize differences in baseline demographics characteristics. The marginal effects of anticoagulant use on rupture risk stratified by INR values were calculated. Results- In unweighted and weighted multivariable analyses, elevated INR values were significantly associated with rupture status among patients who were not anticoagulated (unweighted odds ratio, 22.78; 95% CI, 10.85-47.81 and weighted odds ratio, 28.16; 95% CI, 12.44-63.77). In anticoagulated patients, warfarin use interacts significantly with INR when INR ≥1.2 by decreasing the effects of INR on rupture risk. Conclusions- INR elevation is associated with intracranial aneurysm rupture, but the effects may be moderated by warfarin. INR values should, therefore, be taken into consideration when counseling patients with intracranial aneurysms.

Antihyperglycemic Agents Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias. RESULTS: In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39-0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34-0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status. CONCLUSIONS: Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.

Low Serum Calcium and Magnesium Levels and Rupture of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage, suggesting hypocalcemia- and hypomagnesemia-induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms. METHODS: The medical records of 4701 patients, including 1201 prospective patients, diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. One thousand two hundred seventy-five patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels and ruptured aneurysms. RESULTS: In multivariable analysis, both albumin-corrected calcium (odds ratio, 0.33; 95% confidence interval, 0.27-0.40) and magnesium (odds ratio, 0.40; 95% confidence interval, 0.28-0.55) were significantly and inversely associated with ruptured intracranial aneurysms. CONCLUSIONS: In this large case-control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis caused by hypocalcemia and hypomagnesemia may explain this association.

Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

Clinical patient registry recruitment and retention: a survey of patients in two chronic disease registries.

BACKGROUND: The collection of routine clinical data in the setting of research registries can serve an important role in understanding real world care. However, relatively little is known about the patient experience in registries, motivating us to survey patients enrolled in two chronic disease registries. METHODS: We conducted similar surveys in two disease-based registries based at one academic medical center in the US. One group of patients with rheumatoid arthritis (RA) had been enrolled in a registry, and we focused on retention factors. In a second group of patients with inflammatory bowel disease (IBD) recently enrolled or considering enrollment, we examined factors that would influence their enrollment and willingness to answer frequent questionnaires and give biospecimens. The surveys were analyzed using descriptive statistics and the two cohorts were compared using nonparametric and chi-square tests. RESULTS: We received 150 (50%) completed surveys from RA and 169 (63%) from IBD patients. Mean age of subjects was 62 years in RA and 43 in IBD with more women respondents with RA (83%) than IBD (62%). The two groups described very similar factors as the top three motivations for participation: desire to help others, desire to improve care of own disease, and ease of volunteering. Preferred methods of surveying included mail, e-mail, but telephone was not favored; age was an important correlate of this preference. Respondents preferred surveys either every 1-3 months (28.7% RA and 55.0% IBD) or every 4-6 months (50.7% RA and 29.0% IBD). They differed in the preference for payment for answering surveys with 68.0% with RA answering that no payment was necessary but only 36.1% with IBD felt similarly. CONCLUSIONS: Patients engaged in clinical registries demonstrate a high level of commitment to improve care and many report a willingness to answer questions relatively frequently.

