Brigham Rheumatoid Arthritis Sequential Study Research Articles

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

Symmetrical involvement of the hand joints is described as characteristic of rheumatoid arthritis (RA). Quantitative data on specific patterns of involvement are lacking. The Brigham Rheumatoid Arthritis Sequential Study was created for observational studies of patients with RA and afforded a unique opportunity to answer these questions. 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. 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. 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.

Incidence and predictors of dyspnea on exertion in a prospective cohort of patients with rheumatoid arthritis.

ObjectiveTo investigate the incidence and predictors of dyspnea on exertion among subjects with rheumatoid arthritis (RA).MethodsWe investigated dyspnea on exertion using a prospective cohort, the Brigham RA Sequential Study (BRASS). Clinically significant dyspnea on exertion was defined as a score of ≥ 3 (unable to ambulate without breathlessness or worse) on the validated Medical Research Council (MRC) scale (range 0‐5). We analyzed subjects with MRC score < 3 at BRASS baseline and at ≥ 1 year of follow‐up. The MRC scale was administered annually. We determined the incidence rate (IR) of dyspnea on exertion. We used Cox regression to estimate the hazard ration (HR) for dyspnea on exertion occurring one year after potential predictors were assessed.ResultsWe analyzed 829 subjects with RA and no clinically significant dyspnea on exertion during a mean follow‐up period of 3.0 years (SD 1.9). At baseline, mean age was 55.7 years (SD 13.6), 82.4% of subjects were female, and median RA duration was 8 years. During follow‐up, 112 subjects (13.5%) developed incident dyspnea on exertion during 2476 person‐years of follow‐up (incidence rate 45.2 per 1000 person‐years). Independent predictors of incident dyspnea on exertion were older age (HR 1.03 per year, 95% CI, 1.01‐1.04), female sex (HR 2.22, 95% CI, 1.14‐4.29), mild dyspnea (HR 2.62, 95% CI, 1.60‐4.28), and worsened Multi‐Dimensional Health Assessment Questionnaire score (HR 2.36 per unit, 95% CI, 1.54‐3.60). Methotrexate use, RA disease activity, and seropositivity were not associated with incident dyspnea on exertion after accounting for other dyspnea risk factors.ConclusionDyspnea on exertion occurred commonly in patients with RA. Older women with impaired physical function were especially vulnerable to developing dyspnea on exertion.

Fibromyalgia and the Prediction of Two‐Year Changes in Functional Status in Rheumatoid Arthritis Patients

Previous cross-sectional studies have shown that rheumatoid arthritis (RA) patients with fibromyalgia (FM) have higher disease activity, greater medical costs, and worse quality of life compared to RA patients without FM. We determined the impact of FM on 2-year changes in the functional status of RA patients in a prospective study. Subjects included participants in the Brigham Rheumatoid Arthritis Sequential Study who were enrolled in a substudy of the effects of pain in RA. Subjects completed questionnaires, including the Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and Polysymptomatic Distress (PSD) scale, semiannually, and underwent physical examination and laboratory tests yearly. Of the 156 included RA subjects, 16.7% had FM, while 83.3% did not. In a multivariable linear regression model adjusted for age, sex, race, baseline MDHAQ score, disease duration, rheumatoid factor/cyclic citrullinated peptide antibody seropositivity, disease activity, and psychological distress, RA patients with FM had a 0.14 greater 2-year increase in MDHAQ score than RA patients without FM (P = 0.021). In secondary analyses examining the association between continuous PSD scale score and change in MDHAQ, higher PSD scale scores were significantly associated with greater 2-year increases in MDHAQ score (β coefficient 0.013, P = 0.011). Both the presence of FM and increasing number of FM symptoms predicted worsening of functional status among individuals with RA. Among individuals with RA and FM, the magnitude of the difference in changes in MDHAQ was 4- to 7-fold higher than typical changes in MDHAQ score among individuals with established RA.

Inconsistent Treatment with Disease-modifying Antirheumatic Drugs: A Longitudinal Data Analysis

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. 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. 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. 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.

OP0279 Inconsistent Treatment with Disease-Modifying Anti-Rheumatic Drugs: A Longitudinal Data Analysis

BackgroundCurrent recommendations advocate treatment with disease-modifying anti-rheumatic drugs (DMARDs) in all patients with active rheumatoid arthritis (RA). However, results from contemporary RA cohorts show that even in specialized rheumatology clinics,...

The influence of polygenic risk scores on heritability of anti-CCP level in RA

ObjectiveTo study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients.MethodsWe carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels.ResultsGWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10−11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10−8, and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10−7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants.ConclusionsAnti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels.

