The Division of Rheumatic Diseases at Case Western Reserve University/University Hospitals of Cleveland has deeply devoted to the care of patients with osteoarthritis (OA), rheumatoid arthritis (RA) and related disorders. Investigations on cartilage and chondrocytes biology, autoimmunity, T cell biology and animal models of RA and OA are the cornerstone of our research program the modulation of immune response/inflammation by dietary constituents, and intergrated research with school of dental medicine on relationship of Periodontitis and Rheumatoid Arthritis have been innovative in our division.
Primary research interests of the Members of the Division of Rheumatic Diseases are:
Donald D. Anthony, M.D., Ph.D.
Summary of ongoing and planned research program.
There are 5 areas of related focus that will be investigated over the coming 5 years. They are described in the following.
- Role of immature dendritic cells in host defense against HCV infection.
Acute HCV infection commonly results in chronic persistence (50-90%), making HCV the most common cause of chronic viral hepatitis. There are nearly 4 million Americans chronically infected with HCV (roughly four times the number of HIV infected individuals). The long-term risk of cirrhosis with chronic HCV infection is estimated at 20%, with subsequent increases in the risk for liver failure and hepatocellular carcinoma. Evidence suggests that HCV-specific T cell immunity contributes to the pathogenesis of HCV mediated disease, participating in favorable clinical outcome as well as in organ damage. We and others have observed a relative paucity of HCV specific effector T cells in freshly prepared PBMC from subjects with chronic HCV infection, contrasting with normal frequencies of effector T cells specific for other antigens in the same subjects. These data are consistent with the notion that circulating HCV specific T cells are deficient in effector function, number, or both, while HCV infection does not result in generalized dysfunction of T cells with other specificities. Though the mechanism for the antigen specific dysfunction in HCV infection is unclear, one possible mechanism is abnormal priming and stimulation of HCV specific T cell populations by dysfunctional HCV containing antigen presenting cell (APC) populations. We hypothesize that one consequence of HCV infection is altered DC function. In addition HCV infection may affect T-cell responsiveness to normal functioning DC. To address this hypothesis we will A)Determine the impact of HCV infection on DC phenotype and function; B) Determine the impact of HCV on T cells by characterizing T cell responsiveness in HCV infected and healthy control subjects; and C. Determine the effects of HCV proteins and virus as a direct inhibitor DC function.
- Effect of HIV coinfection on DC function during chronic HCV infection.
We hypothesize that DC subset function is differentially altered as a consequence of HCV vs. HIV infection.
To test this hypothesis we will: A) Characterize and compare the phenotypic and functional differences in freshly prepared MDC and PDC from HCV, HIV, HCV-HIV infected and healthy control subjects for ability to mature in response to TLR ligand, secrete IFN-a and IL-12, process and present antigen, and activate naïve and memory T cells; and B) Determine the relation between DC subset function at baseline and virologic response to IFN-a based therapy.
- Immunity of neoantigen response in HCV, HIV, and HCV-HIV.
HIV infected individuals have been shown to have a pronounced humoral defect in response to neoantigen immunization. In particular, only 73% of HIV infected subjects on highly active antiretroviral therapy seroconvert in response to hepatitis A vaccination, while over 98% of healthy controls respond to hepatitis A vaccine. HCV infected individuals also have impaired response to neoantigen as provided by hepatitis A, hepatitis B, and influenza vaccination, with only 73% of subjects responding to a first dose of standard hepatitis A vaccine, compared to 93% of healthy controls. Responsiveness to neoantigen vaccine in the setting of HCV-HIV coinfection appears to be further impaired above that observed in HIV monoinfection. Whether these defects are a direct result of B cell dysfunction, or are a result of T cell or APC dysfunction is not known. We hypothesize that in HIV infection an impaired response to neoantigen is the result of impaired naïve T cell expansion capacity, DC dysfunction, and B cell dysfunction, while in HCV infection an impaired response to neoantigen is the result of DC dysfunction. We will test this hypothesis by: A) determining if baseline DC, B cell, or T cell frequency or function in HCV, HIV, and HCV-HIV infection predicts neoantigen or recall antigen responsiveness as determined by vaccine induced humoral immune response; and B) determine if vaccine induced memory T cell or B cell response is associated with baseline DC, T cell, or B cell function, or vaccine induced humoral immune response.
Ali Askari, M.D.
