Lymphopenia in primary Sjögren's syndrome is associated with premature aging of naïve CD4+ T cells.

OBJECTIVE: To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality. METHODS: Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated ß-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). RESULTS: In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. CONCLUSION: In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.

Atrial Fibrillation: A New Indicator for Advanced Colorectal Neoplasia in Screening Colonoscopy.

BACKGROUND: Colorectal cancer (CRC) is a common and potentially preventable malignancy. Evidence has emerged that coronary artery disease patients are at increased risk for developing CRC by shared risk factors. Here we investigated an association between CRC and atrial fibrillation (AF), a surrogate marker of cardiovascular risk, in the setting of routine screening colonoscopy. METHODS: We investigated 1949 asymptomatic participants (median age 61 [54-67] years, 49% females) undergoing screening colonoscopy within the SAKKOPI registry (Salzburg Colon Cancer Prevention Initiative). Forty-six participants with AF (2.4%) were identified, and colonoscopy findings were compared to non-AF participants. Propensity Score Matching (PSM) was used to create 1:1 and 3:1 age- and gender-matched couples. RESULTS: Abnormal findings on screening colonoscopy (any form of adenoma or carcinoma) were more common in AF participants with an odds ratios (OR) of 2.4 [1.3-4.3] in the unmatched analysis, and 2.6 [1.1-6.3] and 2.0 [1.1-4.0] in the 1:1 and 3:1 matched groups, respectively. Correspondingly, the odds of finding advanced adenomas or carcinomas was elevated about three-fold across the different matched and unmatched analyses (OR 3.3 [1.1-10.8] for 3:1 matched participants). At the same time, the prevalence and number of colonic lesions were significantly higher in AF participants (63.0% vs. 33.4% for 3:1 matched participants, p < 0.001). Non-CRC related findings on colonoscopy, like diverticulosis, were non-different between groups. CONCLUSION: Participants with AF had a higher burden of advanced premalignant adenomas and CRC in routine colonoscopy screening. Our data suggest that practitioners should monitor the CRC screening status, especially in AF patients.

Association between Cardiovascular Risk and Diabetes with Colorectal Neoplasia: A Site-Specific Analysis.

Several studies have shown site-specific differences in colorectal cancer (CRC) with respect to the risk factors. CRC was shown to be associated with cardiovascular risk (CVR) factors, but site-specific variations have not been investigated so far. This study aimed to assess the associations between the prevalence and subsite-specific differences of colorectal neoplasia and established CVR scores or known coronary artery disease (CAD) in a large asymptomatic European screening cohort (N = 2098). Participants underwent simultaneous screening colonoscopy and CVR evaluation, using the Framingham Risk Score and Heart Score. Lesions found in the colonoscopy were classified by location (proximal/distal colon or rectum). More neoplasias were found in the proximal versus the distal colon (p < 0.001). The Framingham Risk Score and Heart Score showed incremental risk for colorectal adenoma, across the tertiles in the proximal and the distal colon (p < 0.001). The prevalence of adenomas in the rectum was much lower, but also here, incremental risk could be shown for the Framingham Risk but not the Heart Risk Score tertiles. Prevalence of adenomas in the proximal colon was higher in subjects with type 2 diabetes (T2DM) (p = 0.006), but no association was found between adenomas and T2DM in the distal colon (p = 0.618) and the rectum (p = 0.071). Males had a higher CVR and more findings, in the screening colonoscopy, as compared to females, however, no site-specific differences were noted. Patients with known CAD and high CVR have an increased risk of colorectal neoplasia in both the proximal and distal colon. Patients with T2DM have a higher risk for neoplasia in the proximal colon.