Role of Apheresis in Rheumatoid ArthritisRoth, Sanford
doi: 10.2165/00003495-200666150-00001pmid: 17100402
Apheresis, a therapeutic procedure that has been available for decades, has recently been added to the long-term management of rheumatoid arthritis (RA). It is a procedure whereby blood is removed from the body and divided into its various components. With the development of specific instrumentation, it has become possible to target the specific cellular or humoral components to be removed or altered.
Optimising Antiresorptive Therapies in Postmenopausal WomenKarsdal, Morten; Qvist, Per; Christiansen, Claus; Tankó, László
doi: 10.2165/00003495-200666150-00002pmid: 17100403
Accelerated bone turnover with bone resorption exceeding bone formation is a major mechanism underlying postmenopausal bone loss and hence the development of osteoporosis. Accordingly, inhibition of bone resorption is a rational approach for the prevention of osteoporosis. In this context, the most logical option, hormone replacement therapy, reverses the rate of bone turnover to premenopausal levels, whereas the magnitude of inhibition by amino-bisphosphonates and the recently introduced anti-receptor activator of NFκB ligand (RANKL) antibody often exceeds this. As bone turnover has crucial implications for the continuous renewal of bone tissue, the over-suppression of bone turnover has potential consequences for bone quality and strength. Long-term treatment with potent bisphosphonates has recently been associated with osteonecrosis of the jaw and dose-dependent increases in micro-crack accumulation in animals. Although these observations are the subject of ongoing discussions, it is timely to discuss whether the over-suppression of bone turnover below premenopausal levels is really our ultimate goal when defining the success criteria for antiresorptive agents.
B-Cell-Targeted Therapy for Systemic Lupus ErythematosusSabahi, Ramin; Anolik, Jennifer
doi: 10.2165/00003495-200666150-00004pmid: 17100405
Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-α, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.
Familial DyslipidaemiasHachem, Sahar; Mooradian, Arshag
doi: 10.2165/00003495-200666150-00005pmid: 17100406
Plasma lipid disorders can occur either as a primary event or secondary to an underlying disease or use of medications. Familial dyslipidaemias are traditionally classified according to the electrophoretic profile of lipoproteins. In more recent texts, this phenotypic classification has been replaced with an aetiological classification. Familial dyslipidaemias are generally grouped into disorders leading to hypercholesterolaemia, hypertriglyceridaemia, a combination of hypercholesterolaemia and hypertriglyceridaemia, or abnormal high-density lipoprotein-cholesterol (HDL-C) levels.
Cardiovascular Risk in Patients with HIV InfectionBergersen, Bente
doi: 10.2165/00003495-200666150-00006pmid: 17100407
Increased coronary heart disease risk in HIV-positive patients using antiretroviral therapy (ART) has been a controversial topic since 1998 when the dyslipidaemic effect of protease inhibitors (PIs) was recognised. Accumulating evidence suggests an association between ART and increased coronary heart disease risk. In 2003, the large, prospective D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study reported a 26% relative increase in the rate of myocardial infarction per year of exposure during the first 4–6 years of use. As the HIV-population grows older, infectious disease specialists have to consider unfamiliar areas of internal medicine such as lipid-lowering therapy and smoking cessation. Moreover, the ART regimen itself may be a modifiable risk factor, as there are both class differences and within-class differences in the tendency to increase lipids. Most nucleoside reverse transcriptase inhibitors (NRTIs), including the newer agents tenofovir disoproxil fumarate and emtricitabine, have little or no effect on lipid levels or glucose metabolism. One exception is the highly effective NRTI stavudine, which has a dyslipidaemic profile and a negative effect on glucose metabolism. In contrast the non-nucleoside reverse transcriptase inhibitor nevirapine may increase the ‘good cholesterol’ high-density lipoprotein (HDL) cholesterol and thus reduce the total cholesterol : HDL cholesterol index. Most of the PIs have some dyslipidaemic effect, especially ritonavir (alone or in combination with other PIs), fosamprenavir and the novel PI tipranavir. Only atazanavir, and to some extent saquinavir, seem to have little effect on lipid levels and glucose metabolism.
VildagliptinHenness, Sheridan; Keam, Susan
doi: 10.2165/00003495-200666150-00007pmid: 17100408
▴ Vildagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is being evaluated in the treatment of patients with type 2 diabetes mellitus. It improves glycaemic control by inhibiting DPP-4 from inactivating the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, prolonging incretin activity in response to ingestion of nutrients. This allows for increased insulin sensitivity, decreased glucagon secretion and improved β-cell function in a glucose-dependent manner.
▴ Glycaemic control with vildagliptin 50 or 100 mg/day, measured by a change from baseline in mean glycosylated haemoglobin (HbA1c) at study endpoint, was improved relative to placebo in several well designed clinical trials of vildagliptin monotherapy in patients with type 2 diabetes. In randomised active comparator studies, noninferiority of vildagliptin in reducing HbA1c levels from baseline was established to rosiglitazone, but not to metformin.
▴ Vildagliptin also showed efficacy in reducing HbA1c levels in patients with type 2 diabetes when used in combination with metformin, pioglitazone or insulin.
▴ Vildagliptin was generally well tolerated when administered alone or in combination with additional antidiabetic treatment. Gastrointestinal adverse events were mild to moderate in intensity, and occurred less frequently than with metformin. Hypoglycaemic events were rare and occurred at a similar incidence to that with placebo.