Focus on inflammatory muscle changes seen in Dermatomyositis and Polymyositis (2021)

Kanneboyina Nagaraju, DVM, PhD
Binghamton University

A pilot study grant of $200,000 has been provided to Kanneboyina Nagaraju, DVM, PhD of Binghamton University in New York.  Dr. Nagarahu’s research will focus on inflammatory muscle changes seen in Dermatomyositis and Polymyositis and their similarity to those seen in viral infections.  The study will evaluate whether this inflammation can be blocked using viral proteins.  If successful, it could open up a new strategy for potential treatments.

Continuous disease activity monitoring in DM and PM (2020) 

Dr. Alexander Oldroyd
University of Manchester
In this fellowship, Dr. Oldroyd works at the Center for Epidemiology Versus Arthritis to study the effectiveness of measuring continuous disease activity in DM and PM through monitoring gait and symptoms. 

MyotoxICI:  A study of pathomechanism of in immune checkpoint inhibitor-induced myositis (2019)

Yves Allenbach, MD PhD
Sorbonne University, Paris, France
Recently a new form of myositis has emerged as a life-threatening condition.  This is an autoimmune, drug-induced myopathy that happens as an adverse effect of new cancer treatments known as immune checkpoint inhibitors (ICI).  These new treatments dramatically improve cancer outcomes, but may cause autoimmune disease, including myositis, in some patients.  While ICI-induced myositis is rare, patients often have poor prognosis, often with cardiac involvement.  The aim of our study is to analyze the way in which these new cancer treatments cause myositis.  This understanding is important in order to find new treatments for this new entity, since the usual treatments for myositis may not be effective and they may adversely affect the cancer treatment.  In addition, an improved understanding of autoimmune drug-induced myopathies will shed light to underlying cause of other spontaneous forms of myositis.

Autoimmune myositis-associated interstitial lung disease gene expression profiles (2019)

Chelonda Johnson, MD, MHS
University of Pennsylvania
Interstitial lung disease (ILD), lung inflammation, and/or scarring, can be a devastating consequence of autoimmune myositis.  This condition is poorly understood, and physicians have few treatments to offer patients with myositis-ILD.  This research project aims to test for differential gene expression in individuals with myositis-ILD in order to discover what abnormal processes within the lungs may be causing the disease.  This will develop a better understanding of the molecular basis of myositis-ILD, which will help identify potential targets for drug treatments.

Patholigical role of B cells in idiopathic inflammatory myopathies (2019)

Erin M. Wilfong, MD PhD
Vanderbilt University
The idiopathic inflammatory myopathies (IIM), including dermatomyositis, polymyositis, and antisynthetase syndrome, are rare systemic rheumatologic diseases commonly affecting the skin, muscles, and lungs.  While nonspecific immunosuppressive drugs such as azathioprine and mycophenolate mofetil are used to treat this condition, there are no specific treatments to target these diseases as there are for rheumatoid arthritis or systemic lupus erythematosus.  Many patients also fail to respond fully to currently available therapies and suffer significant IIM-related complications and even death.  There is increasing evidence that certain immune system cells called B cells are involved in the development of IIM, and that IIM B cells are abnormal.  The purpose of this project is to better understand the immune mechanisms of IIM by studying how B cells from IIM patients function differently from healthy B cells.  These studies will give critical insights into how the immune system works in people with IIM and to identify targets for new drugs therapeutics for these devastating diseases.

The gut and skin microbiota in patients with DM (2018)

Lisa Christopher-Stine, MD
Johns Hopkins University
The human microbiome consists of 10-100 trillion symbiotic microbial cells, mainly bacteria in the gut, but also fungi, viruses, and even worms. The microbiome is the sum collection of human microbes and their genes existing within and on the human body and has been found to be a leading influence on health and disease. Humans and microbes have evolved together to establish a collaborative relationship over time, but disturbances of this system may occur and lead to several diseases, including autoimmune disorders. Over the last few decades, new insights into human microbial communities have sparked new interest in immunology of the gut and skin and suggest that changes in the human microbiome can also affect the development of rheumatic diseases such as dermatomyositis. This project proposes to examine the potential microbiome disruption in dermatomyositis.