Sjogren’s Syndrome: Long interested in the studies of Sjogren’s syndrome and clinical evaluation of patients with that disease, Dr. Askari has presented and published on the complications of Sjogren’s syndrome and particularly neuro muscular problems. The results of an extensive study on muscular problems in Sjogren’s patients was presented to the clinical research in 1983, many new faces of Sjogren’s syndrome presented to the international meeting in 1999 and neurological complications or Sjogren’s syndrome to the international meeting of 2002. Past and present fellows have participated in the studies and continue to show interest. Dr. Carlos Zevallos, the graduate of 2006, participated in the study on the neuro muscular complications and established a database for education purposes, which now is being expanded by the participation of Dr. Mark Schulte our chief resident and Dr. Rebecca Burns presently a resident and our fellow in 2009. Dr. Askari has continued to lead national and regional meetings of Sjogren’s syndrome every year in May and has established a Sjogren’s Syndrome Center with participation of experts from across the faculty at Case and University Hospitals Case Medical Center. Dr. Askari received two grants from The National Sjogren’s Syndrome Association for establishing this center, as well as establishing an annual lectureship on Sjogren’s Syndrome at Case University Hospitals Medical Center, Department of Medicine. The first lecture in May of 2008 was by Dr. Robert Fox from Scripps clinic and research center in San Diego, California on “Sjogren’s syndrome”. Sjogren’sSyndrome.com
Muscle Disease: With long interest in the study of muscle diseases, Dr. Askari published the landmark paper on steroid induced myopathy in 1976, the guidelines of which have remained unchanged. He also published the landmark study on cardiac involvement in polymositis, dermatomyositis and later the study on phosphofructokinase, a metabolic myopathy. More recently, Dr. Askari presented the results of case series of myopathy to MEET THE PROFESSOR sessions of annual scientific meetings of American College of Rheumatology in 2004/2005 and 2006. The lectures on muscle diseases continue at University Hospitals Case Medical Center and Case Medical School on a continual basis through the year.
Fibromyalgia: Dr. Askari is participant of a study on dysautonomia, which included patients with fibromyalgia, chronic fatigue syndrome, and Raynaud’s phenomenon, and with participation of Dr. Thomas Chelimsky, Director of Autonomic Disorders and Pain Center at University Hospitals. Preliminary results of this study have been presented to the Neurological Society in 2005.
Interrelationship of Rheumatoid and Periodontitis: Linking rheumatoid arthritis and periodontal disease for enhancing the ability to treat both, Dr. Askari is participating in ongoing studies with the faculty and fellows from The School of Dental Medicine lead by Dr. Nabil Bissada. Combined efforts have resulted in the completion of four thesis’ by graduates of Periodontal School, four presentation at national meetings and one paper in the Journal of Clinical Rheumatology 2007. This project is ongoing and at least three other papers are in preparation.
Linking Rheumatoid Arthritis and Periodontal Disease: Enhancing the Ability to Treat Both. (From Value of Research published by Case for, predominant research).
A multidisciplinary research team at Case is making great strides in proving that there is a link between periodontal disease and rheumatoid arthritis—and that the treatment of one disease enhances the treatment of the other. A recent study led by Khaldoun Al-Katma, D.D.S., together with Nabil F. Bissada, D.D.S., M.S.D., professor and chair of the Department of Periodontics at the Case School of Dental Medicine, and Ali Askari, M.D., professor and chair of the Division of Rheumatology at the Case School of Medicine and University Hospitals Case Medical Center, Followed a group of patients with both active rheumatoid arthritis and periodontal disease. For eight weeks, some of the patients received standard gum disease treatment while others did not. A rheumatology examination at the end of this period clearly showed that the severity of the arthritis in the patients receiving gum treatment was reduced. The team also evaluated the effect of treatment of rheumatoid arthritis on periodontal disease and found that the disease modifying anti-rheumatic drugs (DMARDs) to treat arthritis appeared to ameliorate the severity of the gum disease. In addition, the team completed a study that showed that the strain of bacteria in the synovial fluid of one patient with rheumatoid arthritis matched the bacteria found in the dental plaque of the same patient. While the bacteria was present in rheumatoid arthritis, it was not present in osteoarthritis, and the rest of the patients with rheumatoid arthritis.
The possibility of similarities between the inflammatory state in the rheumatoid lining of the joint and the gum inflammation in periodontal disease is being pursued further. Omid Kiarash, D.M.D., M.S.D., working with Jose Arauz-Dutari, D.M.D., D.D.S., assistant professor in the Department of Periodontics, furthers the findings that these two disease entities have much in common. Sixty rheumatoid arthritis patients were examined by a rheumatologist and Dr. Kiarash according to the standard parameters of arthritis and gum disease: the amount of gingival inflammation, depth of the periodontal pocket, clinical attachment loss, presence of plaque, rheumatoid arthritis disease activity score, and the amount of systemic inflammation. Comparing the periodontal status of the patients receiving DMARDs plus anti-tumor necrosis factor therapy (anti-TNF) to those receiving similar DMARDs but no anti-TNF showed that the patients on anti-TNF therapy had healthier periodontal status independent of oral hygiene. The significant differences in the oral health of the two groups showed that the anti-TNF medication to help control the destructive activities within the joints may also prevent the loss of attachment of the periodontal tissues which support teeth.
