SAN DIEGO—Every year, the Rheumatology Research Foundation funds promising cutting-edge research to facilitate and accelerate understanding of fundamental questions about rheumatic diseases to ultimately advance patient care. During a special session, “Disease Targeted Research,” here at the 2013 ACR/ARHP Annual Meeting, held October 26–30, participants heard from three investigators awarded funding through the Foundation. [Editor’s Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org/sessionselect.]
Risky Research
Allen C. Steere, MD, professor of medicine at Harvard University Center for Immunology and Inflammatory Diseases in Boston, who presented research findings on an innovative approach to identifying novel autoantigens recognized by T cells in RA, emphasized the critical role played by the foundation to sponsor innovative research. “This is risky research because of its complexity and newness,” he said. “The Rheumatology Research Foundation is very helpful in supporting innovative, early research like this.”
Dr. Steere, who is known for his work in Lyme disease, described a new method he and his colleagues are using to identify infectious agents or autoantigens in patients with RA. The method uses liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to isolate and analyze HLA-DR–presented peptides in synovial tissue and test the peptides for immunogenicity using the matching patient’s T cells. The feasibility of this approach was proved in an early RA cohort, which showed that peptides identified in inflamed synovial tissue were different from peptides found in cell culture systems. The source proteins for the peptides in the inflamed synovial tissue included candidate RA autoantigens, such as enolase, vimentin, fibrinogen, and collagen. Dr. Steere said a database of these source proteins can be used to search for peptides derived from microorganisms of interest in the pathogenesis of RA, such as Porphyromonas gingivalis.
According to Dr. Steere, in the first patient (a patient with Lyme arthritis) in whom peptides were tested for immunogenicity, he and his colleagues were able to identify endothelial cell growth factor as the first known autoantigen in Lyme arthritis and showed that the autoantigen induces T- and B-cell responses in about 20% to 30% of patients with antibiotic-refractory Lyme arthritis.
In the more recent research, he and his colleagues have shown the possibility of identifying HLA-DR–presented peptides from antigen-presenting cells in the synovial fluid or peripheral blood in RA patients, even in patients with early disease, before initiation of disease-modifying antirheumatic drugs (DMARDs). This creates the potential to explore the immunogenic T-cell repertoire early in the disease, he said.
“There are new techniques for the identification of pathogenic T-cell epitopes in RA or other forms of chronic inflammatory arthritis,” he said. “Knowledge of pathogenic T-cell epitopes could lead to new small molecule therapies in RA, which may provide the next leap in therapies for this illness.”
According to Ted R. Mikuls, MD, MSPH, professor of internal medicine in the division of rheumatology at Omaha VA Medical Center and the University of Nebraska Medical Center in Omaha, who presented research on the association between RA and P. gingivalis, Dr. Steere’s highly innovative approach is exciting because it is poised as a platform for discovery. “Using this approach, we might, for example, begin to identify mechanisms linking oral pathogens such as P. gingivalis with RA,” he said. “Identifying these mechanisms will be central to the development of immune-based interventions that could subsequently be exploited in disease treatment and even prevention.”
The Association Between Oral Pathogens with RA
Dr. Mikuls presented the results of a study that provides further insight into the association of gum disease and P. gingivalis infection with RA risk. He shared the results of a two-aim study undertaken to address several unanswered questions. Among these are whether the association of periodontal disease with RA is driven by shared risk factors (i.e., smoking, HLA-DRB1) or by oral bacterial that causes periodontal disease (P. gingivalis), and whether periodontal disease causes RA or whether it is simply a direct or indirect manifestation of RA.
The case-control study included 617 patients, 287 with RA (cases) and 330 with osteoarthritis (controls) with similar baseline characteristics. (The findings of the study were reported in Abstract 1378.) Patients underwent a standardized exam for periodontal disease (defined as clinical attachment loss >6 mm for 2 or more teeth and one or more sites with a probing depth >5 mm). The study found that periodontal disease was significantly more common in all patients with RA compared to controls (35% vs. 26%, P=0.02) as well as patients with anticyclic citrullinated peptide (aCCP)–positive RA (37% vs. 26%, P=0.007). On multivariate analysis, the study found that the association of periodontal disease with established aCCP-positive RA was independent of shared risk factors including smoking and HLA-DRB1, and also appeared independent of other factors including medication use, comorbidity, and oral hygiene. Another finding was that significantly more patients with periodontal disease had increased RA disease severity.
The study also looked at whether there were neo-epitopes driving the relationship between periodontal disease and RA and identified several preliminary epitopes (such as filaggrin) that could drive the relationship.
“At this point, I think it’s important to recognize the potential links between oral health status and overall health status,” said Dr. Mikuls. “Although it’s clearly premature to suggest that treating gum disease prevents or even improves RA, it’s likely that this will be explored in the near future.”
Quality of Care in RA
Gabriela Schmajuk, MD, MS, assistant professor of medicine at the University of California, San Francisco School of Medicine, summarized findings from a 2011 study that first assessed the use of DMARDs in a nationally representative sample of U.S. patients with RA. Using data from Healthcare Effectiveness Data and Information Set (HEDIS) and Medicare managed care plans, the study found that one-third of Medicare managed care beneficiaries with RA were not receiving DMARD therapy, along with wide variations in beneficiaries who were receiving DMARD therapy, including variations in age, sex, race, geography, health professional shortage areas, and health-plan profit status. For example, lower rates of DMARD use were found in patients who were nonwhite, had lower personal income, lived in the South Atlantic states, and were covered by for-profit health plans.
She then focused her talk on a new analysis done to address the limitations of the first study. These limitations included the inability to assess clinical status, comorbidities, specific drug used, or treating physician; the potential for misclassification of RA diagnosis used within the HEDIS reporting system; and the inability to assess allowances on prescription drug benefits for each health plan.
In the new Medicare fee-for-service analysis, she and her colleagues looked at a sample of 12,634 Medicare fee-for-service patients from 2009. All patients were at least 65 years old with at least two codes for a diagnosis of RA, and enrolled in Part D of Medicare. In addition, data were collected on drug name and dose received, comorbid conditions, and heath provider data. For this analysis, instead of comparing whether people received a DMARD or not, the investigators compared patients with at least one claim for any DMARD with those receiving glucocorticoid monotherapy (>180 day supply or 900 mg of prednisone within a year). The study found that 58% of the 12,634 patients received any DMARD, and that 10% of RA patients received significant doses of steroids alone. Of these latter patients, low-income patients were more likely to receive steroids alone, as were patients without contact with a rheumatologist. Characterizing the finding as “breathtaking,” Dr. Schmajuk said the study found that over 30% of low-income patients with no contact with a rheumatologist received steroids alone. Overall, she said that the Medicare fee-for-service analysis extends and confirms the work of the first study using HEDIS data.
Commenting on the study, Anne Davidson, MBBS, chair of the Rheumatology Research Foundation, an investigator at the Feinstein Institute for Medical Research, and professor of molecular medicine at Hofstra North Shore-LIJ School of Medicine in Manhasset, N.Y., emphasized the wide disparities in the quality of RA treatment among Medicare managed care organizations found in the study. “This is the first step to finding ways to improve patient care among large patient cohorts,” she said.
Mary Beth Nierengarten is a freelance medical journalist in St. Paul, Minn.
