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.

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.

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.

Remission and radiographic outcome in rheumatoid arthritis: application of the 2011 ACR/EULAR remission criteria in an observational cohort.

OBJECTIVES: One goal of remission in rheumatoid arthritis (RA) is to halt joint damage. The authors assessed the progression of radiographic joint damage among RA patients in remission by the new ACR/EULAR criteria (Boolean approach) compared with remission thresholds for the simplified disease activity index (SDAI), clinical disease activity index (CDAI) and disease activity score based on 28 joints and C-reactive protein (DAS28-CRP) in an observational cohort, and evaluated the relationship between time in remission and radiographic joint damage. METHODS: 535 RA patients underwent physical examination and laboratory assessment at baseline, 1 and 2 years. Radiographs at baseline and 2 years were scored by the van der Heijde modified Sharp score (TSS). Positive likelihood ratios for a good radiographic outcome (change in TSS <1 unit/year) were calculated for each of the remission criteria. Radiographic progression was compared between patients in remission at none, one, two and three visits by χ(2) goodness of fit statistics. RESULTS: 20% of patients in ACR/EULAR remission at baseline had radiographic progression, 24% in SDAI remission, 19% in CDAI remission and 30% of patients in DAS28-CRP remission. The positive likelihood ratio for good radiographic outcome was 2.6 for ACR/EULAR criteria, 2.1 for SDAI, 2.8 for CDAI and.1.5 for DAS28-CRP. Reduced radiographic progression was observed for patients with an increasing number of visits in remission (p<0.003 for all criteria, χ(2) goodness of fit statistics). CONCLUSIONS: Patients with RA in remission by any established criteria can experience radiographic progression. An increased number of visits in remission was associated with reduced radiographic damage.

Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study.

The objective of this review is to report on the progress of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry data collection and summarize previous research in understanding therapeutic response to DMARDs using clinical and genetic data. The BRASS Registry, established in 2003, is a large, single-centre, prospective and observational cohort of 1100 RA patients. Patients with either new-onset or established RA disease are recruited from the practices of rheumatologists. Annual visits collect information on demographics, 28-joint DAS-CRP3 (DAS-28-CRP3), medication use, comorbidities and functional status (Modified Health Assessment Questionnaire, Short Form Health Survey 12). Two published studies have utilized BRASS to examine genetic predictors of treatment response. In a cross-sectional study, examining the association between candidate single nucleotide polymorphisms (SNPs) and disease activity in a subset of 120 RA patients on MTX monotherapy, the minor allele of ATIC rs4673993 was associated with low disease activity (P=0.01, DAS-28-CRP3≤3.2). In an international collaboration, 55 BRASS patients receiving anti-TNF therapy were genotyped for 31 SNPs associated with the risk of RA. With our collaborators, we discovered an SNP at the protein tyrosine phosphatase, receptor type, C (PTPRC) gene locus that was associated with EULAR 'good response'. With accurate data collection and the capacity to run genome-wide association studies and SNP analyses, the BRASS Registry has the ability to determine the contribution of genetic variants to disease onset and to assess their usefulness as biomarkers for treatment response and drug toxicity.

Lifestyle and Clinical Risk Factors for Incident Rheumatoid Arthritis-associated Interstitial Lung Disease.

OBJECTIVE: To determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD. METHODS: This nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures. RESULTS: We identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11-5.24 vs normal BMI; OR 2.61, 95% CI 1.21-5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32-7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72-13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73-0.85). CONCLUSION: Obesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest.

Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: Prevalence, risk factors, and impact on mortality.

