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Objective: To investigate elevation of anti-citrullinated protein antibodies (ACPAs) before diagnosis of rheumatoid arthritis (RA) and risks for chronic obstructive pulmonary disease (COPD) or asthma., Methods: We performed a matched cohort study nested within the Nurses' Health Studies among women who donated blood. Women with incident RA after blood draw (self-reported, then confirmed by medical records) were each matched to 3 controls by age, cohort, year, and menopausal factors. Pre-RA ACPA positivity was defined as >99th percentile of control distribution by a research assay or by cyclic citrullinated peptide in a subset. Incident COPD and asthma after index date (date of blood draw) were identified by questionnaires. Cox regression estimated hazard ratios (HRs) for incident COPD or asthma (in separate analyses) associated with pre-RA, pre-RA ACPA+, or pre-RA ACPA- phenotypes each compared to their matched non-RA controls., Results: We analyzed 283 women who were pre-RA and 842 controls; blood was donated a mean ± SD of 9.7 ± 5.8 years before RA diagnosis. Fifty-nine women (20.8%) were pre-RA ACPA+. There were 107 cases of incident COPD and 105 incident asthma cases during 21,489 person-years of follow-up. Pre-RA ACPA+ was associated with increased COPD risk (HR 3.04 [95% confidence interval (95% CI) 1.33-7.00]) after adjusting for covariates including smoking pack-years. Pre-RA ACPA+ had an HR for asthma of 1.74 (multivariable 95% CI 0.72-4.24), similar to the risk of asthma for pre-RA ACPA- (HR 1.65 [95% CI 1.11-2.46])., Conclusion: Women with elevated ACPA before RA diagnosis had increased risk for developing COPD compared to controls. Women who later developed RA were more likely to develop asthma than controls, regardless of pre-RA ACPA status., (© 2020, American College of Rheumatology.)

Objective: To determine the prevalence and clinical characteristics of juvenile idiopathic arthritis (JIA) in Alaska Native children., Methods: Potential cases of JIA were identified by querying administrative data from hospitals and clinics in the Alaska Tribal Health System for codes possibly identifying JIA. Medical record abstraction was performed to confirm criteria met for JIA, demographic and clinical characteristics, and treatment patterns. Individuals age ≤18 years with a confirmed diagnosis of JIA were included. The denominator for prevalence was the 2015 Alaska Area Indian Health Service user population age of ≤18 years., Results: The unadjusted prevalence of JIA in Alaska Native children was 74.6 per 100,000 (age-adjusted 79.0 per 100,000). JIA was more common in females than males (unadjusted prevalence 105.8 versus 45.0 per 100,000). Oligoarthritis was the most common subtype (31% of cases), but polyarthritis and enthesitis-related arthritis were also common (26% and 24% of cases, respectively), with a notably high prevalence of enthesitis-related arthritis. The median age at diagnosis was 9 years. Of the combined cohort with results available, 56% were antinuclear antibody positive, 23% were rheumatoid factor positive, 19% were anti-cyclic citrullinated peptide antibody positive, and 57% had the presence of HLA-B27. Uveitis had been diagnosed in 16% of cases., Conclusion: The prevalence of JIA in Alaska Native children may be higher than the general US population. Enthesitis-related arthritis makes up a higher proportion of cases than in other populations described likely because of the high prevalence of HLA-B27 in this population., (© 2019, American College of Rheumatology.)