OP0051 Joint damage progression in established rheumatoid arthritis: Common and strongly associated with seropositivity

BackgroundDuring the last decade, rheumatoid arthritis (RA) research has mainly focused on early disease, as it has become apparent that early and aggressive treatment can change the long-term outcome of...

Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study.

IntroductionDisease remission has become a feasible goal for most rheumatoid arthritis (RA) patients; however, patient-reported symptoms, such as pain, may persist despite remission. We assessed the prevalence of pain in RA patients in remission according to the Disease Activity Score (DAS28-CRP4) and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria.MethodsData were analyzed from RA patients in the Brigham Rheumatoid Arthritis Sequential Study with data at baseline and 1 year. DAS28 remission was defined as DAS28-CRP4 <2.6. The ACR/EULAR remission criteria included (a) one or more swollen joints, (b) one or more tender joints, (c) C-reactive protein ≤1 mg/dl, and (d) patient global assessment score ≤1. Pain severity was measured by using the pain score from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ). The associations between baseline clinical predictors and MDHAQ pain at baseline and 1 year were assessed by using multivariable linear regression.ResultsAmong the 865 patients with data at baseline and 1 year, 157 (18.2%) met DAS28-CRP4 remission criteria at both time points. Thirty-seven (4.3%) met the ACR/EULAR remission criteria at baseline and 1 year. The prevalence of clinically significant pain (MDHAQ pain ≥4) at baseline ranged from 11.9% among patients meeting DAS28-CRP4 remission criteria to none among patients meeting ACR/EULAR remission criteria. Patient global assessment, MDHAQ function, MDHAQ fatigue, MDHAQ sleep, and arthritis self-efficacy were significantly associated with MDHAQ pain in cross-sectional (P ≤ 0.0005) and longitudinal analyses (P ≤ 0.03). Low swollen-joint counts were associated with high MDHAQ pain in longitudinal analyses (P = 0.02) but not cross-sectional analyses. Other measures of inflammatory disease activity and joint damage were not significantly associated with MDHAQ pain at baseline or at 1 year.ConclusionsClinically significant pain continues among a substantial proportion of patients in DAS28 remission but not among those in ACR/EULAR remission. Among patients in DAS28 remission, patient global assessment, disability, fatigue, sleep problems, and self-efficacy are strongly associated with pain severity at baseline and 1 year, whereas inflammatory disease activity and joint damage are not significantly associated with elevated pain severity at either baseline or 1 year.

TNFα Inhibitors May Improve Asthma Symptoms: A Case Series of 12 Patients With Rheumatoid Arthritis and Asthma

Asthma is a chronic inflammatory disease that constitutes one of the leading causes of chronic obstructive pulmonary disease(1). Most patients with moderate or severe disease are treated with inhaled corticosteroids, but many patients have refractory disease(2). Treatment options for these refractory patients are limited; there are emerging data on the effectiveness of tumor necrosis factor alpha (TNF)α inhibitors(3–5), but there are no long-term studies. In this report, we studied a large prospective RA cohort, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), to identify a case series of patients with both RA and asthma, who were treated with TNFα inhibitors. We aimed to determine whether asthma symptoms correlated with TNFα inhibitor therapy.

Genome-Wide Association Study of Determinants of Anti-Cyclic Citrullinated Peptide Antibody Titer in Adults with Rheumatoid Arthritis

We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.

Associations between Human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study

Background:HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA).Objective:We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in...

Agreement between patient report and medical record review for medications used for rheumatoid arthritis: The accuracy of self‐reported medication information in patient registries

With the growth in patient registries in rheumatic disease research, it is important to validate the collected information. We examined the convergent validity of self-reported medication use for rheumatoid arthritis (RA). In the setting of the Brigham Rheumatoid Arthritis Sequential Study (BRASS), a large registry of patients with RA, we examined the agreement between patients' self-report of current and past RA medication use and information from medical records. For a sample of patients in BRASS, these 2 sources of information were compared using the kappa statistic as well as the percent agreement. The 91 patients selected for assessment were typical of a prevalent RA cohort: >80% were women and the mean disease duration was 16 years. The agreement for current medication use was excellent, ranging from 0.71 for sulfasalazine to 0.96 for methotrexate. However, for past medication use agreement was lower, ranging from 0.13 for methotrexate to 0.74 for aurothioglucose. The weighted kappa for cumulative oral glucocorticoid dose was 0.67. Self-report of current medication use and cumulative oral glucocorticoid dose appears to have moderate to excellent validity. However, self-report of past medication use may not be valid.