Rheumatoid Arthritis

Cure Arthritis Naturally

Cure Arthritis Naturally

Get Instant Access

Rheumatoid arthritis (RA), the most common inflammatory joint disease, is a chronic autoimmune disorder that affects approximately 1% of the population and causes significant disability. The etiology of RA is largely unknown, although current evidence suggests contributions from both environmental and genetic components (271). The chronic inflammation in the arthritic joint is characterized by recruitment of immune cells, including lymphocytes, macrophages, and plasma cells, leading to massive thickening of the synovium accompanied by release of inflammatory mediators, ultimately leading to invasion and destruction of articular cartilage and bone. At the molecular level, chronic inflammatory arthritis is characterized by diminution of T cell factors and an abundance of cytokines and growth factors, such as in-terleukin-6, tumor necrosis factor a (TNF-a), and interleukin-1p (IL-1p), which are produced by macrophages and synovial fibroblasts and play a major role in the progression of joint destruction (272). IL-1p, in particular, is a key cytokine that induces cartilage degradation, whereas TNF-a is a major cytokine involved in joint inflammation (273).

Conventional treatment to manage the symptoms of arthritis uses general anti-inflammatory agents, including both ste-roidal and nonsteroidal drugs, and disease-modifying drugs such as methotrexate. However, none of these pharmacologic agents have yet proven effective in halting the progression of disease. Recently introduced biological agents are more effective in ameliorating arthritis symptoms and halting the progression of disease. In particular, inhibitors of TNF-a and IL-1p have proven effective in preclinical studies as well as in human clinical trials, and the Food and Drug Administration (FDA) has approved the use of IL-1 receptor antagonist (IL-1Ra), soluble TNF-a receptor immunoglobulin Fc, and an anti-TNF-a monoclonal antibody for the treatment of RA.

The use of biologics for arthritis therapy presents several challenges. Because of the relatively short half-life of these proteins and the need for frequent, daily, or weekly dosing, effective levels of the therapeutic protein may not be maintained for extended periods. In addition, therapeutic proteins are administered systemically and may have reduced bioavail-ability in some affected joints. Also, production of biologics such as these proteins often is inefficient, leading to low yields and consequently high costs. Gene transfer may be a more efficient means of delivery of these biological agents. If persistent transgene expression could be achieved following gene transfer, it should circumvent the need for frequent repeat dosing and should allow attainment of steady levels of the product, as opposed to the peaks and troughs associated with intermittent protein administration. Furthermore, with the current advances in manufacturing, the production cost of vectors such as AAV may compare favorably with production costs of biologics.

AAV vectors encoding genes that selectively target key mediators, or that interfere with key biological processes, involved in the pathogenesis of RA have been evaluated in rodent models of inflammatory arthritis. In mice with collagen-induced arthritis (CIA), an AAV vector encoding interleukin-4 demonstrated protection, for up to 7 months, from articular cartilage destruction and amelioration of disease severity (274,275). The therapeutic efficiency of an AAV vector carrying the viral interleukin-10 (vIL-10) under the transcriptional control of the regulated TetON system was evaluated following intramuscular administration to mice with CIA. Expression of vIL-10, specifically induced by doxycycline, persisted for at least 4 months and reduced significantly the incidence and severity of arthritis (275a). In TNF-a transgenic mice, intra-articular injection of AAV encoding soluble TNF recep tor type I significantly decreased synovial hyperplasia, and cartilage and bone destruction (276).

In the streptococcal cell wall-induced rat arthritis model, administration of an AAV vector encoding the rat TNFR:Fc fusion gene, either systemically (intramuscular) or locally (intra-articular), resulted in profound suppression of arthritis. This was reflected in decreased inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and mRNA expression of joint proinflammatory cytokines (277). Moreover, administration of the vector to one joint suppressed arthritis in the contralateral joint. An AAV vector encoding IL-1Ra cDNA was evaluated in a lipopolysaccharide (LPS)-in-duced arthritis model in rats using therapeutic, recurrence, and preventative protocols (278). IL-1Ra expression was up-regulated by LPS-induced joint inflammation and proved efficacious in all protocols. Importantly, the IL-1Ra transgene persisted for more than 3 months and could be induced to express therapeutic levels of soluble IL-1Ra upon LPS administration. This resulted in suppression of inflammation and IL-1p production in the treated knee joints.

Was this article helpful?

0 0
Treating Rheumatoid Arthritis With Herbs Spices Roots

Treating Rheumatoid Arthritis With Herbs Spices Roots

Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.

Get My Free Ebook


Post a comment