“Based on our findings, we encourage dentists to observe the periodontal status of patient with rheumatoid arthritis more diligently and respond decisively. This is also an opportunity for physicians to refer rheumatoid arthritis patients for prescreening to prevent the commonly high rate of tooth loss in these individuals, often a result of periodontal disease,” comments Dr. Kiarash. “It may also mean a new future treatment for periodontitis,” notes Dr. Askari.
Raymond Hong, MD, MBA
Research interests: Osteoporosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus
Dr. Hong is currently engaged in research exploring osteoporosis medication persistence and efficacy. He performs collaborative research in the field of Systemic Lupus Erythematosus investigating T- and B-cell autoreactivity in relationship to complement function. Dr. Hong is an investigator in several clinical trials in the field of Rheumatoid Arthritis.
Charles J. Malemud, Ph.D.
Research Interests: Apoptotic chondrocyte death; synovial joint inflammation
Apoptosis and resistance to apoptosis are two of the most fundamental pathophysiological processes that occur in arthritic human synovial joints. Our studies are designed to evaluate the role played by stress-activated/mitogen-activated protein kinase (SAP/MAPK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in human chondrocyte survival and/or death after activation by pro-inflammatory cytokines, such as tumor necrosis factor-α or soluble mediators such as monosodium urate crystals.
Dr. Edward Medof, MD
In 1986, he was recruited to Case Western Reserve University jointly by Medicine and Pathology to help with renewal of the Multipurpose Arthritis Center in Rheumatology and rebuild immunology in the Department of Pathology. During his time here, he was the first to structurally characterize human GPI anchors and he worked out the human GPI anchor synthetic pathway. Through the use of both human and mouse models, he has made important contributions to multiple diseases including PNH, myasthenia gravis, diabetes, multiple sclerosis, helicobacter and a wide range of ocular immune disorders. Until 2001, he continued teaching second year medical students at Indiana University rheumatology yearly during a one week period as an Adjunct Professor. In the past 5 years, he has turned his attention to T cells and has changed paradigms concerning the T cell activation process.
Among current studies are 1) identification of transcriptional factors which regulate DAF, MCP, and CD59 gene expression and thereby modulate susceptibility to immune injury, 2) in vivo studies of the roles of DAF and CD59 in multiple autoimmune disease models, 3) studies of the function of DAF, MCP, and CD59 in the eye ( corneal transplantation and anterior chamber associated immune deviation (ACAID), 4) investigation of the signals in nascent proproteins which direct GPI attachment, 5) isolation of genes encoding GPI anchor pathway enzymes and cloning of the GPI transamidase that provides for GPI transfer to proproteins, 6) functional analysis of “unaffected” hematopoietic progenitors in PNH marrow that allow for the outgrowth of mutated progenitors, 7) engineering (or “painting”) of cell surfaces with GPI-anchored proteins as an alternative to gene transfer for multiple purposes including the production of tumor cell vaccines, 8) analyses of the roles of intrinsic regulators in diabetic vascular complications and in hypoxia-reperfusion injury, 9) development of recombinant hybrid regulatory proteins for clinical use and 10) characterization of DAF’s newly discovered regulatory role in T-cell responses.
Dr. Roland W. Moskowitz Research Program
- Genetics of osteoarthritis- in 1991, Dr. Moskowitz described the first genetic
defect as a cause of familial osteoarthritis. These studies demonstrated generalized osteoarthritis occurring in families and, more recently, he has been involved in a collaborative study to identify genetic defects in common forms of osteoarthritis.
- Experimental models of osteoarthritis (OA).
Over the past decade, Dr. Moskowitz has been involved in development of models for investigation of osteoarthritis in individuals with this disease. His so-called “walking models” are now utilized by a number of investigators to demonstrate efficacy of various therapies in the treatment of this disease.
3. Treatment Guidelines.
Dr. Moskowitz has been a co-principal investigator in studies carried out by the Osteoarthritis Research Society International developing advisory guidance principles for treatment of osteoarthritis, both medical and surgical.
