Cure JM has been able to support the Cure JM Program of Excellence in JM Research at the Ann & Robert H. Lurie Children’s Hospital of Chicago and the George Washington University Myositis Center, selected studies at the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), in addition to other studies and groups dedicated to gaining a greater understanding of Juvenile Myositis.
The Environmental Autoimmunity Group, NIEHS, has developed a large registry of more than 450 patients with juvenile myositis (JM), who have enrolled with a physician questionnaire and blood sample, through the various clinical protocols. Cure JM has supported the clinical research fellowship of Dr. Gulnara Mamyrova and more recently, provided part-time salary support for another student to enter and analyze a portion of the clinical information. The findings from the Childhood Myositis Heterogeneity Study to date have led to a better understanding of the features of illness associated with each of the distinct clinical subgroups of JM (juvenile dermatomyositis, polymyositis and overlap myositis) as well as the subgroups associated with certain autoantibodies that are present only in myositis patients called myositis autoantibodies. We have also identified several different immune response genes as risk factors for JM and examined environmental factors that precede the onset of illness. We have recently found that ultraviolet radiation exposure close to the onset of illness is associated with juvenile dermatomyositis and with the most common myositis autoantibody in JM called anti-p155/145. GWU Myositis Center has looked at illness features that distinguish juvenile polymyositis and muscular dystrophy and found that muscular dystrophy is clinically very similar in many features to juvenile polymyositis. However, myositis autoantibodies, clinical muscle atrophy and certain muscle biopsy changes can be used to distinguish these two conditions. We are currently continuing analyses of the information collected in this registry to learn more about the outcomes of JM and also about treatments being used and how effective they are. We have already, for example, determined features of JM associated with the development of lipodystrophy, or body fat loss, and what types of metabolism changes patients can develop with this complication of illness. In addition, while death is fortunately a very uncommon complication of JM today, we have been able to determine some features of illness associated with mortality in the few patients who have passed away.
The Environmental Autoimmunity Group, NIEHS has worked for a number of years in developing and validating a core set of clinical measures to determine how active a patient’s myositis is and how much damage (i.e., scar tissue, irreversible changes from previously active disease, etc.) is present. The Chicago Program of Excellence in JM Research and the GWU Myositis Center are two of the participating sites of this international study. Through the IMACS Group, we have also developed combinations of and certain amounts of change in these core set activity measures to determine whether a patient has experienced a clinically important improvement (called Preliminary Definitions of Improvement), which are helpful to see if patients are responding to new treatments, such as in clinical trials. Cure JM has funded salary support for Dr. Peter Lachenbruch to help analyze the data to develop and validate the Myositis Damage Index, a clinical measure that helps doctors tell how much damage myositis patients have. The IMACS Group, in collaboration with PRINTO, is working on a large project to re-examine the Definitions of Improvement, using data from a number of myositis studies and clinical trials from the last decade. Cure JM is presently providing partial support for a final consensus conference in which myositis expert doctors and researchers will be able to meet together and review the top results to decide on new Definitions of Improvement. From this work, we hope to develop better measures of how patients are responding to treatments and improve the ability to conduct clinical trials of new therapies for patients with myositis.
This project through NIEHS is an effort to work with myositis doctors from the United States and Europe to examine a large number of different genes by a method called genome-wide association study (GWAS). The overall goal of this project is to identify new genetic risk factors for juvenile and adult dermatomyositis and genetic risk factors for certain disease complications. Cure JM funded the analysis of many of the DNA samples from patients with juvenile dermatomyositis for this study. The Chicago Program of Excellence in JM Research and the GWU Myositis Center are two of the participating sites of this international study. Through this effort, we have been able to identify the HLA region, one of the main immune response regions, as very important to dermatomyositis, along with several other genes that are known to be risk factors for other autoimmune diseases also to be risk factors for dermatomyositis. A large amount of information was collected in this study, and additional analyses are ongoing to learn more about the HLA region, as well as to learn more about genes that may lead to certain complications of illness, and to identify other genes that are risk factors for myositis. Identification of these genes will help to better understand the pathways involved in the development of JM, and ultimately, from that information, to develop more targeted therapies to treat myositis.
Cure JM has provided funding to Duke Clinical Research Institute for the expansion of the CARRA Registry system and to support enrolling sites for a project entitled “Consensus Treatment Protocols for Moderate-to Severe Juvenile Dermatomyositis”. This is an ongoing study that was open for enrollment in April 2013.
This project is aimed to assess environmental factors in relationship to increased disease activity (flare) in juvenile and adult dermatomyositis and polymyositis. An online survey was conducted for juvenile and adult dermatomyositis and polymyositis patients from US and Canada who were at least 1 year from diagnosis. The survey examined environmental exposures, including smoking, sun exposure, infections, medications, vaccines, stressful life events, and sports activities, during the 6 months prior to disease flare, to see if these exposures differ in patients who experienced a flare within the past 2 years compared to those who did not experience a disease flare. The collected data is being analyzed in 250 patients to learn more about the role of environmental exposures in disease flare.
