Here are summaries of the four newest Discovery Fund Research Projects awarded for 2011-2012 to the Johns Hopkins Division of Rheumatology. These important projects would not be possible without your commitment and support.
Project No. 1: Qualitative Research for Patient Reported Outcomes in Arthritis
Principal Investigator: Clifton O. Bingham III, MD
Most methods that doctors use to determine how well arthritis patients are doing are things that the doctor can “measure”. These are things like the number of swollen or tender joints, blood tests for inflammation, and X-Rays. In rheumatoid arthritis we have questionnaires that ask simple questions about pain, fatigue, and ability to do tasks. However, many parts of having arthritis that are important to patients (sleep, function in a social role such as work or family, level of stress) are not easily “measured”.
Qualitative research is the first step to determine what is important to patients. This involves focus groups and one-on-one interviews with patients. This information is recorded, then put together to find common themes. Like research at the bench, this type of work requires special training and skills. This grant will allow us to work with experienced researchers to interview arthritis patients about their disease. The data we get will allow us to work with other researchers worldwide doing similar studies.
We will then make thorough questionnaires to better “measure” the impact of arthritis on parts of life that are most important to patients. We will ultimately develop a comprehensive disease impact “score”. Doctors can use this score as a factor to decide if a change in treatment is needed. This will improve discussions between doctors and patients and will help to advance the important goal of shared decision making.
Project No. 2: Pilot Study to Determine Whether Antibodies Against Transient Receptor Potential Melastatin Type 8 (TRPM8) are Detected in Scleroderma Patient Sera
Principal Investigators: Livia Casciola-Rosen, PhD & Fredrick Wigley, M
Systemic sclerosis (scleroderma) is a multisystem autoimmune disease with major involvement of skin, lung and gastrointestinal tract. Self-proteins called “autoantigens” are often targeted by the immune system in these patients; to date, there are a small number of proteins (~10- 15) that are known to be scleroderma autoantigens. In some cases, the autoantibodies themselves may also be involved in the disease process by altering (e.g., blocking or activating) the specific function of the protein against which they are directed. New findings are emerging showing that there may be additional as yet undiscovered autoantigens targeted in scleroderma patients.One of the striking clinical features of scleroderma is that almost all patients acquire intolerance to cold temperatures early in the disease process, and develop Raynaud’s phenomenon (RP), which is an exaggeration of the normal responses to environmental temperatures. While the pathogenesis of RP is currently not fully understood, an imbalance between the normal regulation of constriction and dilation of cutaneous blood vessels is postulated. In scleroderma patients, we believe this may be a clue that one or several of the critical regulatory proteins involved in these process is/are being targeted by the immune system.
The aim of the proposed pilot study is to investigate whether a key protein whose function is to detect variations in degrees of cold temperature (termed “TRPM8”) is targeted by the immune system in patients with scleroderma and RP. We will therefore develop and validate a new assay to probe for the presence of antibodies against TRPM8 in these patients; we will also test for this antibody in other disease control and normal control groups. If these antibodies are found specifically in scleroderma patients with RP, subsequent studies (beyond the scope of this proposal) will address the important question of whether the antibodies themselves are pathogenic.
Project No. 3: Effects of Neuromuscular Strain on Orthostatic Responses and Symptoms in Chronic Fatigue Syndrome (CFS)
Principal Investigator: Kevin R. Fontaine, PhD
Chronic fatigue syndrome (CFS) is a mysterious illness estimated to affect about 4 million adults in the United States. Its primary symptom is debilitating fatigue, but it also associates with other symptoms such as headache, poor sleep, joint pain, problems with memory and concentration, tender glands, and exhaustion after even the slightest physical exertion. The biblical Job, Charles Darwin, Florence Nightingale, and General Douglas MacArthur were thought to suffer from it. Although viruses and abnormalities in the immune system and misfiring brain chemicals are suspected to be possible causes, we do not know for sure what the cause is. There’s also no diagnostic test to identify people who have CFS.
The aim of the proposed pilot study is to investigate whether a key protein whose function is to detect variations in degrees of cold temperature (termed “TRPM8”) is targeted by the immune system in patients with scleroderma and RP. We will therefore develop and validate a new assay to probe for the presence of antibodies against TRPM8 in these patients; we will also test for this antibody in other disease control and normal control groups. If these antibodies are found specifically in scleroderma patients with RP, subsequent studies (beyond the scope of this proposal) will address the important question of whether the antibodies themselves are pathogenic.
We have found that more than a few people with CFS have restrictions in the range of motion of their limbs and spine and that applying a strain, such as bending their ankles so that their toes are higher than their heel [called dorsiflexion: see Figure] increases their blood pressure, heart rate, and makes them lightheaded, groggy, and terribly fatigued. In some people with CFS, the symptoms produced by bending their ankles can last for several hours. To learn more about the effects of dorsiflexion, we will conduct an experiment to investigate whether straining the ankles in this way worsens symptoms and increases blood pressure and heart rate compared to holding the ankles in a position of plantar flexion, a position that produces no strain. Twenty people with CFS patients and 10 people without CFS will take part in the study. If we show that dorsiflexion of the ankles increases blood pressure, heart rate, and symptoms only in people with CFS, and that plantar flexion does not increase symptoms, it may help us to develop new ways to assess and diagnose CFS and other related illnesses such as Fibromyalgia. It may also provide us with clues concerning possible causes of, and treatments for, CFS.
Project No. 4: Determination of Topoisomerase I Expression and Discovery of Novel Autoantigens in Early Scleroderma Lung Disease
Principal Investigator: Thomas Grader-Beck, MD
Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and mortality. Patients frequently die from complications of interstitial lung disease with progressive pulmonary fibrosis. The disease pathogenesis is unknown, but antibodies targeting the patient’s own proteins (autoantibodies) are thought to play an important role. Topoisomerase I (topo I) has been identified as a target of autoantibodies in SSc and the presence of antitopo I antibodies is associated with interstitial lung disease in SSc. Whether these antibodies are directly involved in the pathogenesis remains unclear. The expression pattern of topo I and other autoantigens in the lungs in early stages of SSc lung disease is unknown, since patients do not routinely undergo lung biopsy for diagnosis. We have recently identified an inducible mouse model that exhibits a prominent anti-topo I antibody response and demonstrates histological features of early human SSc lung disease. This model represents an ideal opportunity to define the expression and cellular source of topoisomerase I in the target tissue of the lungs and to identify novel autoantigens in lung tissue that may play a role in disease pathogenesis.
We hypothesize that induction of inflammatory lung disease leads to upregulation of tissuespecific autoantigens, including topo-I and that this expression will induce distinct autoantibodies of pathogenetic relevance in early stages of SSc lung disease. We will determine the expression pattern of topo-I in the lungs of disease mice in relation to the emergence of anti-topo-I antibodies and define which cells are expressing topo-I. In a second broader approach, we will screen the protein pool of inflamed lungs for novel autoantigens using well-characterized sera from SSc patients with interstitial lung disease.The results of the proposed study may improve our understanding of pathophysiological mechanisms in early SSc lung disease and lead to identification of novel biomarkers for screening and therapy.
