Research ProgramResearch Goals and Aspirations
The overall mission of the Rheumatology Division is to establish Cedars-Sinai Medical Center as a major center of Rheumatic Disease research in Los Angeles through internal and external alignments. We are planning to take our efforts to the next level utilizing partnerships and collaborations to create research results that will have a major impact on the outcome of chronic Rheumatic Diseases.
Rheumatoid Arthritis (RA)
We approach genetic and environmental risk for RA through the study of pre-clinical disease. By identifying those individuals at risk for RA (the first degree relatives of RA probands) we then examine and discover new at risk biomarkers and environmental triggers and then follow these patients over time to see if they evolve into clinical RA. Based upon prior knowledge of the most powerful risk factor (cigarette smoking) for RA, we now recognize the lung as a primary site of inflammation in these clinically asymptomatic but biomarker positive at risk individuals. Over the past 8 years we have been collaborating extensively with our University of Colorado colleagues in a series of experiments defining lung inflammation in these subjects by high resolution CT scan imaging, sputum evaluation, and broncho-alveolar lavage specimen collections.
In addition, we have embarked upon a health-services project deemed important in the Los Angeles community. We discovered that in the underserved largely Hispanic population of LA County despite adequate control of the disease with modern aggressive biologic therapies these patients still display significant functional disability. From our cross-sectional studies in collaboration with colleagues at Harbor-UCLA Medical center we now know that clinical depression may account for this wide gap in expected outcome. We are now collecting prospective longitudinal data to examine the potentially treatment amenable psycho-social factors that mediate this important outcome.
Achievements in Rheumatoid Arthritis
From our prospective study investigating genetic and environmental risk for the development of RA-related autoimmunity, our group enrolled >1000 first degree relatives and discovered high prevalence of genetic risk factors and RA-related antibodies. However, there was an association between these antibodies and tender joints and CRP levels, suggesting that these autoantibodies are a valid intermediate marker of RA-related autoimmunity. To further evaluate the hypothesis that the lung is involved in the earliest phases of development of RA-related autoimmunity, we assessed the lungs in subjects with RA-related autoantibody positivity without inflammatory arthritis and compared these findings to antibody negative controls as well as patients with early but established RA, utilizing spirometry and high-resolution computed tomographic (HRCT) lung imaging. 76% of antibody + subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities and air trapping compared to 33% of controls. These findings were similar to those found in the early RA subjects. Our data supports the hypothesis that the lung may be the initial site of autoimmunity related injury and could possibly be the trigger for the disease.
Two hundred and fifty one Hispanic subjects from Los Angeles County were extensively studied by our group with a battery of disease and psycho-social testing; these patients represent low-socioeconomic status, uninsured, and immigrant populations collectively described as “vulnerable patients.” Our data indicate a high prevalence of significant depression in Hispanics with RA: 32% of all subjects and 24% of those even with low disease activity had a PHQ-9 equal to or greater than 10 which is double that found in the general population and on the high end of literature reports for RA. Depression appeared to be durable and a pivotal determinant of self-reported disability over time in spite of what appears to be adequate control of RA disease activity with aggressive biologic drug strategies. The findings are capable of generating intervention strategies that could have a major impact on disease and patient outcome.
Program Interactions in Rheumatoid Arthritis
1. University of Colorado - Michael Holers, Kevin Deane, Jill Norris
2. University of Nebraska – Ted Mikuls, Jim O’Dell
3. University of Washington, Benaroya Institute – Jane Buckner
4. Stanford University – William Robinson
5. University of Manitoba – Hani El-Gabalawy
6. University of California San Francisco – John Imboden, Patricia Katz, Ed Yellin
7. UCLA/Harbor Medical Center – George Karpouzas
8. UCLA/CHS – Perry Nicassio
Ankylosing Spondylitis (AS)
AS is highly heritable and a largely under-diagnosed condition. Our initial efforts were to define the gap in genetic susceptibility risk beyond HLA B-27 positivity which only accounts for about 50% of the hereditability of AS. World-wide over the past 10 years we have identified and followed a cohort of approximately 1500 fully characterized AS patients with assessments for disease activity, disease progression, and disease severity. Aberrant and progressive bone formation characterizes these patients and contributes to their disability – we have been exploring biomarker and genetic risks for this aspect of disease progression. These studies will inform us about pathways that could lead to impactful interventions.
New, highly effective almost life changing treatments have been available for AS since 1999, and diagnosing AS in its early stages is imperative. Since the true prevalence of this condition is not known in the USA we have worked with the CDC to develop a population-based tool to identify inflammatory back pain. Coupled with B-27 testing in the most recent NHANES survey (2009-2010) which we initiated and funded, we now have identified the prevalence of inflammatory back pain patients and of axial Spondyloarthritis (axial SpA) in a true population based sample. Finally, it has long been recognized that there is important clinical overlap (the long suspected bone and gut connection) between AS and patients with inflammatory bowel disease (Ulcerative Colitis and Crohn’s Disease). Over the past 4 years we have collaborated with the Gastroenterology Division to identify clinical, genetic, and imaging overlap between these two conditions in an attempt to understand the environmental triggers as well as biomarker and genetic pathways that will inform us of the evolution of each individual phenotype.
