A diagnosis of rheumatoid arthritis (RA) leaves an individual with uncertain prospects for the future. The autoimmune disease attacks the joints, causing pain, swelling, stiffness, fatigue and other symptoms. Medications and lifestyle changes can help people manage their RA, but there is no treatment that cures the disease.
Roughly 1.3 million people in the United States suffer from RA, but hundreds of thousands of them are also at risk for another health challenge: lung disease. The problems may include nodules, airway disease, inflammation of the air sacs and/or the lining of the lung, scarring of the tissue, blood clots, infections and more.
Most people with RA who have lung disease will have only mild respiratory symptoms. However, a substantial number will have interstitial lung disease (ILD) with severe scarring and inflammation of the lungs. The condition, RA-ILD, can diminish the quality of life and increase the risk of death, said Dr. Kevin Deane, professor of Medicine-Rheumatology at the University of Colorado School of Medicine
“If you take all RA patients, some studies suggest that 10% to 15% may die from lung-related processes that can include things like airway disease, RA-ILD and infections, but a substantially higher number will have significant impacts on their lives,” Deane said. For example, these patients may need supplemental oxygen, immune treatments, or drugs to reduce the progression of lung scarring, he said.
“In addition, we work to help prevent lung-related infections through vaccines,” Deane said.
Searching for rheumatoid arthritis-lung disease connection
Deane is part of a multi-front effort on the University of Colorado Anschutz Medical Campus to unravel the RA-ILD links. He is the principal site investigator for the SAIL-RA trial, which is probing for clues that might explain why some people in the early stages of RA (those diagnosed within the past five years) go on to develop severe ILD.
The SAIL-RA project, Deane explained, builds on the recognition that “lots of people with rheumatoid arthritis have mild forms of lung disease that they may never even notice. But then some of those progress. We are doing the study to learn more about how RA-related lung diseases develop and who is at the highest risk for getting the most severe forms,” he said. “Ultimately, we want to learn how best to prevent the lung disease or treat it if it develops.”
The SAIL-RA trial involves a number of components, Deane said. Researchers will assess each patient’s RA, how active it is, the joints involved, how much inflammation is present and blood tests to identify the biomarkers associated with the disease.
Participants will also get a CT scan of the lungs for signs of airway problems, scarring and other findings, a pulmonary function test and a six-minute walk test. After sharing all the test findings with the patients, researchers will follow them over time and conduct reassessments to look for changes, Deane said.
Exploring how lung problems may spawn rheumatoid arthritis
While RA is a frequent trigger for lung disease, the reverse can also be true: the biologic seeds of RA can originate in the lungs. That dynamic is the target of investigations by Deane’s rheumatology colleague Dr. Kristen Demoruelle, who is both a physician and PhD researcher.
A major focus for Demoruelle is understanding the factors that put some individuals with lung disease at risk for developing RA. Her research team uses “induced sputum collection” to gather lung samples and then analyzes them for RA-related antibodies and inflammatory proteins. Demoruelle’s research demonstrated that these agents have a strong presence in the lungs of people at risk for RA. When the RA antibody sputum tests were bolstered with blood antibody tests, roughly 60% of those studied went on to develop RA, Demoruelle said. That percentage was much higher than in those patients who had only a positive blood test, she added.
So, while the SAIL-RA trial looks at how factors in early RA might predict serious lung disease later in life, Demoruelle’s work seeks clues in the lungs that strongly indicate future attacks on the joints.
“We’re trying to add information to figure out how best to predict RA,” Demoruelle said.
A healthy life disrupted
The experience of Marlene Powell illustrates the complex and mysterious relationship between RA and lung disease that Deane, Demoruelle and researchers around the world are trying to unravel.
Powell, now 76, moved to Colorado from her native New Jersey with Tom, her husband of 56 years, in 2019 to be near their four children and nine grandchildren. She said she had been healthy most of her life, raising the kids, volunteering in their schools, and enjoying regular walks, water aerobics and other exercises.
In May 2016, however, Powell’s life dramatically changed. In the midst of downsizing for a move to a new home, Powell suddenly felt severe chest pains.
“I was crumpled up in pain,” she recalled. “I had never felt anything like it. It hit me like a brick.”
Surprise findings of severe lung disease and RA
She thought she was having heart problems, but a pulmonologist diagnosed idiopathic pulmonary fibrosis, the most common type of interstitial lung disease with no known cause. Powell’s primary care physician prescribed prednisone, which cleared the lung symptoms. She said she tried her best to digest the surprise problem and move on.