Validity of the Nurses' health study physical activity questionnaire in estimating physical activity in adults with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) demonstrate reduced aerobic capacity, excess cardiovascular risk, mobility limitations and are less physically active than their healthy peers. Physical activity may decrease RA disease activity through its anti-inflammatory effects and psychological and health benefits. To successfully manage RA symptoms and reduce cardiovascular risks associated with RA through increased physical activity (PA), accurate physical activity assessments are critical. Accelerometry is an objective physical activity measure, but not widely used. Validity of the Nurses' Health Study physical activity questionnaire II (NHSPAQ) has not been determined for estimation of physical activity in RA. This study examined NHSPAQ validity in adults with RA compared to accelerometry-based metabolic equivalents determined (METs) and results of performance tests. We hypothesized NHSPAQ scores would correlate moderately (0.4-0.5) with accelerometer physical activity estimates. METHODS: Thirty-five adults with RA (mean age [SD] 62 (Williams et. al, Health Qual Life Outcomes 10:28, 2012) years, 28 females (80%) recruited from a hospital-based clinic registry participated in a one-week accelerometry trial. Medical data was compiled. Participants completed the NHSPAQ, a self-paced 20-m walk test, and modified timed step test. Participants wore an accelerometer for 7 consecutive days, then completed a physical activity log and another NHSPAQ. Metabolic equivalents (METs) were derived from NHSPAQ and accelerometers using standardized formulas. NHSPAQ METs were correlated with accelerometer METs and data from performance measures. RESULTS: Average disease duration was 21 years (SD = 11), 63% patients took biologics. The average weekly METs reported were 29 (SD = 33) and accelerometer METs were 33 (SD = 22). NHSPAQ METs correlated moderately with accelerometer-derived METs (r = 0.48 95% CI (0.15-0.70). Self-reported PA correlated moderately with Step Test performance (r = 0.50 95% CI (0.18-0.72). CONCLUSION: Patients with RA exhibit low physical activity levels. General fitness measures were moderately correlated with physical activity levels. A moderate significant correlation existed between NHSPAQ and accelerometry METs. These preliminary data suggest the NHSPAQ may be useful to describe physical activity levels in this population.

Multibiomarker disease activity score and C-reactive protein in a cross-sectional observational study of patients with rheumatoid arthritis with and without concomitant fibromyalgia.

OBJECTIVES: To examine the association between a multibiomarker disease activity (MBDA) score, CRP and clinical disease activity measures among RA patients with and without concomitant FM. METHODS: In an observational cohort of patients with established RA, we performed a cross-sectional analysis comparing MBDA scores with CRP by rank correlation and cross-classification. MBDA scores, CRP and clinical measures of disease activity were compared between patients with RA alone and RA with concomitant FM (RA and FM) by univariate and multivariate analyses. RESULTS: CRP was ⩽1.0 mg/dl for 184 of 198 patients (93%). MBDA scores correlated with CRP (r = 0.755, P < 0.001), but were often discordant, being moderate or high for 19%, 55% and 87% of patients with CRP ⩽0.1, 0.1 to ⩽0.3, or 0.3 to ⩽1.0 mg/dl, respectively. Among patients with CRP ⩽1.0 mg/dl, swollen joint count (SJC) increased linearly across levels of MBDA score, both with (P = 0.021) and without (P = 0.004) adjustment for CRP, whereas CRP was not associated with SJC. The 28-joint-DAS-CRP, other composite measures, and their non-joint-count component measures were significantly greater for patients with RA and FM (n = 25) versus RA alone (n = 173) (all P ⩽ 0.005). MBDA scores and CRP were similar between groups. CONCLUSION: MBDA scores frequently indicated RA disease activity when CRP did not. Neither one was significantly greater among patients with RA and FM versus RA alone. Thus, MBDA score may be a useful objective measure for identifying RA patients with active inflammation when CRP is low (⩽1.0 mg/dl), including RA patients with concomitant FM.

Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers.

RATIONALE: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. OBJECTIVES: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. METHODS: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. MEASUREMENTS AND MAIN RESULTS: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. CONCLUSIONS: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Outcomes and costs of incorporating a multibiomarker disease activity test in the management of patients with rheumatoid arthritis.

