So far, 25 Within Our Reach projects have been completed and 24 grant recipients have been awarded an additional $59 million in related grants from the NIH.
Here is a summary of some of the projects, now under way, that were presented in Miami.
Is the Lung Where RA Begins?
The cause of RA might not be known but, given that antibodies tied to RA are present well before any signs of disease show up in the joints, it’s thought that the origin of the disease might be somewhere outside the joints.
One key suspect is the lungs: Smoking is a strong risk factor for RA, dust and pollution might increase the risk of getting RA, and there is a high prevalence of lung disease in RA patients, even in early stages.
Kevin Deane, MD, assistant professor of medicine at the University of Colorado in Denver, is looking for definitive evidence that the lung is, in fact, that starting place for the disease.
Dr. Deane, who received an ACR REF grant in 2009, is studying imaging and lung function of individuals at risk for future RA to see if those with RA antibodies show signs of pulmonary disease compared with those without those antibodies. He also plans to mine samples for further signs of lung involvement in the development of RA.
So far, he and his team have found that 33 out of 45 patients with RA antibodies show airway disease on high-resolution computed tomography (CT) imaging. However, of the 16 controls without the antibodies, only four show airway disease (p<.01).
A key finding is that joint examinations of at risk subjects showed there was no apparent inflammatory arthritis in those with the lung abnormalities, meaning the lung abnormalities predate any clinical sign of RA. Also, MRIs of 18 subjects showed that 13 of the subjects were without synovitis.
Dr. Deane and his research team are also evaluating lung lavage and sputum to collect cell profiles, autoantibodies, protein citrullination data, cytokine and chemokine levels, and to see whether any pathogens are present that might be driving the autoimmunity.
“Longer-term goals are going to be to expand the sample set—lots more subjects … who are at risk for RA,” Dr. Deane said. “We [also] need more with established RA to understand more of the biology of immune generation in the lungs. And then include longitudinal follow-up for these people to see what happens to them over time.”
Test for Interstitial Lung Disease
Even though there have been advances in finding patients with RA and treating their disease, there has not been much progress in helping patients with RA who develop interstitial lung disease (ILD).
RA-related ILD is usually diagnosed after a patient arrives at the physician’s office with cough and shortness of breath. By then, their options are fairly limited. “They’ve already developed very significant abnormalities,” said Sonye Danoff, MD, PhD, assistant professor at the Johns Hopkins University School of Medicine in Baltimore and co-director of its Interstitial Lung Disease Clinic.
Dr. Danoff, who received ACR REF funding in 2010, is investigating the usefulness of a test that might help give RA patients an earlier picture of their risk and help guide rheumatologists on how to treat them.
Chest CT scans are the tool used to diagnose ILD, but it has been shown that even the most experienced radiologists reading scans can vary widely in their interpretations, even though that study is considered the “gold standard” in evaluating the disease.
Dr. Danoff is evaluating the ability of quantitative CT densitometry to give more reliable results.
It’s really been very beneficial to have all the researchers come together and not only show their progress but to get ideas and feedback and establish collaborations.
—David Karp, MD, PhD
CT scans are collections of pixels at varying densities. In quantitative CT densitometry, each pixel’s density is assessed, using a computer algorithm, and then is assigned to a range. A pixel with a density reading of zero is bone and a reading of -1000 is interpreted as emphysema.
The “high attenuation” range of -640 to -250 is the range associated with ILD. The percentage of total pixels in this range is the percentage of high attenuation area (%HAA)—and this is the key number used to assess disease when using quantitative CT densitometry.
Dr. Danoff and her team have already found that using densitometry is more reliable than using expert readers. An expert with extensive experience had an intra-observer kappa score of variability of 65%. But the correlation coefficient of %HAA on 2,653 scans that were re-run, as part of a different study, was .93, showing that it is highly repeatable.
Researchers have also found that quantitative CT densitometry is much better at predicting poor performance on pulmonary function tests at 18 months of follow-up than the expert reads of the CT scans.
Dr. Danoff, whose project is also beginning to look at biomarkers of ILD, said she hopes this could be the beginning of a very useful tool for doctors and patients.
“I would like a very simple test that every radiologist could take to their office and when they met an RA patient for the first time they could say, ‘Here’s what your lifetime risk of developing interstitial lung disease is.’ Not just because we want to know who we should be screening but because it allows us to do primary prevention. And I think that’s where we have to go with this”.
A Better Mouse Model for RA-related Lung Disease
With as many as 80% of RA patients developing signs of disease in the lung, and as many as 20% developing diffuse fibrotic lung disease, the more that is known about how the lung becomes affected, the better. But there is a lot to learn.