4. Diagnostic biomarkers.
Dr. Moskowitz has been involved in the development of biomarkers to evaluate responses to therapy in osteoarthritis. These findings would allow evaluation of therapeutic modalities in a more accurate and simplified fashion as compared to and in addition to past assessments including radiologic and symptomatic approaches.
5. Inflammatory connective tissue disease.
Dr. Moskowitz has recently reported on a previously undescribed efficacy of a specific antibiotic to ameliorate undifferentiated connective tissue disease symptoms, related to their associated anti-inflammatory activity.
Nora Singer, MD
Dr. Singer’s work has focused on the area of T-cell co-stimulation via the cell surface protein CD6 and on identification and characterization of CD6 ligands in synovium and salivary and skin epithelium. She has published her research in the Journal of Immunology, International Immunology and other high quality review journals. She has recently been involved in more patient-oriented research, a major area of emphasis related to translating basic research findings into improving understanding and treatment of patients with rheumatic disease. As an example of her recent studies, she has cloned a mutation in a family with C1r deficiency and systemic lupus erythematosus (SLE) and is currently collaborating with SLE basic scientist to understand the mechanisms of how complement deficiency predispose to SLE. Dr. Singer, based on her reputation has been invited to participate in numerous collaborative pediatric clinical trials, as well as being named site principal investigator in a multi-center NIH prevention trail in pediatric lupus, Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE). As part of her interest in further developing her expertise in translational research, Dr. Singer has assumed the role of Co-director of the Arthritis Translational Research Program and through her efforts has helped our institution compete successfully for number of new clinical trials in the area of rheumatoid arthritis. Dr. Singer has also established a mouse model of coronary vacuities in her laboratory and recently received in her laboratory and recently received a fundable score on her grant application from the Arthritis Foundation that will allow her to continue her basic research efforts in the laboratory. Dr. Singer has an active collaboration with Dr. Tariq Haqqi in the Division of Rheumatic Disease who was also a collaborator on her ROI award, RO1 award, Role of CD6 in Thymic Selection and Immune Response, further demonstrating interdepartmental collaborations.
Johnny G. Su, M.D.
Research Interests: Osteoporosis
Dr. Su is involved in two projects regarding Osteoporosis.
The first project is in collaboration with Dr. Heather Gillespie, first year fellow in the Division, to investigate the association between homocystiene levels and bone mineral density to determine whether high homocysteine levels are predictive of low BMD resulting in increased risk of osteopathic fracture. An association between high homocysteine levels and increased risk of fracture has shown in two separate studies published in the
New England Journal of Medicine in 2004. However, it is unclear whether this association holds true for BMD.
The second project is to investigate the impact of intermittent intra-articular steroids on bone mineral density. It has long been proven that systemic steroids increase risk of osteoporosis and fracture. However, it is unclear whether the frequency and cumulative dose of intra-articular steroids affect bone mineral density with increased risk of fracture as a result of low BMD.
Dr. Su is also in the process of completing a project with the National Databank of Rheumatic Diseases under the auspices of the CHORD Fellowship to look at predictors of osteoporosis in men with rheumatic diseases.
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Terry M. Wolpaw, MD, MHPE
Terry Wolpaw, MD, MHPE is a rheumatologist and the Associate Dean for Curricular Affairs at Case Western Reserve University School of Medicine. She is an Associate Professor of Medicine and a faculty member in the Division of Rheumatology. Her medical school office oversees and supports 1) curriculum development and implementation, 2) curriculum evaluation and outcomes assessment, and 3) faculty development programs. She directs the Scholars Collaboration in Teaching and Learning, a program for faculty and trainees at all levels to develop skills in teaching, curriculum design, and medical education research.
Dr. Wolpaw is among the core faculty who are leading Case School of Medicine in a major curriculum transformation that was first initiated in 2006. The Western Reserve2 curriculum is based on a vision for a school of medicine and health where students engage in interactive small group instruction and develop skills for life long learning, scholarship, clinical mastery and civic professionalism.
Dr. Wolpaw is a recognized national leader in medical education. She was the recipient of one of the first American College of Rheumatology Clinician Scholar Educator Awards, served on the association’s Education Committee and chairs its CARE committee. She served on the AAMC’s expert panel on musculoskeletal medicine and participates annually as one of the invited faculty for the Harvard Macy Institute for Health Science Educators.
Dr. Wolpaw completed a Master’s degree in Health Professions Education at the University of Illinois at Chicago. Her research has focused on learner-centered educational methods for ambulatory settings such as the Rheumatology office. She has developed the SNAPPS method for case presentations to preceptors, based on experiential learning theory, which has been published in Academic Medicine.
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