Objective: Little is known about the experiences, values, and needs of people without arthritis who undergo predictive biomarker testing for the development of rheumatoid arthritis (RA). Our study aimed to explore the perspectives of these individuals and describe their information needs., Methods: A qualitative, multicenter interview study with a thematic analysis was conducted in Austria, Germany and the UK. Individuals were interviewed who underwent predictive biomarker testing for RA and had a positive test result but no diagnosis of any inflammatory joint disease. Participants included patients with arthralgia and asymptomatic individuals. Information and education needs were developed from the qualitative codes and themes using the Arthritis Educational Needs Assessment Tool as a frame of reference., Results: Thematic saturation was reached in 34 individuals (76% female, 24 [71%] with arthralgia, and 10 [29%] asymptomatic individuals). Thirty-seven codes were summarized into 4 themes: 1) decision-making around whether to undergo initial predictive testing, 2) willingness to consider further predictive tests, and/or 3) preventive interventions, including medication, and 4) varying reactions after receiving a positive test result. Individuals with arthralgia were more likely to be willing to take preventive action, undergo further testing, and experience psychological distress than asymptomatic individuals. All participants expressed the need for tailored, patient-understandable information., Conclusion: Individuals at risk of RA are currently the subjects of research aimed at developing better predictive strategies and preventive approaches. Their perceptions and needs should be addressed to inform the future development of interventions combined with education., (© 2019 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To investigate the risk of progression to rheumatoid arthritis (RA) in patients who were cyclic citrullinated peptide (CCP) antibody positive without RA at initial presentation., Methods: We performed a retrospective cohort study of CCP+ individuals seen at a US tertiary care system between 2009 and 2018 who were without RA or other systemic rheumatic disease by medical record review at the time of CCP antibody positivity. Progression to classifiable RA was determined through medical record review. We investigated the risk of progression to RA overall and stratified by CCP antibody level (low: >1 to 2× the upper limit of normal [ULN]; medium: >2 to 3× ULN; high: >3× ULN). Multivariable Cox regression estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for RA by CCP antibody level., Results: We identified 340 CCP+ patients who were without RA or other rheumatic disease at baseline. During 1,047 person-years of follow-up, 73 patients (21.5%) developed RA. The risk of progression to RA increased with CCP antibody level, with 46.0% (95% CI 34.7-55.3) of patients with high-level CCP antibodies progressing to RA by 5 years. Compared to low CCP antibody level, medium (HR 3.00 [95% CI 1.32-6.81]) and high (HR 4.83 [95% CI 2.51-9.31]) CCP antibody levels were strongly associated with progression to RA, adjusting for age, sex, body mass index, smoking, family history of RA, and rheumatoid factor level., Conclusion: Among CCP+ patients without RA, the risk for progression to RA increased substantially with increasing CCP antibody level. This study provides further support for close monitoring for development of RA among CCP+ patients and identifying strategies to mitigate this risk., (© 2018, American College of Rheumatology.)

Objective: To investigate the impact and timing of smoking cessation on developing rheumatoid arthritis (RA) and serologic phenotypes., Methods: We investigated smoking cessation and RA risk in the Nurses' Health Study (NHS) (1976-2014) and the NHS II (1989-2015). Smoking exposures and covariates were obtained by biennial questionnaires. Self-reported RA was confirmed by medical record review for American College of Rheumatology/European League Against Rheumatism criteria. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for RA serologic phenotypes (all, seropositive, seronegative) according to smoking status, intensity, pack-years, and years since cessation., Results: Among 230,732 women, we identified 1,528 incident cases of RA (63.4% of which were seropositive) during 6,037,151 person-years of follow-up. Compared with never smoking, current smoking increased the risk of all RA (multivariable HR 1.47, 95% CI 1.27-1.72) and seropositive RA (HR 1.67, 95% CI 1.38-2.01) but not seronegative RA (HR 1.20, 95% CI 0.93-1.55). An increasing number of smoking pack-years was associated with an increased trend for the risk of all RA (P < 0.0001) and seropositive RA (P < 0.0001). With increasing duration of smoking cessation, a decreased trend for the risk of all RA was observed (P = 0.009) and seropositive RA (P = 0.002). Compared to recent quitters (<5 years), those who quit ≥30 years ago had an HR of 0.63 (95% CI 0.44-0.90) for seropositive RA. However, a modestly increased risk of RA was still detectable 30 years after quitting smoking (for all RA, HR 1.25 [95% CI 1.02-1.53]; for seropositive RA, HR 1.30 [95% CI 1.01-1.68]; reference, never smoking)., Conclusion: These results confirm that smoking is a strong risk factor for developing seropositive RA and demonstrate for the first time that a behavior change of sustained smoking cessation could delay or even prevent seropositive RA., (© 2019, American College of Rheumatology.)