“Really, little is known about the mechanism of lung disease in rheumatoid arthritis,” said Rebecca Keith, MD, a researcher with National Jewish Health in Denver.
She and other researchers there—including David Riches, PhD, professor of pediatrics—are trying to address this with a project that received REF funding in 2009. Using a mouse model meant to mimic the development of RA-related ILD in patients, they are exploring the underlying mechanisms.
These investigators know that the prevalence of the disease rises with age, that joint disease is more common in women and that ILD is six times more common in men than women. Now they have a mouse model that reflects those tendencies.
The point of this effort is not simply to establish biomarkers of these different stages of lung disease but hopefully to gain insight regarding molecular pathways in the process.
—Dana Ascherman, MD
Most mouse models of arthritis do not develop lung disease, and vice versa. However, National Jewish Health researchers have found that the SKG mouse—in which arthritis is brought about by the injection of inflammation-inducing zymosan—is a reliable representation of both RA and lung disease. They tracked the progression of arthritis in female mice and found that it progressed more quickly than in male mice, and that aged male mice had higher levels of hydroxyproline and lower static compliance, which is associated with ILD. They also found that the lung disease is characterized by infiltrating macrophages and CD4-positive T cells.
Researchers have also found that castrated male mice have arthritis scores similar to female mice—low testosterone essentially feminizes the arthritis phenotype. They found a similar effect when looking at the percentage of diseased lung in the mice, and they noted that a lack of testosterone doesn’t bring about the fibrotic lung disease typically seen in aged mice.
“We believe that the SKG mouse is a really good model” for studying RA-related interstitial lung disease, Dr. Keith said. “Surgical castration, or lack of testosterone, in this mouse actually generates more feminine type of phenotype in which there’s increased arthritis severity and prevalence compared to male [mice], but lack of testosterone does not induce that fibrotic lung phenotype. So, as we move forward with these studies, we’re interested in looking at other mechanisms.”
Markers of RA-related Lung Disease
ILD stemming for RA can have devastating effects, making this complication one of the leading causes of morbidity and mortality in RA.
Researchers at the University of Miami are looking for noninvasive peripheral biomarkers to give doctors a marker for disease before it emerges clinically and may no longer be amenable to meaningful treatment. They are also hoping to use autoantibody profiles to show that tissue-specific patterns of protein citrullination distinguish RA patients who do and do not have ILD.
RA-related ILD accounts for between 10% and 20% of mortality in RA patients, making it crucial to find early clues. Getting clues about the precise nature of the lung disease is important because the histopathological subtype influences survival and outcomes for patients, said Dana Ascherman, MD, associate professor of medicine at the University of Miami’s Miller School of Medicine.
In their search for biomarkers, researchers anticipate that expression of CXCR3-binding chemokines and of certain metalloproteinases will be upregulated in cases of RA with ILD. They also anticipate that more extensive biomarker profiles obtained using enzyme-linked immunosorbent assay (ELISA) will differ according to the subtype of the disease. “The point of this effort is not simply to establish biomarkers of these different stages of lung disease but hopefully to gain insight regarding molecular pathways in the process,” Dr. Ascherman said.
Regarding autoantibody profiling, he said there is opportunity for advance even though previous studies haven’t shown a clear link between anticyclic citrullinated peptide titers and lung disease because those studies were limited to the proteins and peptides contained within conventional assays. This project will therefore look at a broader array of citrullinated proteins.
“We can use the anticitrullinated protein antibody profiles as a surrogate measure of protein citrullination that’s occurring in tissue, and thereby identify putative autoantigens,” he said.
This work has drawn early attention to the role of antibodies targeting citrullinated heat shock proteins, molecular chaperones that assist with the folding and unfolding of other proteins, contributing to important cellular metabolic processes.
The Link Between Periodontitis and RA
RA and periodontitis have many ties: shared risk factors, the fact that periodontitis is more prevalent in RA patients and vice versa, and the possibility that treatments for RA might help with the signs and symptoms of periodontitis.
But according to Ted Mikuls, MD, MSPH, professor of medicine at the University of Nebraska Medical Center in Omaha, it’s an under-researched area, with generally small and poorly controlled studies. He is embarking on the largest study to date on the diseases.
Mikuls is particularly interested in the role of Porphyromonas gingivalis (P. gingivalis), a major pathogen in periodontitis, that might play a role in autoantigen presentation and the development of anticitrullinated protein antibodies, which are associated with poor RA outcomes.
Dr. Mikuls’ study sets out to confirm in a larger and better-defined population the links between periodontitis and RA, and to demonstrate that those links are mainly due to infection with P. gingivalis.
He and colleagues will also try to determine whether antibodies to P. gingivalis are more common in people at a high risk for developing RA than in those at lower risk.