OBJECTIVE: The multibiomarker disease activity (MBDA) blood test has been clinically validated as a measure of disease activity in patients with RA. We aimed to estimate the effect of the MBDA test on physical function for patients with RA (based on HAQ), quality-adjusted life years and costs over 10 years. METHODS: A decision analysis was conducted to quantify the effect of using the MBDA test on RA-related outcomes and costs to private payers and employers. Results of a clinical management study reporting changes to anti-rheumatic drug recommendations after use of the MBDA test informed clinical utility. The effect of treatment changes on HAQ was derived from 5 tight-control and 13 treatment-switch trials. Baseline HAQ scores and the HAQ score relationship with medical costs and quality of life were derived from published National Data Bank for Rheumatic Diseases data. RESULTS: Use of the MBDA test is projected to improve HAQ scores by 0.09 units in year 1, declining to 0.02 units after 10 years. Over the 10 year time horizon, quality-adjusted life years increased by 0.08 years and costs decreased by US$457 (cost savings in disability-related medical costs, US$659; in productivity costs, US$2137). The most influential variable in the analysis was the effect of the MBDA test on clinician treatment recommendations and subsequent HAQ changes. CONCLUSION: The MBDA test aids in the assessment of disease activity in patients with RA by changing treatment decisions, improving the functional status of patients and cost savings. Further validation is ongoing and future longitudinal studies are warranted.

Clinical characteristics of RA patients with secondary SS and association with joint damage.

OBJECTIVES: Secondary SS (sSS) is a common extra-articular manifestation of RA. There are conflicting data regarding the association of sSS with worse joint damage. This study aims to characterize sSS patients in an RA cohort and study the association between sSS and joint damage. METHODS: We conducted a cross-sectional study of RA patients with ≥1 year of follow-up at a large academic centre. Subjects with co-morbid diseases that can also result in sicca symptoms were excluded from the analysis. Subjects were considered to have sSS if they were reported as having sSS by their rheumatologist at recruitment into the cohort and had the diagnosis confirmed by chart review. The primary outcome was Sharp score using bilateral hand radiographs at recruitment. We constructed a linear regression model to determine the association of sSS status and Sharp score adjusted by age, gender, disease duration and ACPA and RF status. RESULTS: We studied 829 RA subjects, mean age 57 years, 83% female, mean RA duration 13 years, 74% seropositive; 85 subjects (10.3%) had sSS. We observed a female predominance (95.3%), longer mean disease duration (16.9 years) and higher frequency of RF or ACPA positive among patients with sSS and RA. Having sSS at baseline was associated with higher Sharp scores (P = 0.03), independent of age, gender, RA disease duration and seropositive disease. CONCLUSION: In our RA cohort, RA subjects with sSS had worse joint damage, suggesting that sSS is a marker of more aggressive disease.

The impact of multimorbidity status on treatment response in rheumatoid arthritis patients initiating disease-modifying anti-rheumatic drugs.

OBJECTIVE: When treating RA patients, remission (REM) or at least low disease activity (LDA) is the ultimate therapeutic goal. The aim of this study was to assess the impact of multimorbidity on achieving REM or LDA. METHODS: In a prospective RA cohort, we identified patients initiating any DMARD with follow-up data 1 year after. Treatment effects were measured using the clinical disease activity index (CDAI) and the modified health assessment questionnaire (MHAQ); multimorbidity status was assessed using a counted multimorbidity index (cMMI). The proportion of patients reaching REM or LDA 1 year after DMARD commencement with respect to the cMMI was evaluated. In regression models, we calculated the odds ratio of achieving REM or LDA, and predicted CDAI and MHAQ 1 year after DMARD commencement for various levels of cMMI, adjusting for age, sex, disease duration, serostatus, disease activity at DMARD commencement, number of previous DMARDs, and type of DMARD, steroid and NSAID use. RESULTS: A total of 815 patients started DMARDs; 414 were on the same DMARD after 1 year. The proportion of these patients achieving REM or LDA after 1 year was significantly lower in the patients with higher cMMI, following a linear trend (P < 0.01). After accounting for covariates, the odds ratio for REM associated with each additional morbidity in the cMMI was 0.72 (95% CI 0.55, 0.97) and 0.81 (95% CI 0.70, 0.94) for LDA. One year after DMARD initiation, CDAI (+0.16 per additional morbidity) and MHAQ scores (+0.15 per additional morbidity) were significantly worse (both P < 0.05). CONCLUSION: Increased multimorbidity negatively affects the therapeutic goal of REM and LDA.

Principal components analysis corrects for stratification in genome-wide association studies.

Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.