How Arthritis May Protect Against Alzheimer’s Disease

RA and Amyloid Epidemiological studies have suggested that either rheumatoid arthritis itself – or the anti-inflammatory drugs used to control it – are associated with a reduced risk of developing Alzheimer’s disease. Recent clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) have failed to show a benefit in patients with Alzheimer’s disease and researchers at the University of South Florida have now shown that it may be the disease itself that affords protection.

In a mouse model of Alzheimer’s disease, one of the cytokines that is elevated in patients with rheumatoid arthritis, granulocyte-macrophage colony-stimulating factor (GM-CSF), was shown to improve working memory and learning and to lead to an apparent increase in neural cell connections in the animals’ brains. GM-CSF also led to an accumulation of microglia in the brains of treated animals which was associated with a greater than 50% reduction in β-amyloid peptides. Recombinant human GM-CSF is currently approved to stimulate the production of white blood cells in some cancer patients and the new study, which is published in the Journal of Alzheimer’s Disease, suggests that GM-CSF could also be of benefit to Alzheimer’s patients.

The USF Health Byrd Alzheimer’s Institute plans to begin a pilot clinical trial later this year to investigate recombinant human GM-CSF in patients with mild or moderate Alzheimer’s disease.

Beating Off the Attack in RA

Image: Flickr - Jsome1
Although the exact causes of autoimmune diseases such as rheumatoid arthritis are unknown, tissue damage is mediated, at least in part, by the (inappropriate) action of effector T cells. Regulatory T cells are a specialised population of T cells which play a role in ‘self-tolerance’ by suppressing activation of other immune cells: genetic deficiency in regulatory T cells causes severe autoimmune disease in both mice and humans.

Researchers at NYU Langone Medical Center examined blood samples from 25 patients with rheumatoid arthritis and found that regulatory T cell function was inversely correlated with disease severity. The team have now discovered a way to enhance the activity of regulatory T cells which may eventually lead to new treatments for autoimmune diseases such as rheumatoid arthritis or inflammatory diseases such as Crohn’s disease.

In effector T cells, the calcium-independent protein kinase C, PKC-θ, localises at the site of contact between the T cell and the antigen presenting cell, placing it in the proximity of other enzymes that mediate T cell activation. When regulatory T cells become activated, however, the team found that PKC-θ is localised away from the point of cell-cell contact. In cell culture experiments, PKC-θ inhibitors were shown to boost the activity of regulatory T cells around 5-fold. One of the inhibitors was also shown to be protective in a mouse model of Crohn’s disease.

The study is published in Science Express and the PKC-θ inhibitors were provided by Boehringer-Ingelheim Pharmaceuticals, Inc.

New Trigger for RA

rheumatoid arhtritis handRheumatoid arthritis (RA) is a chronic, typically progressive, autoimmune disease that primarily affects the joints although it can damage other tissues, including heart, lung, and eyes. There is currently no cure for RA and the goal of treatment is reduce joint pain and inflammation, maximise function, and minimise joint destruction and deformity. Newer biological treatments targeting components of the immune system in combination with disease-modifying antirheumatic drugs (DMARDs) are effective in preventing joint damage in some patients, but not all sufferers respond to these treatments and some may relapse despite treatment. The cause of RA remains unknown but both genetic and environmental factors are suspected to play a role.

TLR4 crystal structureResearchers at Imperial College have now identified a new immune trigger that may contribute to the pathology of RA. Tenascin-C is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. The team found that injection of tenascin-C into the joint cavity in mice caused severe joint inflammation and damage and, in a separate experiment, that mice lacking tenascin-C were protected from erosive arthritis. In cultures of cells from rheumatoid arthritis patients, tenascin-C induced synthesis of pro-inflammatory cytokines via activation of Toll-like receptor 4 (TLR4). TLR4 is one of a family of receptors that play a key role in pathogen recognition and activation of innate immunity. Stimulation of TLR4 is known to activate macrophages leading to release of TNF-α, one of the targets of existing biological agents used to treat RA patients. Previous studies had shown that mice lacking TLR4 do not show chronic joint inflammation, and blocking the interaction between tenascin-C and TLR4 may provide a new way to combat RA.

The study is published in the journal Nature Medicine.

Encouraging News for Rheumatoid Arthritis Sufferers

Rheumatoid Arthritis (RA) is a painful, chronic, progressive and disabling auto-immune disease. Newly released data has shown that a novel biologic, Actemra (tocilizumab),  is superior to current standard of care in RA patients. Actemra is a humanised monoclonal antibody to the interleukin-6 receptor that blocks the activity of interleukin-6, a protein that plays a major role in the RA inflammatory process. Actemra is awaiting approval in the United States and Europe.  In Japan, Actemra was approved for the treatment of RA in April 2008.

Other biologics are already used to treat RA and act at different points in the inflammatory process.

Orencia® (abatacept) works by reducing the activation of T-cells, which reduces the activation of other cells in the RA inflammatory process. Humera®(adalimumab), Enbrel®( etanercept) and Remicade® (infliximab) block the action of TNF-alpha, an inflammatory cytokine that leads to tissue damage. Mabthera® (rituximab) targets B cells, one of the key players in the pathogenesis of RA. Kineret® (anakinra) blocks the actions of the cytokine, IL-1.

The biologic medicines are usually prescribed together with the disease-modifying anti-rheumatic drug, methotrexate.
RA cellular pathway