Achievements in Ankylosing Spondylitis
Our AS international consortium over the past 5 years (called TASC, or Triple A-Australian-Anglo-American-Spondylitis Consortium) has identified and confirmed the following AS non-MHC Genes/Loci - IL23R, ERAP 1, 2p15, 21q22, KIF21B, RUNX3, ANTXR2, CARD9, TBKBP1, PTGER4, IL1R2, IL12B, and LTBR, with 5 others either highly likely or probable. The demonstration that the ERAP1 association is restricted to HLA-B27 positive cases reveals a gene-gene interaction and implicates peptide presentation as the likely mechanism underlying the association of HLA-B27 with Ankylosing Spondylitis. We have published these results in 3 Nature Genetics papers with Cedars-Sinai Medical Center supplying the largest USA share of genetic and clinical material.
From our outcome studies of almost 1500 AS cases over the past 5 years we have learned the following: functional disability is multifactorial, treatable, and even reversible regardless of x-ray damage; some occupational physical activities may be detrimental and even cause x-ray damage; and AS patients have a highly impaired quality of life. Gender differences do exist but the causes are unexplained, juvenile onset disease course and outcome is unique, progressive bone fusion is not the rule in AS (suggesting genetic differences), African Americans have a higher individual disease burden despite their less common prevalence of AS, and the role of genetic factors in radiographic outcome appears substantial but the exact mechanisms need to be identified.
To understand the complexities of the relationship between AS and IBD and since serologic activity representing loss of tolerance to microbial antigens is present in IBD we studied 80 AS subjects compared to controls and found an increased individual antibody response to I-2 and ASCA, strongly suggesting that mucosal dysregulation could play a role in AS pathogenesis. Further supporting this concept is another study performed with Fecal Calprotectin, a marker of bowel inflammation in IBD. We found f-Cal to occur at high levels in AS subjects (without symptoms or prior diagnosis of IBD) compared to controls. This evidence of subclinical bowel inflammation present in AS again points to mucosal dysregulation as a key feature and a possible trigger for the disease.
Following the creation, validation, and publication of our inflammatory back pain instrument, we were able to collaborate with the CDC and the National Health and Nutrition Examination Survey (NHANES) to determine the first national estimate of HLA-B27, inflammatory back pain, and axial Spondyloarthritis (SpA) in the USA. Our three publications have shown that 1) HLA-B27 prevalence averages 7% and declines with age, 2) using published case definition criteria, SpA may affect up to 1% of US adults, greater than that reported for Rheumatoid Arthritis, and inflammatory back pain prevalence ranges between 5-6% in US adults. HLA-B27 declining with age suggests a strong genetic risk factor for mortality; this connection needs further exploration.
Program Interactions in Ankylosing Spondylitis
1. National Institutes of Arthritis, Musculoskeletal, and Skin Diseases - Michael Ward
2. University of Texas at Houston – John Reveille
3. University of California at San Francisco – Lianne Gensler
4. Stanford University – Eswar Krishnan
5. University of Oregon – Atul Deodar
6. University of Toronto – Robert Inman
7. University of Alberta – Walter Maksymowych
Systemic Lupus Erythematosus (SLE)
We have assembled 1,000 SLE subjects in a registry and they are now being entered into a research repository. Our initial efforts are focused on pre-clinical disease in first degree relatives (a genetically enriched cohort likely to evolve into SLE) in order to examine which biomarkers and genes will predict the onset of clinical SLE. In collaboration with the CSMC Pathology Department we are examining candidate genes in stored clinical specimens (kidney biopsy tissue) that we can associate with the most severe clinical SLE phenotype.
It is well recognized that premature ischemic heart disease is a cause of increased SLE mortality and occurs with great frequency along with angina chest pain in SLE subjects. Our preliminary studies revealed that microvascular ischemic heart disease is prevalent in SLE women with chest pain and who do not have evidence of macrovascular (large vessel) coronary artery disease. This discovery could be a potential link between a vexing clinical problem (premature ischemic heart disease in SLE women) and a potential mechanism that might be amenable to treatment. Finally, we have observed a significant degree of clinical depression accounting for a major impact on the quality of life in the underserved poor largely Hispanic SLE patients in Southern California with our collaborations with UCLA –CHS, UCLA-Harbor, USC, and LLU. These data have contributed to at least 4 multidisciplinary and multi-institutional reports now published in major journals that speak to clinicians, health service researchers, and bio-psychologists.
