A Multiple Treatment Comparison of Eleven Disease-Modifying Drugs Used for Multiple Sclerosis.

BACKGROUND: Several disease-modifying drug therapies are available for the treatment of multiple sclerosis (MS). To ensure the most appropriate MS management, we assessed the effectiveness and cost-effectiveness of the disease-modifying medicines used for MS. METHODS: We conducted a systematic review including 11 disease-modifying drugs used for treatment of adult patients diagnosed with relapsing-remitting MS. We performed a network meta-analysis using both direct and indirect evidence. We examined the endpoints, annual relapse, disability progression, mortality, serious adverse events and withdrawal from the study due to adverse events. Cost-effectiveness was assessed by developing a decision model. The model calculated costs and quality-adjusted life years (QALYs) with different treatment strategies. Uncertainties in the parameter values were explored with a probabilistic sensitivity analysis and several scenario analyses. RESULTS: Alemtuzumab 12 mg was the most effective against annual relapse (high quality evidence). For disability progression, dimethyl fumarate 240 mg and fingolimod 0.5 mg and 1.25 mg were more effective treatment alternatives (high quality evidence). For withdrawal due to adverse events, the conclusion is unclear due to the low quality of the available evidence. Peg-interferon beta-1a was associated with more adverse events (than the other treatments). None of the examined treatments had an effect on overall mortality compared to placebo. The economic analysis indicated that alemtuzumab was more effective in terms of QALYs and less costly than the other treatment alternatives. Discarding alemtuzumab, three treatment alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be considered cost-effective depending on the willingness-to-pay (WTP) threshold. Assuming a WTP below EUR 111,690 per QALY, interferon beta-1b (Extavia) was approximately 36% likely to be the most cost-effective treatment, followed by peg-interferon beta-1a (approximately 34% likely). CONCLUSIONS: Our results showed that alemtuzumab can be considered as more effective and less costly than the other treatment alternatives. There is a substantial potential cost saving if more patients start on the more effective and less costly treatment alternatives.

More Use of Peritoneal Dialysis Gives Significant Savings: A Systematic Review and Health Economic Decision Model.

BACKGROUND: Patients with end-stage renal disease (ESRD) are in need of renal replacement therapy as dialysis and/or transplantation. The prevalence of ESRD and, thus, the need for dialysis are constantly growing. The dialysis modalities are either peritoneal performed at home or hemodialysis (HD) performed in-center (hospital or satellite) or home. We examined effectiveness and cost-effectiveness of HD performed at different locations (hospital, satellite, and home) and peritoneal dialysis (PD) at home in the Norwegian setting. METHODS: We conducted a systematic review for patients above 18 years with end-stage renal failure requiring dialysis in several databases and performed several meta-analyses of existing literature. Mortality and major complications that required were our main clinical outcomes. The quality of the evidence for each outcome was evaluated using GRADE. Cost-effectiveness was assessed by developing a probabilistic Markov model. The analysis was carried out from a societal perspective, and effects were expressed in quality-adjusted life-years. Uncertainties in the base-case parameter values were explored with a probabilistic sensitivity analysis. Scenario analyses were conducted by increasing the proportion of patients receiving PD with a corresponding reduction in HD patients in-center both for Norway and Europian Union. We assumed an annual growth rate of 4% in the number of dialysis patients, and a relative distribution between PD and HD in-center of 30% and 70%, respectively. RESULTS: From a societal perspective and over a 5-year time horizon, PD was the most cost-effective dialysis alternative. We found no significant difference in mortality between peritoneal and HD modalities. Our scenario analyses showed that a shift toward more patients on PD (as a first choice) with a corresponding reduction in HD in-center gave a saving over a 5-year period of 32 and 10,623 million EURO, respectively, for Norway and the European Union. CONCLUSIONS: PD was the most cost-effective dialysis alternative and was comparable with HD regarding efficacy outcomes. There are significant saving potentials if more end-stage renal patients are started on PD instead of HD.

New anticoagulants as thromboprophylaxis after total hip or knee replacement.

