2012-2013 Grant Awards

Precision Diagnosis using Antibodies in Rheumatic Disease: Identification of Novel Autoantigen Specificities Expressed by Circulating Cells in Systemic Lupus Erythematosus (SLE)

Felipe Andrade, MD, PhD

Each rheumatic disease is composed of various subtypes – these subsets behave differently in terms of complications and responses to therapy, but are not easily distinguished using currently available probes. This project will identify markers in Lupus’ patient’s blood, which will allow categorization into subgroups. These markers may allow more precise diagnosis, monitoring and choice of therapy in those affected by Lupus.

Precise Quantitation of Pathogenic Pathways in Rheumatic Diseases: Interferon Activation in Systemic Sclerosis

Francesco Boin, MD and John Hall, PhD

Scleroderma is a chronic systemic autoimmune disease, that is characterized by fibrosis or hardening (sclero) of the skin (derma) and vascular alterations, causing dysfunction in the tissues. A group of molecular signals called cytokines play a role in causing this dysfunction, but the primary drivers remain unknown. This project is based on some recent discoveries that allow the effects of interferons, proteins made and released by host cells in response to the presence of pathogens, to be distinguished in patient tissue. Scleroderma patients have evidence of a signature of interferon in their tissue and blood, but the precise interferon responsible for this effect remains unknown. This project will precisely define the role of specific interferons in different scleroderma patients, and potentially provide a way to select novel therapies that neutralize specific interferons.

Disease Subsets are the Foundation for Precisely Defining Disease Mechanism: ACE and Scleroderma Renal Crisis

Livia Casciola-Rosen, PhD

One of the devastating consequences of scleroderma is renal crisis, where patients develop severe hypertension and renal failure. An enzyme called ACE pays an important role in this process, and ACE inhibitors can be lifesaving. The source of ACE and the reasons for its high level expression remain unknown. This project will begin to identify the cells that express ACE in scleroderma renal crisis, findings that have implications for understanding disease mechanisms and future therapies.

Sampling Tiny Amounts of the Target Tissue in Individual Patients: Defining the Role of Autoimmunity in Causing Thyroiditis in Women Initiating Interferon-alpha Therapy for Hepatitis C                            

Jennifer Mammen, MD

Different patients are unique in their genetic make-up as are the pathways that predominate in amplifying tissue damage. Recent technological advances have revolutionized the ability to study multiple pathways simultaneously in very tiny amounts of tissue. In this project, the investigators will sample tiny amounts of tissue from patients upon initiation of therapy, and define ways to precisely quantify the activity of distinct molecular pathways in those “micro-biopsies”.

2012 – 2013 Winter Update

Discovery

In 2009 and 2010, the Dr. Ira Fine Discovery Fund made an investment in a study exploring the relationship between cholesterol-lowering (statin) drugs and autoimmune diseases. Little did we know that those two modest grants would lead to a major discovery in autoimmune disease interactions.

Investigators had a hunch that, in some cases, patients taking cholesterol lowering statin drugs experienced a rare yet debilitating autoimmune muscle disease called myositis, a condition where a patient’s immune system mistakenly attacks and destroys healthy muscle tissue.  Researchers began looking for an errant protein, a type of antibody, causing the myositis, which they suspected was being triggered by the statin drug. In what was described as a “Eureka moment”, the offending antibody was found (called HMG CoA), and a great discovery, powered initially by the Dr. Ira T. Fine Discovery Fund, was made. A diagnostic test to screen for this antibody has even been developed.

Return on Investment

Dr. Clifton O. Bingham III, director of the Johns Hopkins Arthritis Center, has been asking questions and listening to his patients in the Rheumatoid Arthritis clinic at Johns Hopkins for years. He has always known that it’s his patients who define the relevant questions and hold key answers to managing their disease. Patients would tell Dr. Bingham what was working, and what wasn’t, and why, but that valuable information had never been compiled into a useable metric before. Then the Dr. Ira Fine Discovery Fund came along.

In 2011, the Discovery Fund awarded Dr. Bingham a grant to capture valuable patient information, formatted scientifically. He was able to hire a quantitative researcher at the JH School of Public Health, who through the development of patient questionnaires and focus groups, conducted the study, asked questions, compiled the information, created a patient “scorecard”, and found patterns and trends in patient experiences that had never been available before.

It seems that Dr. Bingham had the right idea at the right time. Armed with his Discovery Fund study of patient experiences, he was able to apply for additional funding from the newly created “Patient Centered Outcomes Research Institute” (PCORI), established as part of the 2012 Affordable Care Act. He competed for and received one of 50 prestigious initial primary funding grants to continue his research and is now in contention for one other PCORI and two other NIH grants. Dr. Bingham writes that the return on the Discovery Fund’s initial investment has been a whopping 94%. (208% if the other grants are awarded).  For the Dr. Ira Fine Discovery fund, capturing the patient experience turned into a great investment and has profound implications for the understanding and management of rheumatoid arthritis for the future.

New Ideas

This past year marked an exciting new partnership with the Division of Rheumatology at Johns Hopkins in the field of “Precision Medicine,” which refers to the tailoring of medical treatments to the individual characteristics of each patient. Precision medicine allows for highly individualized, focused care where categories of patients afflicted with the same disease, who may react differently to treatments, are identified. Moving forward, our grants will focus on new ways of analyzing the patients own individual information, grouping them into subsets and identifying disease categories, all with the goal of finding and tailoring treatments allowing for better outcomes for patients.

2011-2012 Grants Funded

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.