OBJECTIVE: We aimed to determine the real-world prevalence and investigate risk factors for rheumatoid arthritis (RA)-related lung disease on chest computed tomography (CT) imaging. We also investigated the impact of RA-related lung disease on mortality. METHODS: We studied chest CT imaging abnormalities among RA patients. We determined the presence and type of abnormalities using the chest CT imaging radiologic report. RA-related lung disease was defined as interstitial lung disease (ILD), bronchiectasis, or pleural disease. We examined whether demographics and RA characteristics were associated with RA-related lung disease using logistic regression. RA-related lung disease and mortality was described using survival curves and Cox regression. RESULTS: We analyzed 190 patients who had chest CT imaging performed for clinical indications. Mean age was 64.2 years (SD 11.8), 80.0% were female, and 75.3% were seropositive. RA-related lung disease was detected in 54 patients (28.4%); 30 (15.8%) had ILD, 27 (14.2%) had bronchiectasis, and 18 (9.5%) had pleural disease. RA-related lung disease was reported in both seropositive and seronegative RA (28.7% vs. 27.7%, p = 1.00). Male sex (OR 2.62, 95%CI 1.17-5.88) and current methotrexate use (OR 2.73, 95%CI 1.27-5.61 vs. not current) were associated with RA-related lung disease. Twenty-four (44.4%) patients with RA-related lung disease died during mean 7.0 years of follow-up. RA-related lung disease had HR of 5.35 (95%CI 0.72-39.9) for mortality compared to normal chest CT. CONCLUSIONS: In this real-world study, RA-related lung disease was commonly detected on chest CT imaging regardless of RA serostatus. RA-related lung disease had high mortality, emphasizing the importance in close monitoring of these patients.

Correction to: Association of rheumatoid arthritis-related autoantibodies with pulmonary function test abnormalities in a rheumatoid arthritis registry.

The publisher regrets that the two sections under the Results omitted inadvertently on the original published version of the above article.

Association of Changes in Anticitrullinated Protein Antibody Levels With Resource Use and Disease Activity Measures in Rheumatoid Arthritis Patients a US Observational Cohort.

PURPOSE: Anticitrullinated protein antibody (ACPA) concentration, beyond ACPA positivity, is indicative of more aggressive radiographic progression in patients with rheumatoid arthritis (RA). However, there is limited information on the association of changes in ACPA with resource use measures and/or disease activity measures. We evaluate associations between changes in levels of ACPA and outcomes, including durable medical equipment (DME) use, hospitalizations, and disease activity, in patients with established RA. METHODS: Patients from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study who had ACPA measurements at baseline and month 12 were included. Changes in ACPA levels from baseline to month 12 were categorized as a decrease (<-10%), no change (-10% to +10%), or increase (>+10%). DME use and hospitalizations were assessed twice yearly using patient questionnaires; disease activity was assessed annually. Binary multivariate logistic regression was used to analyze the association between changes in ACPA levels and DME use and hospitalizations; linear regression was used to assess the association with disease activity. FINDINGS: Of 840 patients included in the analysis, 291 (34.6%), 266 (31.7%), and 283 (33.7%) had a decrease, no change, or increase in ACPA levels, respectively. A decrease in ACPA levels was associated with a reduction in DME use (adjusted odds ratio [aOR] = 0.64; 95% CI, 0.44-0.93; P = 0.02) and hospitalizations (aOR = 0.62; 95% CI, 0.41-0.95; P = 0.03) versus no change or increase. Adjusted mean changes in disease activity score in 28 joints (C-reactive protein), total and swollen joint counts, and pain scores were significantly greater in patients with decreased ACPA levels versus those with no change or increase (P < 0.05). IMPLICATIONS: Among patients with RA, reductions in ACPA levels of >10% were associated with reductions in DME use, hospitalizations, and disease activity. ClinicalTrials.gov identifier: NCT01793103.

Association of rheumatoid arthritis-related autoantibodies with pulmonary function test abnormalities in a rheumatoid arthritis registry.

INTRODUCTION: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs). METHODS: We studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics. RESULTS: Among 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30-4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26-4.87), 3.12 (95% CI 1.28-7.61), and 2.30 (95% CI 1.09-4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21-3.27 for RF+ vs. RF-; OR 1.67, 95% CI 1.03-2.69 for CCP+ vs. CCP-) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend < 0.05). CONCLUSIONS: Seropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking.Key points• Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry.• We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA.• Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality.• These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity.

Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study.