Objective: Because of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA-positive RA patients diagnosed during or after 2000 have more severe self-reported limitations and impairments, including restrictions at work, than ACPA-negative RA patients., Methods: A total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used., Results: At disease presentation, ACPA-negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup., Conclusion: In current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets., (© 2017 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Antibodies against citrullinated fibrinogen (anti-Cit-fibrinogen) have been implicated in rheumatoid arthritis (RA) and associated with cardiovascular risk in RA. The objective of this study was to examine the association between anti-Cit-fibrinogens and coronary artery disease (CAD) outcomes., Methods: We performed the study in an RA cohort based in a large academic institution linked with electronic medical record data containing information on CAD outcomes from medical record review. Using a published bead-based assay method, we measured 10 types of anti-Cit-fibrinogens. We applied a score test to determine the association between the anti-Cit-fibrinogens as a group with CAD outcomes. Principal components analysis (PCA) was performed to assess whether the anti-Cit-fibrinogens clustered into groups. Each group was then additionally tested for association with CAD. Sensitivity analyses were also performed using a published International Classification of Disease, Ninth Revision code group for ischemic heart disease (IHD) as the outcome., Results: We studied 1,006 RA subjects (mean ± SD age 61.0 ± 13.0 years; 72.2% anti-cyclic citrullinated peptide positive). As a group, anti-Cit-fibrinogen was associated with CAD (P = 1.1 × 10 -4 ). From the PCA analysis, we observed 3 main groups, of which only 1 group, containing 7 of the 10 anti-Cit-fibrinogens, was significantly associated with CAD outcomes (P = 0.015). In the sensitivity analysis, all anti-Cit-fibrinogens as a group remained significantly associated with IHD (P = 2.9 × 10 -4 )., Conclusion: Anti-Cit-fibrinogen antibodies as a group were associated with CAD outcomes in our RA cohort, with the strongest signal for association arising from a subset of the autoantibodies., (© 2017, American College of Rheumatology.)

Objective: Osteoporotic fractures are associated with high morbidity and mortality. Persons with rheumatoid arthritis (RA) have twice the risk of osteoporosis-related fracture than age-matched controls, the causes for which remain unknown. We investigated contributions of RA characteristics, medication use, and body composition to low bone mineral density (BMD) in patients with RA., Methods: Data were from the Arthritis, Body Composition, and Disability Study (n = 138; 82 women, 56 men). Demographic, clinical, laboratory, and functional variables were collected at study visits. Body composition (fat, lean muscle, and BMD) was measured by dual x-ray absorptiometry. Linear regression analyses evaluated the association between predictors and femoral neck BMD., Results: Average disease duration was 19 years, 70% of patients were rheumatoid factor positive, and 55% were high-positive anti-cyclic citrullinated peptide (anti-CCP). Age and high anti-CCP positivity were negatively associated with BMD after controlling for other variables (β = -0.003 and -0.055, respectively, P < 0.05). Appendicular lean mass index (ALMI) was positively associated with BMD (β = 0.053, P < 0.0001). In high anti-CCP positivity participants, increasing anti-CCP levels were associated with a negative linear trend in BMD (β = -0.011, P = 0.026)., Conclusion: High anti-CCP positivity and ALMI were strongly associated with BMD in patients with RA. The linear relationship of anti-CCP levels with lower BMD supports the hypothesis that processes specific to RA negatively impact BMD. In contrast, ALMI was positively associated with BMD, emphasizing the importance of this potentially modifiable risk factor. Our findings highlight the complicated interplay of RA disease-specific and functional factors and their impact on bone mass., (© 2017, American College of Rheumatology.)

Objective: Environmental factors are of importance for the etiology of rheumatoid arthritis (RA), but much remains unknown concerning the contributions from distinct occupational hazards. We explored the association between occupation and the risk of anti-citrullinated protein antibody (ACPA)+ RA or ACPA- RA., Methods: We analyzed 3,522 cases and 5,580 controls from the Swedish population-based Epidemiological Investigation of Rheumatoid Arthritis case-control study. A questionnaire was used to obtain information on work history and lifestyle factors. Blood samples were drawn for serologic analyses. Unconditional logistic regression was used to calculate the odds ratio (OR) of RA associated with the last occupation before study inclusion. Analyses were performed with adjustments for known environmental exposures and lifestyle factors, including pack-years of cigarette smoking, alcohol use, body mass index, and education., Results: Among men, bricklayers and concrete workers (OR 2.9, 95% confidence interval [95% CI] 1.4-5.7), material handling operators (OR 2.4, 95% CI 1.3-4.4), and electrical and electronics workers (OR 2.1, 95% CI 1.1-3.8) had an increased risk of ACPA+ RA. For ACPA- RA, bricklayers and concrete workers (OR 2.4, 95% CI 1.0-5.7) and electrical and electronics workers (OR 2.6, 95% CI 1.3-5.0) had an increased risk. Among women, assistant nurses and attendants had a moderately increased risk of ACPA+ RA (OR 1.3, 95% CI 1.1-1.6). No occupations were significantly associated with ACPA- RA among women., Conclusion: Mainly occupations related to potential noxious airborne agents were associated with an increased risk of ACPA+ or ACPA- RA, after adjustments for previously known confounders., (© 2017, American College of Rheumatology.)