Increased frequency of CYP2C9 variant alleles and homozygous VKORC1*2B carriers in warfarin-treated patients with excessive INR response.

BACKGROUND: Several studies have linked mutations in the genes encoding cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) to a reduced warfarin dose requirement and an increased risk of bleeding with warfarin treatment, but the implementation of genotyping as routine practice is still controversial. The objective of this study was to investigate whether the frequencies of CYP2C9 variant alleles (*2 and *3), and VKORC1 haplotypes (*2A/B) were increased in a population of warfarin-treated patients with an excessive INR response. METHODS: All patients with INR values >5 detected by routine monitoring at Diakonhjemmet Hospital, Oslo, Norway, between October 2006 and January 2009 were prospectively enrolled in the study (n = 131, 'cases'). A group of patients with normal INR values (2-3) were randomly included as the reference population (n = 130, 'controls'). The frequencies of CYP2C9 variant alleles *2 (430C > T) and *3 (1075A > C), VKORC1 haplotypes *2A (1173G > T) and *2B (1173G > T + 497T >G), and the respective genotypes were compared between the study groups by chi-square tests [odds ratio (OR) of cases vs. controls with 95% confidence intervals (CI) calculated for the various end-points]. RESULTS: About two thirds of the patients in the high INR group were in the maintenance phase of the treatment (>3 weeks from first warfarin dose to measurement of INR >5). The frequency of CYP2C9 variant alleles (sum of *2 and *3) was significantly higher in patients with high INR cases than in the controls (OR 1.6, 95% CI 1.03-2.52; p = 0.036). Observed frequencies for each of the variant alleles were also higher in the cases than in the controls (i.e., 2C9*3: OR 1.97, 95% CI 0.91-2.41, p = 0.073; 2C9*2: OR 1.36, 95% CI 0.88-1.58, p = 0.246). There were no significant differences in VKORC1*2 haplotype frequencies between the two subgroups, but the number of homozygous VKORC1*2B carriers was significantly higher in cases than in controls (OR 2.72, 1.02-7.24; p = 0.039). CONCLUSION: The presence of CYP2C9 variant alleles and the homozygous VKORC1*2B genotype was associated with elevated INR values in warfarin-treated patients. These results support the implementation of genotyping as a tool to identify patients with an increased risk of excessive anticoagulation during warfarin treatment.

Biomarkers in early rheumatoid arthritis: longitudinal associations with inflammation and joint destruction measured by magnetic resonance imaging and conventional radiographs.

OBJECTIVE: To examine associations between a panel of soluble biomarkers and progressive joint destruction assessed by magnetic resonance imaging (MRI) and conventional radiographs as well as longitudinal associations with disease activity assessed clinically and by MRI in early rheumatoid arthritis (RA) patients. METHODS: 84 early RA patients were evaluated at baseline, 3, 6 and 12 months with clinical examination, serum and urine sampling, MRI scans of the dominant wrist and conventional radiographs of the hands. A panel of biomarkers (sCTX-I, uCTX-II, sOPG, sYKL-40, sCOMP and sMMP-3) was assessed by ELISA. MRI images and conventional radiographs were scored according to the RA MRI score (RAMRIS) and the van der Heijde modified Sharp score (SHS), respectively. Longitudinal associations between biomarkers and MRI inflammation and disease activity score (DAS28) and association with the progression of damage were examined with adjustments for known predictors. RESULTS: The baseline sCTX-I level predicted progression in joint destruction assessed by MRI and conventional radiographs, whereas the uCTX-II level was a predictor of progression in SHS but not RAMRIS. Consistent associations, both with MRI inflammation (synovitis and bone marrow oedema) and DAS28 were found for sYKL-40 and sMMP-3 in addition to C-reactive protein at baseline and in longitudinal analyses. Associations remained significant in multivariate analyses. CONCLUSION: Levels of sCTX-I and uCTX-II were significant predictors of progressive joint destruction, whereas sMMP-3 and sYKL-40 were merely markers of joint inflammation. The clinical value of these markers for use in individual patients is limited due to a considerable overlap in levels of patients with progression and no progression.

Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study.

INTRODUCTION: Radiographic progression in rheumatoid arthritis (RA) has in several studies been shown to be predicted by serological markers widely used in daily clinical practice. The objective of this longitudinal study was to examine if these serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration. METHODS: 163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up. RESULTS: During the study period, DXR-BMD decreased by median (inter quartile range) 1.7% (4.1 to 0.4), 2.8% (5.3 to 0.9) and 5.6% (11.7 to 2.3) after 1, 2 and 5 years, respectively. Elevated baseline anti-CCP, RF, ESR and CRP levels were in univariate linear regression analyses consistently associated with DXR-BMD change at all time-points. Anti-CCP and ESR were independently associated with hand DXR-BMD in multivariate linear regression analyses. Elevated anti-CCP levels were consistent and independent predictors of loss in cortical hand bone during the study period, with the odds ratios (95% confidence interval) 2.2 (1.0 to 4.5), 2.6 (1.1 to 6.2) and 4.9 (1.4 to 16.7) for the 1, 2, and 5-year follow-up periods, respectively. CONCLUSIONS: Anti-CCP and ESR were found to be independent predictors of early localised BMD loss. This finding adds to the understanding of anti-CCP and ESR as important predictors of bone involvement in RA.

The significance of heparin-coated veno-venous bypass circuits in liver transplantation.

We studied the effects of veno-venous bypass (VVBP) circuit surface heparinization on the activation of the plasma defence systems (coagulation, fibrinolysis, kallikrein-kinin and complement) and leukocyte activation in a prospective randomized study in 20 patients during and 1 day after liver transplantation (OLT). To our knowledge, this is the first study of this kind where the possible benefits of surface heparinization of the VVBP circuit in OLT have been investigated. Twenty patients were randomized to either heparin-coated (HC) VVBP equipment or to otherwise identical noncoated (NC) circuits. Five blood samples were drawn during the OLT procedure: one just before VVBP, three during VVBP and one 5 min after portal venous reperfusion (PVR). A further sample was taken 1 day after the operation. Components of the blood coagulation, fibrinolytic and kallikrein-kinin systems were analysed using functional assays (chromogenic peptide substrate assays) or enzyme immunoassays (EIA). Complement system factors and granulocyte activation, represented by myeloperoxidase (MPO) release, were analyzed by EIA. Activation of the plasma defence systems occurred in both groups at an early stage during OLT and a further activation occurred 5 min after PVR. MPO levels were slightly elevated 5 min after PVR. However, no significant differences between the two groups were observed. Significant activation of the humoral defense systems was found in both groups during OLT. A considerably larger study, including at least 330 patients, is necessary to fully assess the possible benefits of surface heparinization of the VVBP circuit.