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The progress that has been seen in the management of many aspects of rheumatoid arthritis (RA) has not been paralleled for the pulmonary disease that remains the second most common cause of death among these patients, an Australian expert reported here at the annual meeting of the Florida Society of Rheumatology.
Many of the other extra-articular components of RA such as ocular disease and vasculitis have "essentially disappeared," and the goal for joint symptoms today is remission, but pulmonary disease in RA actually appears to be on the rise, said Andrew Ostor, MD, of Cabrini Medical Center in Melbourne, Victoria.
The reasons for that may include patients' increased longevity, better methods of detection, and the effects of treatment, he noted. In addition, dyspnea is replacing pain and stiffness as a barrier to mobility, and so is being reported more often by patients.
RA-associated interstitial lung disease (ILD) is a progressive, although potentially reversible, fibrotic lung disease of the parenchyma. Very little is known about its pathogenesis, and conflicting views exist on everything from epidemiology to management, he observed.
Postmortem studies have detected lung disease in up to 80% of patients, and changes on chest x-rays are seen in 30%-50% of cases. Clinically significant disease is present in approximately one in 10 patients, and is associated with considerable morbidity.
The most common subtype is usual interstitial pneumonia, representing two-thirds of cases and characterized by fibrosis and honeycombing, while nonspecific interstitial pneumonia, with variable levels of alveolitis and inflammation, is present in one-quarter of cases.
Men and older smokers are more commonly affected by usual interstitial pneumonia, while women and younger patients typically develop the nonspecific subtype. Other subtypes of ILD include cryptogenic organizing pneumonia and overlap syndromes.
Current thinking about the pathogenesis of RA suggests that the disease may actually originate in the lung, possibly through changes such as citrullination associated with smoking and other environmental exposures, Ostor explained. "When I was at Cambridge University [where he formerly directed the rheumatology clinical research unit], a student asked me if it's possible to have RA without arthritis, and indeed, we now have identified a number of cases in which lung disease was the initial disease manifestation."
The first step in the work-up of a patients with shortness of breath or cough is a chest x-ray, which may reveal a nodular pattern if ILD is present, predominantly in the lower zones. Pulmonary function tests typically show a restrictive pattern, with reduced forced vital capacity and total lung capacity.
"Almost all of the drugs we use in RA have been implicated in lung disease," he said. Of particular concern has been the pneumonitis that is associated with methotrexate in 0.5% to 7.25% of patients. This is an idiosyncratic immune reaction that can be precipitated by the use of tumor necrosis factor (TNF) inhibitors, with an estimated mortality of 10%-25%. The American College of Rheumatology does not recommend the use of methotrexate for patients with RA-ILD.
"In just the last 3 months, three young women have rung me up saying they were short of breath," Ostor said, adding that he had them stop their methotrexate.
The data thus far have been "reassuring" overall for biologics, although case reports have suggested some cases of pulmonary disease exacerbations and anti-TNF-induced ILD, he said. He and his Cambridge colleagues reported on five patients who developed lung complications after treatment with infliximab (Remicade); four had preexisting usual interstitial pneumonia. There now have been at least 100 cases of induction or exacerbations of RA-ILD with anti-TNF therapy.
"This may have been reporting bias, but there are no hard and fast rules on disease management presently," he said.
Pulmonary complications also have been reported for other agents, including rituximab (Rituxan), tocilizumab (Actemra), and in clinical trials of tofacitinib (Xeljanz), he noted. "We are just starting to gain an understanding of the JAK [Janus kinase] inhibitors in the real world. In studies, there were cases of exacerbations of lung disease that may have been ILD but were classified as 'infection-no organism found.' We're now looking at the JAKs across all indications looking for a flag for ILD."
Abatacept (Orencia), however, has shown promise as a safe option, and a clinical trial to evaluate this agent in RA-ILD is in the planning stages.
Other treatments have derived from different patient groups, such as steroids, azathioprine, and pirfenidone (Esbriet) used in idiopathic pulmonary fibrosis, and cyclophosphamide or mycophenolate mofetil (Cellcept) used for scleroderma ILD.
"So the take-home message is that pulmonary disease in RA is still a bit of a mess, and we have a long way to go. It's complicated, there is no established therapy or validated trials, and there are possible confounding factors such as infection. Treatment must be individualized," he concluded.
Ostor reported having no financial disclosures.