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.