Clinical and preclinical pulmonary disease in newly diagnosed rheumatoid arthritis: a two-year follow-up study.

OBJECTIVE: Pulmonary disease is a major cause of excess mortality among patients with rheumatoid arthritis (RA). Interstitial lung disease (ILD) is a feared complication, but the benefit of screening is unknown. The aim of this study was to assess the frequency of pulmonary disease, including ILD, in early RA. METHOD: Patients with newly diagnosed RA were recruited prospectively at a single centre and underwent systematic pulmonary function tests (PFTs) and computed tomography (CT) scans at inclusion and after two years. RESULTS: The study included 150 patients (mean age 57 years, 63% female; 59% current or former smokers). Of these, 136 underwent baseline PFTs and 137 CT. Mean forced expiratory volume in one second was 99% predicted and forced vital capacity 106%. Mean diffusing capacity of the lungs for carbon monoxide (DLCO) was 84% predicted. Frequently detected CT abnormalities were pulmonary nodules (42%), bronchiectasis (29%), and emphysema (20%). Two patients had clinically significant ILD and six had mild reticulation suggestive of preclinical ILD. No ILD progression was identified at two-year follow-up. Smoking was associated with DLCO<80% (p=0.004), combined hyperinflation and diffusion impairment (residual volume>120% and DLCO<80%) (p=0.004), and visual emphysema on CT (p<0.001). CONCLUSION: Emphysema and bronchiectasis were common, but most patients had mild disease with preserved lung function. Preclinical or clinical ILD was seen in a minority in this early phase of RA. These findings suggest symptom-based screening and primary intervention focusing on smoking cessation rather than screening for ILD at the time of RA diagnosis.

Left ventricular function at two-year follow-up in treatment-naive rheumatoid arthritis patients is associated with anti-cyclic citrullinated peptide antibody status: a cohort study.

OBJECTIVES: In rheumatoid arthritis (RA), the role of autoimmunity, especially anti-cyclic citrullinated peptide antibody (anti-CCP) level, and the time-course of left ventricular (LV) function is unknown. The objective was to assess LV function and the amount of coronary calcium in relation to anti-CCP levels in a cohort of treatment-naive RA patients, and to assess changes in these parameters during a 2 year follow-up period. METHOD: Sixty-six steroid- and disease-modifying anti-rheumatic drug-naive RA patients were treated with methotrexate according to the Danish national guidelines. We assessed LV function by conventional echocardiography and speckle-tracking echocardiography. We estimated the amount and progression of coronary calcium by coronary computed tomography. Patients were examined at the time of diagnosis and after 2 years. RESULTS: Patients with elevated anti-CCP at baseline and after 2 years, compared to those with non-persistently elevated anti-CCP, had significantly less improvement in S´ (1 ± 1.4 cm/s vs 0.2 ± 0.9 cm/s; p = 0.04) and a worsening in global longitudinal systolic strain (GLS) (0.6 ± 1.8% vs -1 ± 2.8%; p = 0.04). There was a significant correlation between ΔGLS over 2 years and anti-CCP at 2 year follow-up (r = 0.36; p = 0.006). We observed a small progression of coronary calcium score during the 2 year follow-up period. No differences in progression were found between patients with high anti-CCP titres at baseline and 2 year follow-up (n = 12) and patients with normal/low anti-CCP titres (n = 32) (23.8 ± 40.3 vs 22.6 ± 68.9; p = 0.96). CONCLUSIONS: Deformation analysis by speckle-tracking echocardiography is a valuable tool to detect early development of myocardial dysfunction despite normal ejection fraction in RA.

c-MYC is a radiosensitive locus in human breast cells.

Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.