Role of innate immune and metabolic pathways in mediating muscle weakness in myositis (2018)

Johanna Parkes, PhD
SUNY Binghamton
In myositis, muscle weakness may occur before inflammation, and muscles may remain weak after the inflammation has been successfully treated with drugs that suppress the immune system. Therefore, muscle symptoms cannot be completely explained by the immune system actively attacking the muscle. It has been shown that signals from the immune system, called type I interferons, reduce the ability of muscle cells to generate energy via mitochondria. It has also been shown that when muscle cells can’t generate enough energy, they aren’t able to repair themselves after damage. The weakness and poor ability to repair damage to muscles seen in myositis may be due to these interferons reducing the capacity of muscle cells to produce energy via mitochondria. This project tests two supplements that increase the ability of cells to produce energy via mitochondria called AICAR and GW501516. The project will measure the impact of these supplements in cells from myositis patients and in a mouse model of myositis to see if they improve muscle strength in myositis.

High resolution cellular phenotyping of myositis patients starting rituximab therapy (2017)

Simon Rothwell, PhD
University of Manchester, UK
The idiopathic inflammatory myopathies, also known as myositis, are a group of rare autoimmune diseases. In these diseases, the immune system, which normally protects the body against infections, attacks its own muscle tissue leading to muscle wastage and weakness. Other complications may occur, such as characteristic skin rashes, or lung disease. There are many different treatments for myositis, however not everyone responds well to these treatments. A new drug called rituximab is beginning to be used in myositis. This drug reduces the number of B-cells in the blood thereby reducing inflammation and improving symptoms. It would be useful to predict whether this drug will work in someone before they take it to prevent unnecessary exposure to side effects. There may be certain cells, or markers, in someone’s blood which give us clues as to whether someone will respond well or not. This project will use a new technology to look at the cells in patients’ blood before they begin rituximab treatment, to see if we can predict those that will respond. We may also be able to identify cells that differ between different subgroups of disease, such as polymyositis and dermatomyositis. In addition, looking at the cells of patients with myositis will tell us a lot about what may be causing the disease, and which cells we should research in the future.

Interleukin-31, a novel mediator of itch in dermatomyositis and a specific target for suppression by a novel agent, ajulemic acid (2017)

Victoria Werth, MD
Philadelphia Veterans Administration Medical Center and the University of Pennsylvania
Itch is a frequent and severe problem in many patients with dermatomyositis, having a dramatic impact on the quality of life and for which current treatments are frequently ineffective. We propose to characterize the source and regulation of a protein (interleukin (IL)-31) that is increased in the skin of patients with itch in dermatomyositis. The goal is to understand the mediators of this itch and then to characterize the mechanism of a potential therapy (ajulemic acid) for this difficult problem.

Development and validation of classification criteria for PM and DM (2006)

Ingrid Lundberg, MD, PhD
Karolinska Institutet, Stockholm, Sweden
This study attempted to understand how muscle inflammation causes weakness, speculating that a loss of small blood vessels in the muscles leads to low oxygenation in muscle tissue and loss of muscle strength. Results indicated a lower frequency of small blood vessels in myositis patients compared to healthy individuals, both in the early and in late phase of disease. Indirect signs of low oxygen tension in muscles from these patients could also contribute to low muscle performance and muscle weakness.

Why are inflamed muscles weak? How does the immune system affect muscle function in patients with poly- and dermatomyositis? (2005)

Ingrid Lundberg, MD, PhD
Karolinska Institutet, Stockholm, Sweden
Through this award, the grantee established a European myositis network, which now has more than 2,500 patients from 20 centers worldwide. This research registry is available to myositis investigators from around the world, offering opportunities for ongoing research on risk factors as well as for clinical trials testing new treatments for myositis.

