Modeling the progression of rheumatoid arthritis: a two-country model to estimate costs and consequences of rheumatoid arthritis

OBJECTIVE: Two simulation models were developed to analyze the cost-effectiveness of new treatments that affect the progression of rheumatoid arthritis (RA). METHODS: We used data from 2 cohorts of patients with early RA who had been followed up since disease onset (up to 15 years). In the Swedish study, 183 patients were followed up for a mean of 11.3 years. In the UK study, 916 patients were followed up for a mean of 7.8 years. Disease progression over 10 years was modeled as annual transitions between disease states, defined by Health Assessment Questionnaire (HAQ) scores. A regression model was used to estimate transition probabilities conditional on age, sex, and time since onset of disease, in order to allow simulation of different patient cohorts. Costs and utilities associated with different HAQ levels were based on data from the cohort studies and cross-sectional surveys. RESULTS: Costs increase and quality of life decreases as RA progresses. In Sweden, total annual costs range from 4,900 dollars to 33,000 dollars per patient, compared with 4,900 dollars to 14,600 dollars in the UK. Cumulative costs over 10 years for patients starting in disease state 1 (HAQ < 0.6) are 54,600 dollars in Sweden and 26,600 dollars in the UK. The cumulative numbers of quality-adjusted life-years (QALYs) are 5.5 and 5.6, respectively. Both costs and QALYs were discounted at 3%. CONCLUSION: The 2 models, which were based on different patient cohorts, reach a similar conclusion in terms of the effect of RA over 10 years. They appear to accurately capture disease progression and its effects and can therefore be useful in estimating the cost-effectiveness of new treatments in RA.     

In vivo regulation of inducible no synthase in immune-mediated liver injury in mice

Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A). Here we investigated the in vivo effects of tumor necrosis factor (TNF)-alpha and/or interferon (IFN)-gamma, two mediators of con A-induced liver injury, the TNF receptor (TNFR) usage leading to iNOS expression, and its connection with nuclear factor kappaB (NF-kappaB) activation. In conclusion, iNOS expression in vivo is dependent on both TNF-alpha and IFN-gamma. Although con A-induced liver injury depends on both TNFR1 and TNFR2, TNF-dependent iNOS expression is mediated exclusively by TNFR1 and requires NF-kappaB activation.     

Spinal cord stimulation for refractory angina pectoris: a retrospective analysis of efficacy and cost-benefit

BACKGROUND: Patients with refractory angina pectoris have severe symptoms despite optimal medication, but are not suitable for revascularisation. Spinal cord stimulation (SCS) has been used for treating refractory angina pectoris since 1985. The efficacy of SCS has been proven by randomised controlled trials and follow-up studies have shown that SCS is a safe treatment. The objective of the current study was to retrospectively analyse the clinical outcomes and cost-benefit of SCS in patients with refractory angina pectoris. METHODS: Eighteen months after SCS implantation, the effects on Canadian Cardiovascular Society (CCS) functional level and acute symptom relief of 24 patients with permanent SCS were analysed by review of medical records. Nineteen of these 24 patients were able to report their anginal frequency, nitroglycerin consumption and subjective perception on physical activity and quality of life. RESULTS: Angina frequency decreased from a median of 14.0 to 2.3 attacks/week (p < 0.01). Nitroglycerin intake decreased from a median of 27.5 to 1.5 doses/week (p < 0.01). Canadian Cardiovascular Society angina class improved from a median of three to two (p < 0.001). During a three-year period before SCS implantation, the hospitalisation rate and duration related to coronary artery disease increased progressively. The duration of hospitalisation increased from a median of three to 10 days/patient/year. In the year after SCS implantation the duration of hospitalisation decreased to a median of 0 day/patient/year (p < 0.001). The cost of hospital care due to coronary artery disease decreased significantly thereafter. The total cost of SCS procedure was recovered within 16 months after implantation, which is less than 40% of the device life span. CONCLUSIONS: This retrospective study indicates that SCS treatment alleviates angina symptoms and improves quality of life. The treatment is also effective in preventing hospitalisations and saving costs in hospital care. A prospective study is warranted to confirm the current observations.     

Compound library development guided by protein structure similarity clustering and natural product structure

To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.     

ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells

Endothelial cells (EC) play a central role in inflammatory immune responses and efficiently induce effector functions in T cells, despite lacking the classical costimulatory ligands CD80 and CD86. By using the mAb HIL-131 we now demonstrate that human inducible costimulator-ligand (ICOS-L), a molecule related to CD80/CD86, is constitutively expressed on human EC in vivo. In vitro, ICOS-L expression was strongly enhanced on human umbilical vein EC and microvascular EC by the inflammatory cytokines tumor necrosis factor alpha and IL-1beta, and to a lower extent by stimulation of EC by CD40 or lipopolysaccharide. Coculture of MHC class II(+) EC with resting memory CD4(+) T cells in the presence of superantigen led to a marked up-regulation of ICOS on T cells and to the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-10, IL-13). When these cocultures were performed in the presence of the inhibitory mAb HIL-131, secretion of all cytokines was reduced by about 50-80%, indicating that ICOS-L is a major costimulator in EC-mediated T cell activation. Taken together, our data suggest an important physiological role of ICOS-L in the reactivation of effector/memory T cells on the endothelium controlling the entry of immune cells into inflamed tissue.     

Preserved circadian rhythm of serum insulin concentration at low plasma glucose during fasting in lean and overweight humans

Circadian rhythms in glucose metabolism are well documented. Most studies, however, evaluated such variations under conditions of continuous glucose supply, either via food intake or glucose infusion. Here we assessed in 30 subjects circadian variations in concentrations of plasma glucose, serum insulin, and C-peptide during a 72-hour fasting period to evaluate rhythms independent from glucose supply. Furthermore we assessed differences in these parameters between normal-weight (n = 20) and overweight (n = 10) subjects. Blood was sampled every 4 hours. During fasting, plasma glucose, serum insulin, and C-peptide levels gradually decreased (all P < .001). While there was no circadian variation in plasma glucose levels after the first day of fasting, serum levels of insulin were constantly higher in the morning (8.00 h) than at night (0.00 h) (P < .001), although the extent of this morning-associated rise in insulin levels decreased with the time spent fasting (P = .001). Also, morning C-peptide concentrations were higher compared to the preceding night (P < .001). The C-peptide/insulin ratio (CIR) decreased during prolonged fasting (P = .030), suggesting a decrease in hepatic insulin clearance. Moreover, CIR was significantly lower in the morning than at the night of day 1 and day 2 of fasting (P = .010 and P = .004, respectively). Compared to normal-weight subjects, overweight subjects had higher plasma glucose, as well as serum insulin and C-peptide levels (all P < .03). Data indicate preserved circadian rhythms in insulin concentrations in the presence of substantially decreased glucose levels in normal-weight and overweight subjects. This finding suggests a central nervous system contribution to the regulation of insulin secretion independent of plasma glucose levels.     

The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

Aim

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

Methods

The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.

Results

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HR_PFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HR_OS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

Conclusions

Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.