OBJECTIVE: To evaluate rheumatoid arthritis (RA) disease activity and risk of RA-associated interstitial lung disease (RA-ILD). METHODS: We investigated disease activity and risk of RA-ILD using the Brigham RA Sequential Study (BRASS, 2003-2016). All patients were diagnosed as having RA according to accepted criteria. Disease Activity Scores in 28 joints (DAS28) and covariate data were measured prospectively at annual study visits. Diagnosis of RA-ILD was determined by review of images from clinically indicated chest computed tomography scans. We analyzed patients without RA-ILD at baseline. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for RA-ILD, using annually updated DAS28 data, with adjustment for known RA-ILD risk factors (age, sex, smoking status, RA duration, and serologic status). We performed alternative analyses that did not censor at the time of missing DAS28 data and included adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, and presence of rheumatoid nodules. RESULTS: Among 1,419 participants, the mean ± SD age was 55.8 ± 14.2 years, and 68.6% were seropositive for either cyclic citrullinated peptide or rheumatoid factor. We identified 85 incident cases of RA-ILD during a mean ± SD follow-up duration of 8.9 ± 4.2 years per patient. The moderate/high disease activity group had a multivariable HR of 2.22 (95% CI 1.28-3.82) for RA-ILD compared to the remission/low disease activity group. Risk of RA-ILD increased across disease activity categories: multivariable HR 1.00 (reference) for remission, 1.41 (95% CI 0.61-3.28) for low disease activity, 2.08 (95% CI 1.06-4.05) for moderate disease activity, and 3.48 (95% CI 1.64-7.38) for high disease activity (P for trend = 0.001). For each unit increase in the DAS28, the risk of RA-ILD increased by 35% (95% CI 14-60%). Results were similar in analyses that included follow-up for missing DAS28 data and with adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, or presence of rheumatoid nodules. CONCLUSION: Active articular RA was associated with an increased risk of developing RA-ILD. These results suggest that decreasing systemic inflammation may alter the natural history of RA-ILD development.

Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort.

INTRODUCTION: To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA). METHODS: Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR-BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2-immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1-3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] < 2.6) and bone loss was also explored. RESULTS: A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [-], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2- group. DXR-BMD was lower in the anti-CCP2+ vs. the anti-CCP2- groups (Gp1-3 vs. anti-CCP2-: P < 0.0001 for left and right hands). DXR-BMD decreased with increasing anti-CCP2 titer (P < 0.001 for left and right hands). Patients with low DXR-BMD were less likely to have a DAS28 (CRP) < 2.6 (P = 0.0181). CONCLUSION: Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity. FUNDING: Bristol-Myers Squibb. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01793103.

Association of anti-cyclic citrullinated protein antibodies, erosions, and rheumatoid factor with disease activity and work productivity: A patient registry study.

OBJECTIVES: To evaluate associations between the presence of anti-cyclic citrullinated protein antibodies (anti-CCP) and rheumatoid factor (RF) and other outcomes, including joint erosions and both clinical and economic endpoints, in patients with rheumatoid arthritis (RA). METHODS: Data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS), a prospective registry of adult RA patients with established or recent-onset RA, were analyzed. Logistic regression models were constructed to test associations between anti-CCP/RF seropositivity and erosive disease and the presence of anti-CCP/RF seropositivity plus erosive disease and (1) RA severity; (2) hospitalizations; (3) durable medical equipment (DME) use; and (4) worker productivity (e.g., employment status). Covariates in these models included patient age, gender, race, body mass index (BMI), number of comorbidities, and treatment. RESULTS: Among 1309 registrants, those who were positive (vs. negative) for anti-CCP were 2.72 times more likely to have erosions (OR = 2.72; 95% CI: 1.77-4.18; P < 0.001). Individuals positive (vs. negative) for RF were 36% more likely to have erosions (95% CI: 0.88-2.08; P = 0.162). Patients with anti-CCP seropositivity and erosions were significantly more likely to: (1) have higher disease activity as measured by the Disease Activity Score in 28 joints C-reactive protein (DAS28-CRP ≥ 2.6); (2) be hospitalized; (3) use DME; and (4) be unemployed, disabled, or long-term disabled. CONCLUSIONS: For the first time in a "real-world" setting including patients with both recent-onset and chronic RA, this study demonstrated that the combination of anti-CCP seropositivity and erosions were significantly associated with more adverse clinical and health-economic consequences, including a lower probability of low disease activity and higher health resource utilization, despite use of biologic disease-modifying antirheumatic drugs by many patients. This dual presentation may signal a need for more intensive therapies, even when observed in patients with chronic, as well as recent-onset, RA. Trial registration [Brigham and Women's Hospital (BWH) Rheumatoid Arthritis Sequential Study; Registry URL: https://clinicaltrials.gov/ct2/show/NCT01793103; ClinicalTrials.gov Identifier NCT01793103].

