Theresa Wampler Muskardin – Profiling RA for Personalised Treatment

Theresa Wampler Muskardin – Profiling RA for Personalised Treatment

Dr. Theresa Wampler Muskardin is a junior faculty member at New York University School of Medicine. She received her medical degree from Wayne State University School of Medicine in 2004 and specializes in Rheumatology. Her goal as a researcher is to one day be able to provide therapy tailored to the individual patient’s disease and personal immunology resulting in more effective treatment and eventually a cure.

Time is of the Essence

Worldwide, rheumatoid arthritis (RA) is the most common inflammatory joint disease, with serious manifestations of the disease also occurring beyond the joints. Effective treatment as soon as possible after diagnosis is critical to good patient outcomes. Remission within the first 3 months of therapy is now the goal, and is the best predictor of remission at one year. Huge strides have been made in how we treat this disease. Unfortunately for many the approach to treatment is one of trial and error, with physicians unable to predict which medications will work for which patients.

TNF a Role Player in RA

Cytokines are small protein molecules that are important cell signalling molecules that act as immunomodulating agents. One such cytokine important in the development and progression of RA is tumor necrosis factor (TNF). In patients with RA, levels of TNF in the synovial fluid are raised. Synovial fluid reduces friction between articular cartilage of synovial joints during movement. Raised levels on TNF lead to local inflammation as the synovial cells produce enzymes such as collagenase, that break bonds in collagen. Clinical application of anti-TNF drugs for RA was first demonstrated in 2003 by Marc Feldman and Ravinder Maini. TNF inhibitors (TNFi) are now the most common biologic treatment used in the treatment of RA.

A TNFi is a drug that suppresses the physiologic response to tumor necrosis factor, a protein involved in the inflammatory response. Notable side effects of TNFi include lymphomas, infections (especially reactivation of latent tuberculosis), congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Responses to TNFi are variable, with approximately 30% not responding and another 30% achieving only partial response. It commonly takes between 3-6 months to trial medications for a patient before some level of success is achieved. Active disease persists in a substantial number of patients even after a trial of a couple of medicines, during which time the disease seems to become more difficult to treat and damage accrues. According to Dr. Muskardin, a major unmet goal in the treatment of RA is to define parameters of the abnormal immune response that allow for rational selection of therapy. Thus, she is using her ANRF grant on a study designed to improve treatment statistics by better determining what medications will work best for which patients.

A Pathway Persisting

Interferons (IFN) are a subclass of cytokines that play roles in infection, cancer, inflammation and autoimmunity. IFNs are secreted by many cells including immune cells like lymphocytes (natural killer cells, B-cells and T-cells), macrophages, fibroblasts (cells that produce collagen), osteoblasts (bone building cells) and many others. Type I IFN has been shown to have a pathogenic role in many rheumatic conditions, including systemic lupus erythematosus, Sjögren syndrome, myositis and systemic sclerosis. Many genetic risk factors for rheumatic diseases lie within the type 1 interferon pathway. In normal immune responses, type I IFNs have a critical role in the defence against viruses. In many rheumatic diseases, however, large subgroups of patients demonstrate persistent activation of the type I interferon pathway. Basically, instead of switching off when inflammation is no longer an appropriate response, it is left on. 

In vitro studies indicate that IFN and TNF-α are able to cross-regulate; high levels of one of these cytokines can inhibit the production of the other cytokine. In humans, a comparable phenomenon has been found to exist in which anti-TNF-α therapy resulted in increased serum type I IFN activity. These data suggest type I IFN as a candidate marker for anti-TNF-α failure, as it is conceivable that in selected patients anti-TNF-α therapy may intensify a pre-existing tendency towards high type I IFN. A number of clinical trials are underway for therapies that block type I interferon and/or the type I interferon pathway, thus preventing continuous activation of the pathway. Preliminary data from these clinical trials is extremely promising.

High Profile Research

Recently, Dr. Muskardin and her team demonstrated that baseline levels of serum type-1 interferon activity can predict which RA patients would not respond to TNFi. Building on these findings, as an ANRF scholar Dr. Muskardin is planning to analyze blood from RA patients to define biological subgroups, categorized according to levels of serum type-1 interferon that will predict an individual patient’s response to tumor necrosis factor inhibitor (TNFi) treatment.

In conjunction with the blood analysis, Dr. Muskardin will be examining synovial tissue (the fluid that lubricates our joints). The synovial tissue from rheumatoid arthritis patients will be stained to help clarify the underlying biology of the type 1 interferon pathway and its ability to predict whether a patient will respond to TNFi. The proposed study will provide powerful validation of this finding which will be necessary to translate the findings into more effective patient treatment.

No Longer Anybody’s Guess

Prognostic serum markers would considerably expedite the process of attaining control over disease activity and avoid subjecting patients to unnecessary medications with unnecessary physical and financial cost implications. Being able to predict response to a potential treatment prior to beginning the therapy would signify a major advancement in RA treatment. As early treatment of RA is key, a reduced time taken to find an effective treatment would have immeasurable benefits, including limiting the damage to effected joints and preventing permanent disability. Effective treatment administered in the therapeutic ‘window of opportunity’ would reduce the overall disease burden of RA.

At ANRF, we are proud to support Dr. Muskardin and wish her well as she strives to beat RA in a time sensitive race.    


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ANRF
Article Author
Arthritis National Research Foundation
arthritisresearch@curearthritis.org

The Arthritis National Research Foundation's mission is to provide initial research funding to brilliant, investigative scientists with new ideas to cure arthritis and related autoimmune diseases. Writing articles about the patients affected and the science being done to find a cure shows why we need to come together to #CureArthritis!

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