Achievements in SLE
Heart disease in the SLE population has drawn our considerable attention, and we have embarked on a series of studies to understand its relationship to inflammation and other SLE related factors using a sensitive detection method (cardiac magnetic resonance imaging, or CMRI) to evaluate microvascular coronary dysfunction. We enrolled 20 SLE women with angina and no prior documented coronary artery disease (CAD) and 10 reference control women in a pilot study to evaluate the presence of myocardial ischemia measured by adenosine-stress CMRI perfusion abnormalities. All patients underwent coronary computed tomography angiography (CCTA); among patients with complete data, 44% displayed evidence of CMRI reversible perfusion abnormality but no evidence of obstructive CAD on CCTA. Framingham risk scores were low and traditional risk factors did not predict these findings; multivariable linear regression identified SLE as the only significant predictor of the results. We propose that these findings are extremely relevant and can be used to justify further studies including the possibility of disease prevention.
Program Interactions in SLE
1. CSMC Heart Institute—Noel Bairey Merz, Puja Mehta, Chrisandra Shufelt, Yuching Yang
2. CSMC Imaging—Daniel Berman, Louise Thomson, Barry Pressman
3. Oklahoma Medical Research Foundation – Judith James, Eliza Chakravarty, Swapan Nath
4. St. Luke’s Medical Center, Manila, Philippines – Sandra Navarra, Evan Vista
5. Loma Linda Medical Center – Emmanuel Katsaros, Ioana Moldovan
6. UCLA – Perry Nicassio
7. UCLA/Harbor Medical Center – George Karpouzas, Dilrukshie Cooray, Sharon Adler
8. University of Southern California – Karina Torralba, Shintaro Shinada, William Stohl
9. SLICC Consortium – worldwide – 40 investigators
10. Rush Medical Center, Chicago – Meenakshi Jolly
11. Children’s Hospital, Los Angeles – Andreas Reiff, Anusha Ramanathan
12. Cincinnati Children’s Hospital – John Harley
Vasculitis syndromes are rare yet devastating clinically to patients and families. At CSMC we have initiated a multidisciplinary Vasculitis program in conjunction with the Vasculitis Clinical Research Consortium, the international group of researchers who study the epidemiology, genetics, and environmental risk of these diseases as well as innovative therapies.
Program Interactions in Vasculitis
1. Stanford University – Cornelia Weyand
2. Cleveland Clinic – Carol Langford
3. University of Pennsylvania – Peter Merkel
4. Massachusetts General Hospital – John Stone
Primary Sjogren’s Syndrome
PSS is a prototype autoimmune condition with marked organ specificity, multiple autoantibodies and lymphocyte dysregulation, and tissue/organ damage that is poorly understood. In conjunction with a consortium of PSS researchers centered at Oklahoma Medical Research Foundation we are assembling a cohort to study the susceptibility as well as severity and genetic risk for this uncommon yet quite severe clinical syndrome. These patients will be contributing serum and plasma biomarkers, tissue samples, and clinical information into a large national consortium. In another effort in collaboration with Dr. David Wong of the UCLA School of Dentistry we have begun to collect saliva specimens to identify biomarker predictors of not only PSS but possibly those PSS patients who evolve into lymphoma.
Program Interactions in Sjogren’s Syndrome
1. Oklahoma Medical Research Foundation – Kathy Moser, Hal Scofield
2. UCLA School of Dentistry – David Wong
OA is one of the most prevalent rheumatic diseases which affect half the population of the world age 65 or older. OA occurs in multiple forms and is a disease of articular cartilage and bone accompanied by subchondral bone thickening, bony outgrowths, and mild chronic nonspecific synovitis. Our research focuses on hand OA for which little is understood regarding the pathogenesis, but familial aggregation and heritability studies indicate a significant genetic role. We have an ongoing study to assess genetic associations of carefully-defined phenotypes of hand OA classified by specific clinical and radiographic phenotypes. To date, over 500 subjects with hand OA have participated in our study, and over 140 siblings have been enrolled. The long-term goal is to advance the understanding of the genetic, molecular and cellular mechanisms involved in hand osteoarthritis.
Program Interactions in Osteoarthritis
1. CSMC Medical Genetics – Jerome Rotter, Kent Taylor, Xiuqing Guo
2. Centers for Disease Control – Rosemarie Hirsch, Charles Dillon
3. UCLA – Roy Altman, Dan Cohn
The Rheumatology Division served as the Southern California site for an international observational study of bone health, the GLOW or Global Longitudinal study of Women in postmenopausal women over age 55. As part of this study of 60,000 women at 17 sites in 9 countries we have recruited 3200 women locally. To our surprise, approximately 10% of these women have had a fracture but are not on any osteoporosis treatment. Further, working with University of Alabama at Birmingham (UAB), we at CSMC are studying novel ways of “activating” these patients to start osteoporosis therapy using storytelling through the web and DVDs to address barriers to starting therapy. This year we are running focus groups to identify barriers as well as facilitators to starting osteoporosis therapy.
SPECIAL AWARDS AND COMMITTEES
National Awards – Michael Weisman, MD
2010 ACR/REF Excellence in Investigative Mentoring Award
CSMC Special Committees – Michael Weisman, MD & Mariko Ishimori, MD
2012 Journal Writing Workshop Series, Clinical Scholars Program