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Novel Insight into the Role of Alpha-actinin-1 in Rheumatoid Arthritis

Abstract: The knowledge of rheumatoid arthritis (RA) pathology is rapidly advancing and becoming more and more complex, and a simple fact is that the major organ targeted by RA pathogenic factors is the synovium. It is well known that fibroblast-like synovial (FLS) cell is the major cell-type for constructing synovium. Following stimulation by pro-inflammatory cytokines, FLS cells are phenotypically changed to have the capability to proliferate abnormally. Recently we demonstrated that α-actinin-1 (ACTN1) gene is significantly increased in synovial tissues obtained from RA, as compared to osteoarthritis (OA). We therefore reviewed the literature about α-actinins (ACTNs) and we now propose that ACTN1 may function as a "terminal effector" of intracellular signalings initiated by tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in RA. Future research on ACTN1 may help to improve the current therapeutic and diagnostic strategies of RA. ... Read more

Pharmacogenomics in Childhood Rheumatic Disorders: A Foundation for Future Individualized Therapy

Abstract: Investigating the effect of genotype on drug response in children is an evolving field, with many challenges, but there is great potential to optimize safe and effective use of drugs in children. An exponential increase in available medications for use in children with rheumatic disease has opened seemingly endless genotype/phenotype relationships to explore, but challenges inherent in studying rare diseases and the often overlooked role of ontogeny contribute to limitations in pharmacogenomic studies in this population. With careful recognition of the importance of development, improved phenotyping with the incorporation of biomarkers, and expanding collaborative efforts on a national and even international scale, the field of pediatric rheumatology has the opportunity to strategically study the new therapeutic armamentarium available and provide individualized safe and effective therapies to our population of patients. ... Read more

Rheumatoid Arthritis and Alzheimer's Disease: Genetic and Epigenetic Links in Inflammatory Regulation

Abstract: Controversial data are available about the relationship between Alzheimer's disease (AD) and rheumatoid arthritis (RA). An inverse relationship between AD and RA, due to different factors, was previously described. Similarly to RA, AD pathogenesis is multifactorial and different findings support the inflammatory pathogenetic hypothesis. Several inflammatory mediators are involved in the disease onset and progression regulated by genetic and epigenetic mechanisms. Among them, inteleukin-6 (IL-6) and interleukin-1 (IL-1) as pro-inflammatory soluble factors produced by monocytes-macrophages and tumor necrosis factor alpha (TNF-α) produced by activated macrophages and mononuclear cells represent key molecules in the induction and maintenance of chronic inflammation in RA. In particular a link with the T allele of the SNP 3953 T/C in the IL-1 gene and an overexpression of miR-146a appears to be common to both RA and AD. In this review we will discuss the genetic and epigenetic regulation of the inflammatory cascade in RA and AD to find out the possible links between RA and AD onset. ... Read more

TNF-alpha Antagonism and Cancer Risk in Rheumatoid Arthritis: Is Continued Vigilance Warranted?

Abstract: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthritis that can lead to significant damage and dysfunction of involved joints. Prior to 1998, treatment options were limited to disease modifying anti-rheumatic drugs, commonly referred to as DMARDs like methotrexate, sulfasalazine, hydroxychloroquine, and gold salts. Tumor necrosis factor alpha (TNF-α) is a central cytokine that drives the inflammation in RA; hence inhibition of TNF-α offers an attractive treatment strategy in RA. The introduction of TNF-α inhibitors, a class of biologic DMARDs, has dramatically changed the treatment of RA as these are highly effective therapies. Medication-related adverse events remain a major problem in health care. This is true of the TNF-α antagonists as well, with particular concerns about increased risks of infections and malignancy. Because clinical trials performed prior to medication approval are limited by the number and clinical complexity of participants and the duration of the trials, post-marketing surveillance is critical in identifying adverse events. In order to better clarify the safety issues related to the use of TNF-α inhibitors in RA, several studies using large observational registries along with pooled meta-analyses of these studies have been published. This review will summarize the data from these recent studies on the question of malignancy risk associated with TNF-α inhibitor use in RA. It is comforting that the data from these studies do not support an increased risk of cancer, except non-melanoma skin cancer, with the use of TNF-α antagonists in adults with RA. ... Read more

New and Future Agents in the Treatment of Rheumatoid Arthritis

Abstract: Rheumatoid arthritis (RA) is the most common inflammatory musculoskeletal disease and an important cause of diminished quality-of-life for the affected individuals and with a major impact on society because of decreased work-force participation. Treatment of RA has been advanced dramatically during the past two decades by the advent of biological therapies. A large number of such agents have been approved and several additional ones are in late-stage clinical developments. Because of the high price of biologics, pharmacoeconomical considerations have become an important part of the appraisal of such medications. Current therapeutic developments include the development of additional biologics with various specific targets, the development of small-molecule compounds with similar efficacies, and entirely new approaches to treat autoimmune inflammatory diseases such as RA. ... Read more

Immunological Tolerance in the Therapy of Rheumatoid Arthritis

Abstract: Dramatic progress in the treatment of Rheumatoid Arthritis (RA) has led to an early and aggressive treatment strategy, combining DMARDS with biological agents. Since these therapies are able to induce initial clinical control, attention has shifted toward the maintenance of this state. Tools to maintain long-term remission are still lacking but may be found in the ability to establish immunological tolerance. Tolerance can be induced in several specific and nonspecific ways, including manipulation of costimulatory signals, induction of regulatory T cells, and tolerization to heat shock proteins. Induction of disease control with the current combination therapies, followed by progressive withdrawal in parallel with re-establishing immunological tolerance, may be an attractive approach in the near future. ... Read more

Malignancy Risk in Autoimmune Rheumatic Diseases

Abstract: Autoimmune diseases are chronic disorders and are highly prevalent in the population. It is thus logical to see whether patients with autoimmune rheumatic diseases are more prone to cancer. Studies show that most autoimmune diseases are not linked to cancer. However, patients with rheumatic arthritis or systemic lupus erythematosus do have an increased risk for lymphoma. ... Read more

Drug Targets in Immunological Diseases: Focus on Rheumatoid Arthritis

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate have been the mainstay treatments for rheumatoid arthritis for decades. In the past few years, anti-TNF-α (tumor necrosis factor-α) biopharmaceuticals have sparked a revolution. More drugs targeting the inflammation pathway are in the works. ... Read more

Drug Profile: Humira

Other Names: D2E7, Adalimumab.

Maker: Abbott Laboratories.

Disease Treated: Adult moderate to severe cases of rheumatoid arthritis who have had an inadequate response to disease-modifying anti-rheumatic drugs (DMARDs).

Approval Status: Approved by the US FDA for marketing on December 31, 2002.

Chemical/Biological Nature: HUMIRA is a recombinant all human IgG1 monoclonal antibody specific for human tumor necrosis factor alpha (TNF-α). Components responsible for the antibody’s specificity were discovered by phage display technology (Discovery Medicine, November 2002). The monoclonal antibody is composed of the human antibody heavy and light chain variable regions ... Read more

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