We approach genetic and environmental risk for Rheumatoid Arthritis (RA) through the study of preclinical 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 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 eight 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 computed tomography 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 Los Angeles County, despite adequate control of RA 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 collecting prospective longitudinal data to examine the potentially treatment amenable psychosocial factors that mediate this important outcome.
Achievements in Rheumatoid Arthritis
From our prospective study investigating genetic and environmental risks for the development of RA-related autoimmunity, our group enrolled more than 1,000 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 C-reactive protein (CRP) levels, suggesting that these autoantibodies are valid intermediate markers 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. We utilized spirometry and high-resolution computed tomographic lung imaging. We found that 76 percent of antibody-positive subjects had airways abnormalities, including bronchial wall thickening, bronchiectasis, centrilobular opacities and air trapping, compared with 33 percent of controls. These findings were similar to those found in the early RA subjects. Our data support the hypothesis that the lung may be the initial site of autoimmunity-related injury and could possibly be the trigger for the disease.
A total of 251 Hispanic subjects from Los Angeles County were extensively studied by our group with a battery of disease and psychosocial 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. We found that 32 percent of all subjects and 24 percent of those even with low disease activity had a PHQ-9 score 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
- University of Colorado — Michael Holers, MD; Kevin Deane, MD; Jill Norris, PhD
- University of Nebraska — Ted Mikuls, MD; James O'Dell, MD
- University of Washington, Benaroya Research Institute — Jane Buckner, MD
- Stanford University — William Robinson, MD; Cornelia Weyand, MD, PhD; PJ Utz, MD
- University of Manitoba — Hani El-Gabalawy, MD
- University of California, San Francisco — John Imboden, MD; Patricia Katz, MD; Ed Yelin, PhD, Lianne Gensler, MD
- Harbor - UCLA Medical Center — George Karpouzas, MD
- Community Health Services in the UCLA Fielding School of Public Health — Perry Nicassio, PhD
- University of Southern California — Elizabeth Ortiz, MD
- Children's Hospital of Los Angeles — Andreas Reiff, MD
- University of California, Irvine — Sheetal Desai, MD