Muscle weakness experienced by patients with myositis – Is there a connection between IL-1a and muscle function? (2004)

Stina Salomonsson, MD
Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
This project examined the role of the pro-inflammatory cytokine interleukin-1 (IL-1) in myositis. Researchers demonstrated that this inflammatory factor was found in muscle fibers as well as inflammatory and endothelial cells, establishing the crucial role of IL-1 in the development of polymyositis and dermatomyositis. The effects of both strength and endurance training on mouse models was investigated to determine what kind of training might best improve physical performance in myositis patients.

The role of granulysin in muscle fiber injury in idiopathic inflammatory myopathies (2004)

Satoshi Okada, MD
Stanford University, Stanford, CA
This project sought to determine whether granulysin (a protein that acts to destroy foreign cells as part of the body’s response to infection) plays a role in muscle injury in patients with myositis. Researchers, who had previously reported the role of granulysin in leukemic cells, detected granulysin in muscle tissues of patients with myositis. A difference was found in the mechanism of cell death caused by granulysin between muscle cells and leukemic cells. Researchers hope to apply these findings to cancer, myositis, and other autoimmune diseases.

RNA exosome-specific immune responses and autoimmune myositis (2002)

Xiao-Feng Yang, MD, PhD
Baylor University College of Medicine, Houston, TX
This study investigated the role of alternative splicing in autoimmune diseases, in which the body’s immune system mistakenly attacks its own tissue. Comparisons were made between 45 proteins associated with autoimmune disease and 9,554 proteins randomly-selected from the human genome. It was found that alternative splicing within specific regions occurred in all of the proteins (called auto-antigens) that elicited this autoimmune attack. Alternative splicing was found in only 42 percent of the randomly selected proteins. When the different protein forms reached a threshold of difference, immune tolerance to self-proteins broke down; this finding could someday lead to better treatment for autoimmune diseases such as myositis.

New therapeutic targets in DM (2014)

Xavier Suárez-Calvet, MSc, PhD candidate
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
The underlying cause and development of dermatomyositis (DM) is not fully understood, but recent studies have shed new light on the potential underlying biological mechanism of this complex disease. It has been demonstrated that RIG-I, a particular enzyme important in the antiviral response, is overly present in DM muscle but not in other inflammatory myopathies. In vitro studies suggest that the activity of this enzyme could explain a sustained autoimmune mechanism in DM muscle. This project attempts to better understand the underlying causal mechanisms involved in DM by identifying triggering factors that initiate and/or perpetuate inflammation in DM muscle. The results of these studies should identify new therapeutic targets and set the basis to design an animal model for DM that will further aid research into this disease.

The role of RLR innate immunity in initiating and perpetuating DM (2013)

Xavier Suárez-Calvet, MSc, PhD candidate
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Dermatomyositis (DM) is an immune-mediated myopathy characterized by weakness and muscle inflammation. The mechanisms that initiate or perpetuate the immune response are not known. It has been demonstrated that a particular group of immune factors known as RIG-I-like receptors (RLR) plays a role in DM. One RLR receptor, RIG-I, which is important in defending the body against viral infections, is more prevalent in the muscle fibers in DM patients but not in those with polymyositis or inclusion-body myositis. This suggests that the body’s immune response to viruses or tissue damage are important in triggering DM. This study further investigates the role of RIG-I and other molecules that arise when this viral response is activated.

Mitochondria abnormalities in DM (2010)

Arun Varadhachary, MD, PhD
Washington University, St. Louis, MO
Based on the observation of structural and functional changes in the energy-producing organelles of muscle fibers affected by myositis, the broad aim of this work was to understand the changes in metabolism associated with inflammatory myopathies. Patients with inflammatory myopathies are being followed to prospectively study alterations in metabolism as they proceed through treatment.

Characterization of CD4+CD8+ double positive T cells in DM (2007)

Eun-Ha Kang, MD
University of Pittsburgh, Pittsburgh, PA
This study examined the ability of certain auto-antigens to trigger innate immune responses in a mouse model of myositis. In further studies, the researcher examined blood from myositis patients using regenerating muscle cells to identify the auto-antigens.