Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis.

OBJECTIVE: To identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS). METHODS: Cohorts of male and female patients with AS and age- and sex-matched healthy control subjects were selected, and the levels of serum cytokines (interferon-γ [IFNγ], tumor necrosis factor α, interleukin-17A [IL-17A], and IL-6) were examined by enzyme-linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches. RESULTS: The frequency of IL-17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS-associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex-related immune profiles were independent of HLA-B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS. CONCLUSION: The results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex-related differences in the clinical features of AS and could provide a rationale for sex-specific treatment of AS.

Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes: a systematic review of interventional studies.

BACKGROUND: Diabetes and vitamin D deficiency are global epidemics. Researchers have long been exploring the role of potentially modifiable factors to manage type 2 diabetes. We conducted a systematic review of prospective studies and randomized controlled trials that involved vitamin D supplementation and specifically intended to study glycemic outcomes related to type 2 diabetes. METHODS: Two authors independently searched Medline and PubMed for longitudinal studies that had assessed the effect of vitamin D supplements on glycemic control, insulin resistance and beta-cell dysfunction in patients with diabetes. RESULTS: Seventeen randomized control trials and seven longitudinal studies with a minimum follow-up of one month were included. Results of the various short-term studies (follow up ≤ 3 months) suggested that vitamin D supplementation had a positive impact on glycemic control and metabolic parameters such as insulin resistance and beta cell dysfunction. However, the evidence was weak due to the low methodological quality of the studies. There was no significant effect on HbA1c, beta cell function and insulin resistance in the long-term studies (follow up > 3 months). There existed heterogeneity in the methodology of the studies, inclusion criteria, mode of supplementation of vitamin D and the duration of follow up. CONCLUSIONS: Current evidence based on randomized controlled trials and longitudinal studies do not support the notion that vitamin D supplementation can improve hyperglycemia, beta cell secretion or insulin sensitivity in patients with type 2 diabetes. Large-scale trials with proper study design, optimal vitamin D supplementation and longer follow up need to be conducted.

Analysis of the effect of the oral contraceptive pill on clinical outcomes in women with ankylosing spondylitis.

OBJECTIVE: There are unexplained sex-specific changes in the clinical expression of ankylosing spondylitis (AS). We sought to examine the potential effect of exogenous estrogen in the form of oral contraceptive pills (OCP) on AS initiation and severity. METHODS: This cross-sectional study consisted of women with AS from the membership of the Spondylitis Association of America. Measures of disease severity included use of biological agents and hip replacement surgery, while Bath AS Functional Index (BASFI) scores served as a surrogate marker of disability. Information was obtained using a patient questionnaire on patient demographics, OCP use, pregnancy history, AS duration, medication use, and hip replacement. RESULTS: There were 571 women with AS who participated in our study, consisting of 448 OCP ever-users and 123 non-OCP users. The mean age of OCP users was 42.7 yrs (± 11.5) and of non-OCP users, 48.4 yrs (± 12.1). No difference was noted in the age at initial onset of back pain. However, OCP users were significantly younger at the time of diagnosis of AS (36.5 yrs vs 39.1 yrs, p = 0.02). There were no significant differences between the 2 groups in tumor necrosis factor inhibitor or opioid use, BASFI scores, pregnancy complications, or hip surgery. CONCLUSION: The use of exogenous estrogens in the form of OCP is not associated with a measurable effect on initiation or severity of AS. Biologic and social factors may contribute to earlier diagnosis of AS in OCP users. This is the largest study to date investigating the potential effect of exogenous estrogens in women with AS.

Elevated serum anti-flagellin antibodies implicate subclinical bowel inflammation in ankylosing spondylitis: an observational study.

INTRODUCTION: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) share genetic and clinical features. IBD is associated with the presence of antibodies to a variety of commensal microorganisms including anti-Saccharomyces cerevesiae antibodies (ASCA), antineutrophil cytoplasmic antibodies (ANCA), anti-I2 (associated with anti-Pseudomonas activity), anti-Eschericia coli outer membrane porin C (anti-OmpC) and anti-flagellin antibodies (anti-CBir1). Subclinical intestinal inflammation may be present in up to 65% of patients with AS. This study evaluated the presence of antimicrobial antibodies in patients with AS alone, patients with AS and concomitant IBD (AS-IBD) and a control group of patients with mechanical back pain (MBP). METHODS: Sera were tested by ELISA for ASCA IgG and IgA, anti-OmpC, anti-CBir1 and ANCA in 76 patients with AS alone, 77 patients with AS-IBD and 48 patients with MBP. Antibody positivity rates, median quantitative antibody levels and the proportion of patients with antibody levels in the 4th quartile of a normal distribution were compared between the three groups of patients. RESULTS: Patients with AS alone demonstrated higher anti-CBir1 antibody positivity rates and median antibody levels than MBP patients. Anti-CBir1 positivity in AS was associated with elevation of acute phase reactants. AS-IBD patients demonstrated elevated responses when compared to AS alone for ASCA, anti-OmpC and anti-CBir1. Quartile analysis confirmed the findings. CONCLUSIONS: These data suggest that adaptive immune responses to microbial antigens occur in AS patients without clinical IBD and support the theory of mucosal dysregulation as a mechanism underlying the pathophysiology of AS.