This project was coordinated through the GWU Myositis Center to evaluate health care transitioning process for patients with juvenile onset myositis from pediatric to adult health providers. The data were collected by using an anonymous online website for myositis patents and their families. The study results identified that there are deficiencies in the health care experiences of the myositis patients and their families regarding knowledge of the illness, self-advocacy, understanding of the policies in transitioning to adult health care providers, and vocational readiness. In addition, it was found, as children with chronic disease and complex medical issues grow up, parents attribute less self-advocacy to their child’s delay in their level of independence. This research suggests that patients with juvenile myositis and their families are in need of additional education and guidance to help them get ready for transitioning their health care to adult care providers.
The GWU Myositis Center team is participating in screening, referring patients and performing myositis assessments of patients with juvenile and adult dermatomyositis for a pilot trial for 5 patients with calcinosis to administer sodium thiosulfate, a chelator with anecdotal success treating juvenile dermatomyositis patients with calcinosis, by laser therapy. The GWU Myositis Center has also been involved in a study to develop new classification criteria for juvenile and adult myositis.
The Chicago Program of Excellence in Myositis Research studied 90 JDM patients, of who 52 were untreated and without calcifications: no deposits developed during a mean follow-up period of <4 years. Of the 5 untreated JDM patients with calcifications, 4/5 had resolution of the calcifications and the last patient’s calcifications diminished. Of the seven treated JDM patients referred with calcifications, only one totally resolved, and one developed calcifications after 36 months of therapy. These data suggest that early immunosuppressive therapy may impair the development of dystrophic calcifications in JDM, for only 7.0% of this total group had calcifications, compared to 20-40% in published reviews. None of the 52 initially untreated children without calcifications developed them at a later time. We speculate that dystrophic calcifications in JDM are preventable by the use of early aggressive therapy.
The laboratory characterized the composition of theses calcifications, which is continuing to be studied at different times in the disease course.
In children with JDM, the small blood vessels—such as the capillaries of the fingernail beds, are almost always damaged, leaving fewer, more bizarre capillaries. The Chicago Program of Excellence in Myositis Research’s laboratory developed a reliable method to quantitate the number of nailfold capillaries in the nailbeds over time. If the child has had symptoms for a short time they may be initially normal but the capillaries will decrease after 5-6 months of symptoms , and are a very useful aid to diagnosis—differentiating JDM from other muscle problems. This loss of nailfold capillaries is directly associated with the inability to absorb prednisone given by mouth, compared with giving prednisone by vein, providing the reason for high dose IV steroid therapy that has proven to be so useful in treating children with JDM, that is now in use nationally. We now know that the loss of nailfold capillaries is also associated with earlier heart disease in older patient with JDM who had not been treated as aggressively as we do now.
In addition to proving that prednisone was not absorbed well when there was nailfold capillary drop out, the Chicago Program of Excellence in JM Research documented that the higher dose achievable by IV steroids was more successful in treating JDM, and this approach is part of a national consensus CARRA protocol. Data also documented that MMF (CellCept) was useful as a possible therapeutic agent. It was reported that treatment with TNF-inhibitors (such as Etanercept) might make JDM worse and our formal drug study of the use of Etanercept in active JDM was just accepted for publication, showing that care is needed in the patient selection, for if the JDM is inactive, then Etanercept can be used to treat problems such as psoriasis and severe arthritis, both of which occur in children who also have JDM.
We need more effective therapies to treat children with JDM. Therefore we must understand the disease pathways. In 2000, we found, using gene expression studies that Type 1 interferons were involved and then we learned that they induced other genes. Type 1 interferon activity was increased in children with JDM and associated with gender –girls but not boys were more affected by this gene family. Autoimmune disease, especially Lupus, is more prevalent in the families of children with JDM and an international study showed that the genes associated with autoimmune disease are also “turned on” in both adults and children with dermatomyositis. The Chicago Program of Excellence in JM Research found that the muscle of children with JDM expresses specific markers of inflammation related to blood vessels, and that factors that influences gene expression (DNA methylation, micro RNAs) are selectively suppressed, opening pathways for potential new therapies. 30% of children with long-standing JDM develop calcifications. The laboratory characterized the composition of these calcifications, which is continuing to be studied at the Chicago Program of Excellence in Myositis Research.
Working with pediatric rheumatologist, Imelda Balboni, MD, PhD, at the Stanford School of Medicine, the Chicago Program of Excellence in JM Research sent JDM sera that was tested for its ability to induce the production of interferon alpha activity in JDM. Antibodies were detected, using autoantigen microarray analysis, which is able to identify the presence of antibodies very sensitively. A study of 36 patients with JDM, revealed that certain autoantibodies might contribute to the stimulation of interferon alpha production in JDM. Interferon alpha acts as “gasoline” in autoimmune disorders, making the disease symptoms more severe. This is the first demonstration that the autoantibodies themselves may contribute to stimulating disease activity.
Interstitial lung disease (ILD) is a severe complication of IIM, but there are no guidelines for testing for its presence. A Cure JM sponsored study of 38 JM patients found that 1/3 had impaired lung function. The recommendation based on the results is that Pulmonary Function Testing in children with IIM should be considered to identify and bring t a halt progressive scarring of lung tissue through directed immunotherapy. In addition, the study revealed that lung damage is associated with the presence of some of the Myositis Specific/Associated antibodies, an elevated level of serum neopterin (which can indicate pro-inflammatory immune status), older age at diagnosis and shorter duration of untreated disease at diagnosis.