“For a while, I just let it be,” Powell said.
A few months later, however, she saw a pulmonologist in New York who conducted a “barrage” of tests that revealed she had RA. Another physical ordeal followed.
Shortly before Thanksgiving, Powell said she woke up with her legs, shoulders and feet painfully swollen.
“My feet didn’t fit in my shoes,” she said. “I couldn’t walk. I was in excruciating pain.”
Demoruelle, who now treats Powell, said the sudden attack underscores the unpredictable nature of RA.
“With RA, we see different types of presentations,” she said. “For some people, it is a very sudden and severe onset; for other people, it can be more slowly increasing over months. For other people, it can have more remitting and relapsing symptoms in the beginning.”
Similarly, Demoruelle added, in a patient with RA-ILD, lung symptoms can crop up suddenly, as they did with Powell, or appear more subtly.
Lung disease progresses
In 2017, Powell began infusions of rituximab, a medication that provided relief for both her RA and lung disease. The twice-yearly treatments “completely arrested both diseases,” she said. After the 2019 move to Colorado, she got pulmonary rehabilitation and other care for her RA-ILD from a team led by Dr. Joshua Solomon, a pulmonologist at National Jewish Health, and an associate professor of Pulmonary Sciences and Critical Care Medicine at the University of Colorado School of Medicine on the Anschutz Medical Campus.
Powell was stable for a year.
But in 2020, she noticed she was getting winded during her daily walks with Tom. By January 2021, she needed supplemental oxygen when she exercised. She then declined very rapidly and eventually needed oxygen around the clock. In August of 2021, she returned to New York in hopes of breathing more easily at sea level. She met with the medical director of the Lung Transplant Program at New York Presbyterian Hospital, who concluded she needed a new lung. He referred Powell to Dr. Alice Gray, associate professor of Pulmonary Sciences and Critical Care Medicine at the University of Colorado.
Powell returned to Colorado and met with Gray, who listed her for a lung transplant in July 2022. By that time, even with a standing oxygenator and special cannulas, Powell said, “it became increasingly difficult to breathe.”
In September of that year, a struggling Powell met again with Gray at UCHealth University of Colorado Hospital. Gray told Powell she would find a donor and called two days later with the news that she had done so. Dr. Jordan Hoffman, with the UCHealth Thoracic Surgery – Anschutz Medical Campus team, successfully transplanted Powell’s new left lung. Within four days, she was completely free of supplemental oxygen.
Return to health
Today, Powell says she deals with “little spurts” of RA pain but treats it with Tylenol. Her freedom from debilitating lung disease easily overshadows that problem. Powell walks regularly, does yoga, and has regained 20 of the 30 pounds she lost during her long battle to breathe. She’s gotten back to cooking, a joy of life for a self-described foodie from an Italian-American background who relishes whipping up dishes with her family.
In a poignant moment last August, Powell got a chance to do so on a return trip to New York for Tom’s 80th birthday and to see two of their sons who had moved back from Colorado. The family was once again cooking together.
“My children are awesome cooks,” Powell said. In the midst of the preparations, her oldest son turned to her with tears in his eyes. “He said, ‘Mom, I didn’t think we’d be able to do this again.’ ”
Demoruelle hopes that ongoing research can offer earlier diagnosis and prevention for patients like Marlene Powell.
“It is certainly our hope that with more research, we can improve clinical screening approaches and screening guidelines so that for patients with RA-ILD, their [lung disease] can be found as early as possible so that treatment can be started earlier and hopefully reduce their development of symptoms,” Demoruelle said.
A collective drive for more research
Meanwhile, researchers at the University of Colorado continue to explore other avenues to understanding the roots of RA-ILD. For example, studies in 2018 and 2022 co-authored by University of Colorado pulmonary medicine and critical care specialists Drs. Joyce Lee and David Schwartz identified a variant of the MUC5B gene as a risk factor for RA-ILD. Dr. Fan Zhang, a Ph.D. researcher and colleague of Deane and Demoruelle in Medicine-Rheumatology, is studying how to use machine learning to analyze cells in joint and lung tissue of patients with RA-ILD and perhaps find common markers that drive inflammation.
The varied research has a common aim, Deane said.
“These studies are in parallel and are converging on ways to identify who is at the highest risk for getting lung disease; and if they have lung disease, who is at the highest risk of progressing and having severe disease; and then ultimately identifying targets for treatment,” he said.
For more information on the SAIL-RA study, visit Study | Search Results | Research Studies | School of Medicine | University of Colorado (cuanschutz.edu).