miR-30a-5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis.

Ischemia-induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments involve the use of anti-VEGF agents but are not successful in all cases. In this study we determined that miR-30a-5p is another important mediator of retinal angiogenesis. Using a rodent model of ischemic retinopathy, we show that inhibiting miR-30a-5p reduces neovascularization and promotes tissue repair, through modulation of microglial and endothelial cell cross-talk. miR-30a-5p inhibition results in increased expression of the death receptor Fas and CCL2, to decrease endothelial cell survival and promote microglial migration and phagocytic function in focal regions of ischemic injury. Our data suggest that miR-30a-5p inhibition accelerates tissue repair by enhancing FasL-Fas crosstalk between microglia and endothelial cells, to promote endothelial cell apoptosis and removal of dead endothelial cells. Finally, we found that miR-30a levels were increased in the vitreous of patients with proliferative diabetic retinopathy. Our study identifies a role for miR-30a in the pathogenesis of neovascular retinal disease by modulating microglial and endothelial cell function, and suggests it may be a therapeutic target to treat ischemia-mediated conditions.

Obstructive lung diseases and risk of rheumatoid arthritis.

Introduction: Smoking is an established risk factor for both lung diseases and rheumatoid arthritis (RA). Chronic mucosal airway inflammation may result in immune tolerance loss, neoantigen formation, and production of RA-related autoantibodies that increase the subsequent risk of RA. In this review, we aimed to summarize the current evidence supporting the role of obstructive lung diseases and subsequent risk of RA.Areas covered: We identified scientific articles discussing the biologic mechanisms linking mucosal airway inflammation and RA risk. We also identified studies investigating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, chronic tuberculous and nontuberculous mycobacterial infections, and interstitial lung disease with subsequent risk for RA.Expert opinion: The current evidence supports the hypothesis that mucosal airway inflammation may increase the risk of developing RA. However, most studies investigating this relationship have been retrospective and may not have adequately addressed the role of smoking. Larger prospective studies may provide stronger evidence for obstructive lung disease and RA risk. Determining the role of obstructive lung disease in RA pathogenesis may provide opportunity for RA prevention and screening strategies, while identifying novel biologic mechanisms that could offer targets to improve treatment and outcomes.

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.

Potential of Lifestyle Changes for Reducing the Risk of Developing Rheumatoid Arthritis: Is an Ounce of Prevention Worth a Pound of Cure?

PURPOSE: Lifestyle may be important in the development of rheumatoid arthritis (RA). Therefore, changing behaviors may delay or even prevent RA onset. This article reviews the evidence basis for the associations of lifestyle factors with RA risk and considers future directions for possible interventions to reduce RA risk. METHODS: The literature was reviewed for cross-sectional studies, case-control studies, cohort studies, and clinical trials investigating potentially modifiable lifestyle factors and RA risk or surrogate outcomes on the path toward development such as RA-related autoimmunity or inflammatory arthritis. The evidence related to cigarette smoking, excess weight, dietary intake, physical activity, and dental health for RA risk were summarized. FINDINGS: Cigarette smoking has the strongest evidence base as a modifiable lifestyle behavior for increased seropositive RA risk. Smoking may increase seropositive RA risk through gene-environment interactions, increasing inflammation and citrullination locally in pulmonary/oral mucosa or systemically, thereby inducing RA-related autoimmunity. Prolonged smoking cessation may reduce seropositive RA risk. Evidence suggests that excess weight can increase RA risk, although this effect may differ according to sex, serologic status, and age at RA onset. TDietary intake may also affect RA risk: overall healthier patterns, high fish/omega-3 polyunsaturated fatty acid consumption, and moderate alcohol intake may reduce RA risk, whereas caffeine and sugar-sweetened soda consumption might increase RA risk. The impact of physical activity is less clear, but high levels may reduce RA risk. Periodontal disease might induce citrullination and RA-related autoimmunity, but the effect of dental hygiene behaviors on RA risk is unclear. Although the effect size estimates for these lifestyle factors on RA risk are generally modest, there may be relatively large public health benefits for targeted interventions given the high prevalence of these unhealthy behaviors. With the exception of smoking cessation, the impact of behavior change of these lifestyle factors on subsequent RA risk has not been established. Nearly all of the evidence for lifestyle factors and RA risk were derived from observational studies. IMPLICATIONS: There are many potentially modifiable lifestyle factors that may affect RA risk. Improving health behaviors could have large public health benefits for RA risk given the high prevalence of many of the RA risk-related lifestyle factors. However, future research is needed to establish the effects of lifestyle changes on RA risk or surrogate outcomes such as RA-related autoimmunity or inflammatory arthritis.

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.