“The aim is somewhat ambitious, but I think we’re on track to do this,” Dr. Mikuls said, “to enroll 600 patients into the study with systematic physical examinations and several other detailed measures.”
Another Look at Periodontal Disease
Another study examining the role of periodontal disease in RA is under way, headed by Clifton Bingham III, MD, assistant professor of medicine at Johns Hopkins University. Dr. Bingham and his team are analyzing data from 200 RA patients who have gotten a comprehensive oral exam.
“One of the questions that I had was: What about early rheumatoid arthritis specifically, people at the beginning of their disease, what does periodontal disease look like in that cohort?” he said.
The researchers have split the study patients into early RA and more advanced RA groups. They’ve found that periodontal disease is common and significant in both groups. “We’re seeing very, very high numbers here in our entire population,” Dr. Bingham said. “The bottom line from this shows that certainly, in patients who have very early rheumatoid arthritis, both the prevalence and severity is the same as in patients with established disease.”
In fact, 20% of the prospective participants could not participate because they didn’t have 20 teeth left in their mouths.
The researchers are also looking at how bacterial and human peptidylarginine deiminase (PAD), the enzymes that citrullinates proteins, functions and is expressed in periodontal tissues, as well as how it is involved in generating autoantigens in patients with RA and periodontitis. They’ve found that citrullination and PADs are expressed both in periodontitis and normal cheek mucosa and tissue of the tonsil.
This team is also taking a close look at P. gingivalis, finding that it contains citrullinated proteins, and that RA patients make antibodies both to noncitrullinated and citrullinated versions of PAD-Pg.
So far, the work has further demonstrated the importance of the mouth in understanding RA, Dr. Bingham said. “One of the things that I’ve learned over doing this for the past five years or so is that the mouth does have a lot of information in it,” he said. “It’s frequently ignored, and I’m trying to teach fellows that you need to look in the mouth like you need to look at the feet.”
Comparison of RA Treatments
When an RA patient fails to respond to methotrexate and an anti–tumor necrosis factor (TNF) drug, rheumatologists are often left with a difficult decision: What do they do next?
Patients’ and physicians’ main choices are to try an intravenous TNF inhibitor; the monoclonal antibody rituximab; abatacept (Orencia), which works by inhibiting T cells; or tocilizumab (Actemra), which blocks interleukin-6 (IL-6).
However, Larry Moreland, MD, chief of the division of rheumatology at the University of Pittsburgh, said there’s no way to make an informed decision. “There’s really no data to suggest that one of these is better than the other,” he said. “No one’s compared these head to head, and no company’s ever going to do that.”
Dr. Moreland has received a planning grant from the ACR, and he and his team are proposing a comparative effectiveness trial. Planning is expected to take a year, and then they will have to seek further funding for the trial.
Because of the financial constraints of buying or getting donations of the drugs from the manufacturers for a traditional randomized trial, he is proposing that patients willing to participate have a drug chosen at random and then have their insurance pay for the drug.
Those making the assessments of the patients to see how they are responding to their drug would be blinded, although the patients would not be.
“If you don’t have appropriate insurance then you won’t be eligible for this study,” Dr. Moreland said, “but we’re basically going to measure what’s happening in the real world.”
I would like a very simple test that every radiologist could take to their office and when they met an RA patient for the first time they could say, ‘Here’s what your lifetime risk of developing interstitial lung disease is.’
—Sonye Danoff, MD, PhD
Markers for Cardiovascular Risk in RA
Patients with RA are at a higher risk for cardiovascular events, but it is difficult to tell which individuals in this group are at greatest risk.
Framingham scores are not very useful because they don’t perform well in women or younger individuals, the groups most affected by RA. Joan Bathon, MD, chief of the division of rheumatology at Columbia University in New York City, is searching for biomarkers that might gauge risk better.
Dr. Bathon, who received ACR funding in 2010, has amassed data from 600 RA patients in whom atherosclerosis has been measured; she will soon start the systematic process of identifying protein markers that hopefully will identify high-risk patients. She and her team have been refining assays, but she expects the first data to be generated by the end of the year.
“Can we say in the blood of these 600 people that there are biomarkers that identify that subset that has really severe atherosclerosis?” she said. “And if we can identify those, then maybe we can take that biomarker into a bigger population where they’re actually having heart attacks and see if it performs as a predictor.”
The REF funds groundbreaking research resulting in better care and treatment for more than 50 million Americans affected by rheumatic diseases. As the largest private funding source of rheumatology research and training programs in the U.S., the REF has awarded over $50 million to more than 1,000 recipients in the past five years. For more information about the REF and the Within Our Reach campaign, visit www.rheumatology.org/REF.
Thomas Collins is a freelance medical writer based in Florida.