A School-Based Intervention to Increase Lyme Disease Preventive Measures Among Elementary School-Aged Children.

PURPOSE: Educational interventions to reduce Lyme disease (LD) among at-risk school children have had little study. The purpose of this study was to evaluate whether a short in-class LD education program based on social learning theory and the Health Belief Model (HBM) impacted a child's knowledge, attitude, and preventive behavior. METHODS: Students in grades 2-5 in 19 elementary schools were selected in an area that was highly endemic for LD. The children received an educational intervention or were on a wait list as controls. Their knowledge, attitudes, and self-reported preventive behaviors were surveyed before implementing the program and 1 year later. General linear regression analyses adjusting for age, gender, and baseline variables were used to measure the impact of the intervention. RESULTS: There were 3570 participants in the study: 1562 received the intervention, and 2008 were controls. The mean age for both groups was 9.1 years, with 53% women in the intervention group and 50% women in the control group. The children in the intervention group increased their overall knowledge of LD more than the children in the control group (overall knowledge score improvement, mean difference (SD) 1.38 (1.3) vs. 0.36 (1.3) p < 0.0001). All children in classes receiving the intervention reported an increase in precautionary behavior, positive attitude toward taking precautions, and self-efficacy compared with the wait list controls. Two LD cases were confirmed during the follow-up period, one in the intervention group and one in the controls. CONCLUSIONS: These findings demonstrate that a short in-class educational program that includes elements of the HBM, including: (1) awareness and knowledge about the disease, (2) benefits of preventive behavior, and (3) confidence in ability to perform preventive behaviors can improve knowledge, attitude, and self-reported precautionary behavior among at-risk children. www.clinicaltrials.gov : NCT00594997.

Effects of Achieving Target Measures in Rheumatoid Arthritis on Functional Status, Quality of Life, and Resource Utilization: Analysis of Clinical Practice Data.

OBJECTIVE: To evaluate associations between achieving guideline-recommended targets of disease activity, defined by the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) <2.6, the Simplified Disease Activity Index (SDAI) ≤3.3, or the Clinical Disease Activity Index (CDAI) ≤2.8, and other health outcomes in a longitudinal observational study. METHODS: Other defined thresholds included low disease activity (LDA), moderate (MDA), or severe disease activity (SDA). To control for intraclass correlation and estimate effects of independent variables on outcomes of the modified Health Assessment Questionnaire (M-HAQ), the EuroQol 5-domain (EQ-5D; a quality-of-life measure), hospitalization, and durable medical equipment (DME) use, we employed mixed models for continuous outcomes and generalized estimating equations for binary outcomes. RESULTS: Among 1,297 subjects, achievement (versus nonachievement) of recommended disease targets was associated with enhanced physical functioning and lower health resource utilization. After controlling for baseline covariates, achievement of disease targets (versus LDA) was associated with significantly enhanced physical functioning based on SDAI ≤3.3 (ΔM-HAQ -0.047; P = 0.0100) and CDAI ≤2.8 (-0.073; P = 0.0003) but not DAS28-CRP <2.6 (-0.022; P = 0.1735). Target attainment was associated with significantly improved EQ-5D (0.022-0.096; P < 0.0030 versus LDA, MDA, or SDA). Patients achieving guideline-recommended disease targets were 36-45% less likely to be hospitalized (P < 0.0500) and 23-45% less likely to utilize DME (P < 0.0100). CONCLUSION: Attaining recommended target disease-activity measures was associated with enhanced physical functioning and health-related quality of life. Some health outcomes were similar in subjects attaining guideline targets versus LDA. Achieving LDA is a worthy clinical objective in some patients.

