Timely recognition of the pulmonary manifestations of RA is critical in light of the fact that respiratory involvement is identified as the second leading cause of mortality in patients with RA. Pulmonary disease in RA patients may not be routinely sought by rheumatologists and internists in the absence of cost-effective, accurate and time-efficient means of screening. An adequate screening tool that could easily be integrated into clinical care would represent a critical step in early identification and treatment of these conditions. In the present study, we demonstrated that pulmonary symptoms in combination with other easily measured variables can predict PFT abnormalities in patients with RA, and can identify patients in greatest need of further workup.
Nearly one-third of subjects in this prospective RA cohort demonstrated PFT abnormalities, and the majority of these patients carried no prior pulmonary diagnosis. As might be expected, respiratory symptoms were statistically more common in patients with abnormal PFTs. Specific symptoms in combination with commonly assessed patient characteristics were highly predictive of PFT abnormalities. We conclude that, beyond smoking, factors such as positive RF and anti-CCP antibodies and ongoing corticosteroid treatment may, in combination with pulmonary symptoms, identify individuals in need of further pulmonary evaluation. A simplified schematic of this screening approach (Figure ) indicates how these findings might guide subsequent evaluation with PFTs.
The findings of our study are supported by prior studies that have identified individual factors in association with lung disease. High titers of anti-CCP antibodies have been associated with the presence of pulmonary fibrosis in patients with RA [42
]. The association of corticosteroid use with PFT abnormalities could be related to the effects of the drug itself or, more probably, identifies patients with severe or difficult to treat RA, a known risk factor for PFT abnormalities [16
]. In the present study we were unable to determine the diagnosis for which corticosteroids were prescribed. Corticosteroid use may therefore be a marker of RA disease activity or a marker of lung disease.
Previous studies have reported association of symptoms and/or patient and disease characteristics with lung disease in RA patients. Our results are not directly comparable given differences in primary outcome and targeted population. Dawson and colleagues [10
] detected no difference in the prevalence of respiratory symptoms (dyspnea New York Heart Association grades II and III and productive cough) in 28 patients with HRCT-documented ILD compared to 122 patients without [10
]. Gabbay and colleagues a priori
divided 36 early RA patients based on symptoms, PFT and HRCT results, but did not test predictor variables against a uniform outcome [12
]. The study by Gochuico and colleagues enrolled 64 RA patients without respiratory symptoms [17
], and thus was primarily focused on identifying prevalence and predictors of pulmonary disease in asymptomatic RA patients. A number of isolated factors have been found to associate with ILD in RA patients, including cigarette smoking, male gender, higher HAQ score, genetic predisposition, the presence of other extra-articular manifestations of RA and treatment with methotrexate [6
In contrast to previous studies, ours is the first study to exclude patients with clinically apparent CVD, thus increasing the likelihood that the reported respiratory symptoms truly reflected lung disease, rather than cardiac disease. Furthermore, to control for confounding by subclinical CVD, we adjusted for the severity of subclinical CAD in our analyses. We found no statistically significant association between subclinical CAD and PFT abnormalities in our population. Furthermore, the association between pulmonary symptoms and PFT abnormalities was not affected after adjusting for subclinical CAD.
The present study differs from previously described cohorts in a number of other important matters. Because this analysis is nested in a larger ongoing natural history study, our patient cohort is extensively characterized with available demographic, lifestyle and anthropometric information. The number of subjects is considerably larger than in previous studies. Measures of functionality (beyond the HAQ score) are available, including accurate recording of exercise. Patients with RA may be physically deconditioned, and this may interfere with recognition of respiratory symptoms. The information available in our study allowed us to address this potential confounder as both HAQ scores and reported exercise were included and neither demonstrated a significant effect in multivariable modeling.
There are some notable limitations in our study. PFTs are not the gold standard for detecting respiratory disease. We chose to use PFTs rather than computed tomography scans as our marker of lung disease in this analysis as they provide a common and low-risk diagnostic modality that often precedes radiographic evaluation in clinical practice. We believe that using a more sensitive imaging method might strengthen our associations by identifying parenchymal abnormalities in patients who reported symptoms but were found to have normal PFTs. The small number of patients with lung disease in this cohort results in large confidence intervals in multivariate analysis. This points to the need for replication of these findings in a larger patient population.
There may have been an unintentional selection bias against patients with significant lung disease who may have elected not to participate in our study. In this case, however, we would expect to observe stronger associations between symptoms and PFT abnormalities had such patients participated. Furthermore, in the current study, coronary artery scanning occurred 1.3 to 2.5 years before pulmonary function testing. This might have lead to an underestimation of coronary disease that developed in the intervening time. Finally, our results may not be completely applicable in practice where RA patients with clinically significant CVD are more common. In a population with a higher frequency of CVD, respiratory symptoms may be less specific to pulmonary disease. This can only be addressed by a larger study in a population not restricted for clinically significant CVD.