OBJECTIVES: Due to a high risk of thromboembolism in patients undergoing major orthopedic surgery, it has become standard practice to give thromboprophylactic treatment. We assessed the relative efficacy and cost-effectiveness of two new oral anticoagulants, rivaroxaban and dabigatran, relative to subcutaneous enoxaparin for the prevention of thromboembolism after total hip replacement (THR) and total knee replacement surgery (TKR). METHODS: We conducted a systematic review of the literature to assess efficacy and safety, and evaluated quality of documentation using GRADE. Cost-effectiveness was assessed by developing a decision model. The model combined two modules; a decision tree for the short-term prophylaxis and a Markov model for the long-term complications and survival gain. RESULTS: For rivaroxaban compared with enoxaparin, we found statistically significant decreases in deep vein thrombosis, but also a trend toward increased risk of major bleeding. For mortality and pulmonary embolism there were no statistically significant differences between the treatments. We did not find statistically significant differences between dabigatran and enoxaparin for our efficacy and safety outcomes. Assuming a willingness to pay of EUR62,500 per QALY, rivaroxaban following THR had a probability of 38 percent, and enoxaparin following TKR had a probability of 34 percent of being cost-effective. Clinical efficacy had the greatest impact on decision uncertainty. CONCLUSIONS: Dabigatran and rivaroxaban are comparable with enoxaparin following THR and TKR regarding the efficacy and safety outcomes. However, there is great uncertainty regarding which strategy is the most cost-effective. More research on clinical efficacy of rivaroxaban and dabigatran is likely to change our results.

Detection of immunotoxicity using T-cell based cytokine reporter cell lines ("Cell Chip").

Safety assessment of chemicals and drugs is an important regulatory issue. The evaluation of potential adverse effects of compounds on the immune system depends today on animal experiments. An increasing demand, however, exists for in vitro alternatives. Cytokine measurement is a promising tool to evaluate chemical exposure effects on the immune system. Fortunately, this type of measurement can be performed in conjunction with in vitro exposure models. We have taken these considerations as the starting point to develop an in vitro method to efficiently screen compounds for potential immunotoxicity. The T-cell lymphoma cell line EL-4 was transfected with the regulatory sequences of interleukin (IL)-2, IL-4, IL-10, interferon (IFN)-gamma or actin fused to the gene for enhanced green fluorescent protein (EGFP) in either a stabile or a destabilised form. Consequently, changes in fluorescence intensity represent changes in cytokine expression with one cell line per cytokine. We used this prototype "Cell Chip" to test, by means of flow cytometry, the immunomodulatory potential of 13 substances and were able to detect changes in cytokine expression in 12 cases (successful for cyclosporine, rapamycin, pentamidine, thalidomide, bis(tri-n-butyltin)oxide, house dust mite allergen (Der p I), 1-chloro-2,4-dinitrobenzene, benzocaine, tolylene 2,4-diisocyanate, potassium tetrachloroplatinate, sodium dodecyl sulphate and mercuric chloride; unsuccessful for penicillin G). In conclusion, this approach seems promising for in vitro screening for potential immunotoxicity, especially when additional cell lines besides T-cells are included.

Development of the "Cell Chip": a new in vitro alternative technique for immunotoxicity testing.

Predictive testing of immunotoxicity associated with chemical compounds is complicated and cannot be accomplished with a single test. As most of the existing tests for immunotoxicity employ experimental animals, there is an increasing need for alternative tests in vitro. We have developed a new system for in vitro immunotoxicity testing, which employs changes in cytokine expression observed in vitro as an endpoint indicating potential for perturbation of the immune system in vivo. This system named "fluorescent cell chip" (FCC) is based on a number of genetically modified cell lines that regulate the expression of a transgene coding for fluorescent protein enhanced green fluorescent protein (EGFP) in a similar way as they regulate expression of IL-1beta, IL-2, IL-4, IFN-gamma, IL-10, TNF-alpha, and beta-actin. Morphological and functional features of selected cell lines expressing EGFP under the control of cytokine promotors were compared with maternal cell lines and this comparison showed that critical functional features of the maternal cell lines were preserved in EGFP expressing cells. Two chemicals with known immunotoxic activities, cyclosporine A and potassium tetrachloro-platinate(II), mediated compound-specific pattern of inhibition and activation of reporter gene expression. Thus, the "fluorescent cell chip" has demonstrated potential for application as a predictive screening test for immunomodulatory activities of chemicals. The major advantage of this approach is the possibility to apply this test in high throughput screening of high number of compounds for their well defined biological activity.

Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae.

We have investigated the localization and function of the epidermal growth factor receptor (EGFR) in normal cells, in cholesterol-depleted cells and in cholesterol enriched cells. Using immunoelectron microscopy we find that the EGFR is randomly distributed at the plasma membrane and not enriched in caveolae. Binding of EGF at 4 degrees C does not change the localization of EGFR, and by immunoelectron microscopy we find that only small amounts of bound EGF localize to caveolae. However, upon patching of lipid rafts, we find that a significant amount of the EGFR is localized within rafts. Depletion of the plasma membrane cholesterol causes increased binding of EGF, increased dimerization of the EGFR, and hyperphosphorylation of the EGFR. Addition of cholesterol was found to reduce EGF binding and reduce EGF-induced EGFR activation. Our results suggest that the plasma membrane cholesterol content directly controls EGFR activation.