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) and the NHS II . 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.

The vertebrate circulatory system is composed of closely related blood and lymphatic vessels. It has been shown that lymphatic vascular patterning is regulated by blood vessels during development, but its molecular mechanisms have not been fully elucidated. Here, we show that the artery-derived ligand semaphorin 3G (Sema3G) and the endothelial cell receptor PlexinD1 play a role in lymphatic vascular patterning. In mouse embryonic back skin, genetic inactivation of Sema3G or PlexinD1 results in abnormal artery-lymph alignment and reduced lymphatic vascular branching. Conditional ablation in mice demonstrates that PlexinD1 is primarily required in lymphatic endothelial cells (LECs). In vitro analyses show that Sema3G binds to neuropilin-2 (Nrp2), which forms a receptor complex with PlexinD1. Sema3G induces cell collapse in an Nrp2/PlexinD1-dependent manner. Our findings shed light on a molecular mechanism by which LECs are distributed away from arteries and form a branching network during lymphatic vascular development.

Objective. Inflamed airways are hypothesized to contribute to rheumatoid arthritis (RA) pathogenesis due to RA-related autoantibody production, and smoking is the strongest environmental RA risk factor. However, the role of chronic airway diseases in RA development is unclear. We undertook this study to investigate whether asthma and chronic obstructive pulmonary disease (COPD) were each associated with RA.Methods. We performed a prospective cohort study of 205,153 women in the Nurses' Health Study (NHS, 1988(NHS, -2014 and NHSII (1991NHSII ( -2015. Exposures were self-reported physician-diagnosed asthma or COPD confirmed by validated supplemental questionnaires. The primary outcome was incident RA confirmed by medical record review by 2 rheumatologists. Covariates (including smoking pack-years/status) were assessed via biennial questionnaires. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for RA were estimated using Cox regression.Results. We identified 15,148 women with confirmed asthma, 3,573 women with confirmed COPD, and 1,060 incident RA cases during 4,384,471 person-years (median 24.0 years/participant) of follow-up in the NHS and NHSII. Asthma was associated with increased RA risk (HR 1.53 [95% CI 1.24-1.88]) compared to no asthma/COPD after adjustment for covariates, including smoking pack-years/status. Asthma remained associated with increased RA risk when analyzing only never-smokers (HR 1.53 [95% CI 1.14-2.05]). COPD was also associated with increased RA risk (HR 1.89 [95% CI 1.31-2.75]). The association of COPD with RA was most pronounced in the subgroup of eversmokers age >55 years (HR 2.20 [95% CI 1.38-3.51]).Conclusion. Asthma and COPD were each associated with increased risk of incident RA, independent of smoking status/intensity and other potential confounders. These results provide support for the hypothesis that chronic airway inflammation may be crucial in RA pathogenesis.

Objective To evaluate the effects of long‐term physical activity on subsequent risk of rheumatoid arthritis (RA) in a prospective cohort study. Methods This study investigated physical activity and RA risk among women from the Nurses' Health Study II (1989–2015). Physical activity exposures and covariates were prospectively obtained using biennial questionnaires. Two rheumatologists independently reviewed the medical records of women who self‐reported a new diagnosis of RA on biennial questionnaires and who screened positive for RA based on a supplemental survey. All incident RA cases met the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA. The primary analysis investigated the long‐term cumulative average number of hours spent in recreational physical activity 2–8 years prior to the RA diagnosis, a time span chosen to reduce the potential for reverse causation bias, since early RA affects physical activity prior to diagnosis. Estimated Cox regression hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the risk of RA serologic phenotypes (all, seropositive, or seronegative) in relation to physical activity categories. The analyses were adjusted for body mass index (BMI) at age 18 years and time‐varying potential confounders, and the mediating effect of updated BMI on the interaction between physical activity and RA risk was quantified. Results Among the 113,366 women analyzed, 506 incident RA cases (67.0% with seropositive RA) were identified during 2,428,573 person‐years of follow‐up. After adjustment for confounders, including smoking, dietary quality, and BMI at age 18 years, increasing cumulative average total hours of recreational physical activity was associated with a reduced risk of RA, as follows: HR 1.00 for <1 hour/week (reference), HR 1.00 (95% CI 0.78–1.29) for 1 to <2 hours/week, HR 0.92 (95% CI 0.72–1.17) for 2 to <4 hours/week, HR 0.84 (95% CI 0.63–1.12) for 4 to <7 hours/week, and HR 0.67 (95% CI 0.47–0.98) for ≥7 hours/week (P for trend = 0.02). The proportion of the effect between physical activity and RA mediated by updated BMI was 14.0% (P = 0.002) for all RA and 20.0% (P = 0.001) for seropositive RA. Conclusion Higher levels of physical activity were associated with reduced RA risk. These results add to the literature implicating metabolic factors in the pathogenesis of RA.

BackgroundAnti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis.MethodsWe performed a nested case-control study among women in two prospective cohorts, the Nurses’ Health Study (NHS; 1976–2014) and NHSII (1989–2015). Blood was obtained on a subset (NHS: 1989–1990; NHSII: 1996–1999). Cases met 1987 ACR or 2010 ACR/EULAR RA criteria by medical record review and were classified as seropositive (ACPA+ or rheumatoid factor positivity) or seronegative by clinical laboratory testing at diagnosis. We identified RA cases with blood drawn before the date of RA diagnosis (index date), matching each to three controls by age, cohort, year, time from blood draw to index date, and menopause. Pre-RA ACPA elevation for cases was defined as >99th percentile of the control distribution on a research assay composed of autoantibodies targeting citrullinated protein epitopes or positivity on the second-generation commercial assay for cyclic citrullinated peptide. Asthma status and covariates were obtained through biennial questionnaires before blood draw. Conditional logistic regression estimated ORs and 95%CIs for RA by pre-RA ACPA and clinical serostatus, adjusted for matching factors, smoking pack-years, passive smoking, and body mass index (BMI).ResultsWe identified 284 incident RA cases and 849 matched controls; mean age at the index date was 61.2 years (SD 10.1). Blood was drawn 9.7 years (mean; SD 5.8) before the index date. We identified 96 (33.8%) RA cases with elevated pre-RA ACPA. At blood draw, 17.7% of pre-RA ACPA+ cases and 6.3% of matched controls (p = 0.0008) reported clinician-diagnosed asthma. After adjusting for matching factors, smoking pack-years, passive smoking, and BMI, asthma was significantly associated with pre-RA ACPA+ RA (OR 3.57, 95%CI 1.58,8.04). Asthma was not associated with overall RA (OR 1.45, 95%CI 0.91,2.31), but was significantly associated with seropositive RA (OR 1.79, 95%CI 1.01,3.18).ConclusionsAsthma was strongly associated with ACPA elevation in blood drawn prior to RA diagnosis, independent of smoking. Chronic mucosal airway inflammation may contribute to ACPA development and RA pathogenesis.