The effect of three years of TNF alpha blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study

INTRODUCTION: The aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-alpha) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS). METHODS: This is a prospective cohort study of 111 consecutive AS outpatients who started TNF-alpha blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly. RESULTS: After three years, 72 patients (65%) were still using their first TNF-alpha blocking agent. In these patients, TNF-alpha blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physician's global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life. CONCLUSIONS: Three years of TNF-alpha blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF-alpha blocking therapy in AS, in addition to the currently used more subjective measures

Obstructive sleep apnea in combat-related posttraumatic stress disorder:a controlled polysomnography study

Background: Obstructive sleep apnea (OSA) may be highly prevalent in posttraumatic stress disorder (PTSD) and may exacerbate PTSD complaints. Objective: Our objective was to determine whether the prevalence of OSA was high in a sample of Dutch veterans with PTSD as compared to age- and trauma-matched controls, and whether OSA was associated with more severe PTSD complaints. Methods: We determined the apnea hypopnea indices (AHI) with polysomnographic registrations in 20 veterans with PTSD, 24 veterans without PTSD, and 17 healthy controls. PTSD severity and nightmare complaints were assessed with the Clinician-Administered PTSD Scale (CAPS). Results: The prevalence of an AHI>10 was 29% in PTSD, 21% in trauma controls, and 29% in healthy controls (x2= 0.60, df=2, p=n.s.). The mean CAPS score in patients with OSA (n=6) was significantly higher than in patients without OSA (pB0.05), while nightmare severity was similar in PTSD patients with OSA as compared to PTSD patients without OSA (p=n.s.). Furthermore, there was a significant correlation between AHI and CAPS score in PTSD patients (r=0.46,

Photoproduction of pions and etas in nuclei

We calculate the cross sections for inclusive one-pion, two-pion and eta photoproduction in nuclei in the photon energy range from 300 MeV to 900 MeV within the framework of a semi-classical BUU transport model. Our results are compared with existing experimental data and discussed with respect to a calculation of the total photoabsorption cross section.Comment: 30 pages LaTeX including 13 postscript figure

Nucleosomes in serum as a marker for cell death

The concentration of nucleosomes is elevated in blood of patients with diseases which are associated with enhanced cell death. In order to detect these circulating nucleosomes, we used the Cell Death Detection-ELISA(Plus) (CDDE) from Roche Diagnostics (Mannheim, Germany) (details at http:\textbackslash{}\textbackslash{}biochem.roche.com). For its application in liquid materials we performed various modifications: we introduced a standard curve with nucleosome-rich material, which enabled direct quantification and improved comparability of the values within (CVinterassay:3.0-4.1%) and between several runs (CVinterassay:8.6-13.5%), and tested the analytical specificity of the ELISA. Because of the fast elimination of nucleosomes from circulation and their limited stability, we compared plasma and serum matrix and investigated in detail the pre-analytical handling of serum samples which can considerably influence the test results. Careless venipuncture producing hemolysis, delayed centrifugation and bacterial contamination of the blood samples led to false-positive results; delayed stabilization with EDTA and insufficient storage conditions resulted in false-negative values. At temperatures of -20 degreesC, serum samples which were treated with 10 mM EDTA were stable for at least 6 months. In order to avoid possible interfering factors, we recommend a schedule for the pre-analytical handling of the samples. As the first stage, the possible clinical application was investigated in the sera of 310 persons. Patients with solid tumors (n = 220; mean = 361 Arbitrary Units (AU)) had considerably higher values than healthy persons (n = 50; mean = 30 AU; P = 0.0001) and patients with inflammatory diseases (n = 40; mean = 296 AU; p = 0.096). Within the group of patients with tumors, those in advanced stages (UICC 4) showed significantly higher values than those in early stages (UICC 1-3) (P = 0.0004)

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study.

Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications on QoL. QoL data of Fabry patients as assessed by the EuroQol five dimension questionnaire (EQ-5D) from two international centers of excellence were collected. The aim of this study was to evaluate the effect of sex, phenotype, age, different states of disease severity, pain, and ERT on EQ-5D utilities. For 286 adult FD patients (mean age 42.5 years, 40% men, 60% classical phenotype) 2240 EQ-5Ds were available. QoL is decreased in men as well as women with FD, especially in older men with a classical phenotype. At age 50, utility was lower in men with classical FD compared to those with non-classical disease (β = -0.12, 95% CI: -0.23 - 0.01, p = 0.037) with further difference in the years thereafter. Cardiovascular complications, stroke or transient ischemic attacks, multiple FD-related complications and pain were also associated with decreased utilities. Overall, no change in utility was seen in patients on ERT over a mean follow-up of 6.1 years. FD leads to a decreased QoL compared to the general population. Disease complications and pain both negatively influence QoL. Adequate assessment and treatment of pain as well as improved strategies to prevent disease complications are needed to improve QoL in the FD population

Development and performance of the Clinical Trials ESSDAI (ClinTrialsESSDAI), consisting of frequently active clinical domains, in two randomised controlled trials in primary Sjogren's syndrome

Objective. To develop and evaluate the Clinical Trials EULAR Sjogren's Syndrome Disease Activity Index (ClinTrialsESSDAI), consisting of frequently active clinical domains of the ESSDAI, using two randomised controlled trials in primary Sjogren's syndrome (pSS). Methods. The ASAP-III trial in abatacept (80 pSS patients) and TRACTISS trial in rituximab (133 pSS patients) were analysed. The most frequently active clinical domains were selected, and ClinTrialsESSDAI total score was calculated using existing weightings of the ClinESSDAI (which also excludes the biological domain). Performance of the ClinTrialsESSDAI was compared to ClinESSDAI and ESSDAI. Responsiveness was assessed using standardised response mean (SRM), and discrimination was assessed using adjusted mean difference. Results. Besides the biological domain, the most frequently active domains were glandular, articular, haematological, constitutional, lymphadenopathy and cutaneous. These domains were selected for the ClinTrialsESSDAI. At primary endpoint visits, SRM values of ClinTrialsESSDAI, ClinESSDAI and ESSDAI were respectively -0.65/-0.59, -0.63/-0.59 and - 0.64/-0.61 for abatacept/placebo and -0.33/-0.13, -0.34/0.12 and -0.41/-0.16 for rituximab/placebo. Adjusted mean differences between active treatment and placebo groups were respectively -1.7, -1.4 and -1.1 for ASAP-III and -1.1, -1.1 and -1.2 for TRACTISS. Conclusion. The ClinTrialsESSDAI, consisting of six frequently active clinical domains of the ESSDAI, shows closely similar responsiveness and discrimination between treatment groups compared to the ClinESSDAI and ESSDAI. Therefore, this ClinTrialsESSDAI is not preferable to ClinESSDAI and ESSDAI for use as primary endpoint. A composite endpoint combining response at multiple clinically relevant items seems more suitable as primary study endpoint in pSS