Do rheumatologists know best? An outcomes study of inconsistent users of disease-modifying anti-rheumatic drugs.

OBJECTIVE: Current recommendations advocate treatment with disease-modifying anti-rheumatic drugs (DMARDs) in all patients with active rheumatoid arthritis (RA). We analyzed short-term disease outcome in patients according to the consistency of DMARD use in a clinical rheumatology cohort. METHODS: Patients in an RA registry (n = 617) were studied for DMARD use at semi-annual study time points during the first 18 months of follow-up and were divided into 4 groups according to the number of study time points with any DMARD use [0-1 study time points (n = 31), 2 study time points (n = 24), 3 study time points (n = 77), and 4 study time points (n = 485)]. The primary outcome analyses were performed at 24 months and included Disease Activity Score 28 (DAS28-CRP), modified Health Assessment Questionnaire (MHAQ) change, Short Form Health Survey-12 physical and mental summary scores (SF-12 PCS, SF-12 MCS), EuroQol 5-Dimensional health index (EQ-5D), and radiographic progression. Unadjusted, adjusted, and analyses stratified for seropositivity and disease activity were performed. A secondary analysis investigated 36-month outcomes. RESULTS: No significant 24-month outcome differences could be found between the DMARD use categories. For seropositive patients, there was evidence of a linear trend for SF-12 PCS (p = 0.02) and EQ-5D (p = 0.01) with worse outcomes for inconsistent DMARD users. At 36 months, there was a linear trend for higher DAS28-CRP scores for inconsistent users (p < 0.01). CONCLUSIONS: Overall, we found poor correlation between inconsistent DMARD use and short-term disease outcome. However, outcome in the longer term could be negatively influenced by inconsistent DMARD use, as well as short-term outcome in seropositive patients.

Inconsistent treatment with disease-modifying antirheumatic drugs: a longitudinal data analysis.

OBJECTIVE: Current recommendations advocate treatment with disease-modifying antirheumatic drugs (DMARD) in all patients with active rheumatoid arthritis (RA). We investigated the frequency of and reasons for inconsistent DMARD use among patients in a clinical rheumatology cohort. METHODS: Patients in the Brigham Rheumatoid Arthritis Sequential Study were studied for DMARD use (any or none) at each semiannual study timepoint during the first 2 study years. Inconsistent use was defined as DMARD use at ≤ 40% of study timepoints. Characteristics were compared between inconsistent and consistent users (> 40%), and factors associated with inconsistent DMARD use were determined through multivariate logistic regression. A medical record review was performed to determine the reasons for inconsistent use. RESULTS: Of 848 patients with ≥ 4 out of 5 visits recorded, 55 (6.5%) were inconsistent DMARD users. Higher age, longer disease duration, and rheumatoid factor negativity were statistically significant correlates of inconsistent use in the multivariate analyses. The primary reasons for inconsistent use identified through chart review, allowing for up to 2 co-primary reasons, were inactive disease (n = 28, 50.9%), intolerance to DMARD (n = 18, 32.7%), patient preference (n = 7, 12.7%), comorbidity (n = 6, 10.9%), DMARD not being effective (n = 3, 5.5%), and pregnancy (n = 3, 5.5%). During subsequent followup, 14/45 (31.1%) inconsistent users with sufficient data became consistent users of DMARD. CONCLUSION: A small proportion of patients with RA in a clinical rheumatology cohort were inconsistent DMARD users during the first 2 years of followup. While various patient factors correlate with inconsistent use, many patients re-start DMARD and become consistent users over time.