TO THE EDITOR,
 
Rheumatoid Arthritis-associated airway disease (RA-AWD) is a commonly overlooked pulmonary manifestation of Rheumatoid Arthritis (RA).(1) Its prevalence varies widely, from 8 to 60%, depending on the source of the cases (hospital-based studies or autopsy) and the criteria used to define RA-AWD, whether based on symptoms, pulmonary function tests (PFTs), or imaging.(1)
 
The spectrum of manifestations ranges from small (bronchiolar) to large airway disease.(2) Despite its high prevalence and complexity, there are few studies in the literature characterizing RA-AWD, and even fewer evaluating its longitudinal course.(3)
 
In the present study, we describe the longitudinal behavior of PFTs in patients with RA-AWD. This single-center retrospective study involved subjects aged 18 years or older, diagnosed with RA-AWD at a tertiary pulmonary clinic, that were followed between 2016 and 2017. RA-AWD was defined by the absence of interstitial lung disease (ILD) and the presence of features of airway disease on high-resolution computed tomography (HRCT) of the chest, not explained by other diagnoses, such as asthma or COPD. Since smoking is in the causal pathway of RA and likely in the causal pathway of RA-AWD, it was not used as an exclusion criterion.(2)
 
In order to be considered eligible, patients were required to have undergone a chest HRCT and PFTs. Baseline PFTs were defined as the earliest PFT within a 6-month interval since the HRCT. Up to four additional PFT results were retrieved from the electronic health records (EHR) for estimating the rate of change in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. Clinical data were obtained from the EHR. This project received institutional review board approval from the Clinics Hospital’s ethics committee (Process No. 2.825.510).
 
The earliest available chest HRCT was qualitatively analyzed by two independent readers (LKD and MVYS) for the presence of RA-AWD. Inconsistencies were resolved through consensus (kappa agreement between readers: 0.71).
 
Imaging findings of RA-AWD were categorized as follows: unequivocal bronchial thickening, mosaic attenuation, centrilobular micronodules, and/or focal or multifocal bronchiectasis.
 
The annual rate of change in FEV1, FVC, and the FEV1/FVC ratio were estimated using a mixed regression model (random slopes and intercepts), including age, sex, and baseline FEV1, FVC, and FEV1/FVC (respectively) as covariates. The R Statistical Package was used in the analysis.
 
Among the 2,495 patients who underwent a follow-up visit at our pulmonary clinic between 2016 and 2017, 96 (3.8%) matched our case definition for RA and pulmonary involvement. Forty-eight out of these 96 (50%) subjects fulfilled the criteria for RA-AWD. The majority of individuals with seropositive RA were females in their sixth decade of life, and the mean disease duration was 15 years. Approximately half of the RA-AWD subjects (48%) had never smoked. No differences were observed between RA-AWD and Rheumatoid Arthritis Interstitial Lung Disease (RA-ILD) regarding previous tuberculosis (TB) contact or treatment for latent TB.(4) Additional clinical variables are shown in Table 1.

 
The most common HRCT findings among the RA-AWD patients were unequivocal bronchial thickening in 46 (96%), followed by mosaic attenuation in 30 (63%), centrilobular micronodules in 28 (58%), and focal or multifocal bronchiectasis in 23 (48%).
 
Forty-four patients had at least two PFTs included in the longitudinal analysis. The median interval between the first and last PFTs analyzed was 20 months [IQR: 9.3 – 22.5]. The mean baseline FVC was 79 ± 19% of the predicted value, FEV1 was 65 ± 22% of the predicted value, and the FEV1/FVC ratio was 0.65 ± 0.17, characterizing a mild obstructive ventilatory defect (OVD) (Table 1). A statistically significant annual decline in FVC was observed (-1.45% predicted, 95% CI: -2.37 to -0.53), while the FEV1 remained stable (-0.62% predicted, 95% CI: -1.54 to 0.30), leading to a statistically significant increase in the FEV1/FVC ratio of 0.01 (95% CI: 0.005 to 0.016), suggesting air trapping and/or hyperinflation (Figure 1).

 
As expected for a sample of RA patients, half of the subjects had been exposed to tobacco. Excluding patients with a smoking history from the analyses would likely bias the results, as smoking is in the direct causal pathway of RA itself.(5) Functionally, one case of mild OVD evolved with FVC reduction and an increase in the FEV1/FVC ratio, suggesting air trapping/hyperinflation, replicating previous longitudinal findings in RA-AWD.(3) Of note, the estimation of air trapping/hyperinflation by the FEV1/FVC ratio is considered accurate when compared to the residual volume/total lung capacity ratio.(6) In COPD, air trapping/hyperinflation is associated with an increased risk of disease exacerbation, a higher degree of dyspnea, and a poorer quality of life. While these aspects were not assessed in our study, they should serve as plausible research hypotheses to be investigated in RA-AWD.(7)
 
The tomographic findings observed in this study are consistent with what has been previously described.(2) Additionally, despite this cohort originating from an endemic region for TB, the proportions of bronchiectasis and bronchial wall thickening (common TB sequelae) found in our sample were similar to previous reports on RA-AWD from non-endemic TB regions.(8,9)
 
This study had some limitations. Firstly, it was a retrospective single-center study. Nevertheless, our sample characteristics are similar to previous RA-AWD reports in the literature.(1,2,3,9) Secondly, data on HRCT follow-up were unavailable. On the other hand, our study thoroughly characterized the baseline HRCT findings and the longitudinal PFT behaviour in RA-AWD subjects, suggesting air trapping/hyperinflation as an important mechanism of disease progression. Patients self-reported environmental exposure avoidance and smoking cessation; hence, these factors are unlikely to be the causal determinants of our functional longitudinal findings. A past history of tuberculosis treatment was present in only 8% of our sample, and the removal of these patients did not alter the results (data not shown).
 
In conclusion, in the present cohort, RA-AWD was characterized by small and large airway imaging findings that were associated with an obstructive ventilatory defect. During follow-up, the observed increase in air trapping and/or hyperinflation potentially accounted for the reduction in FVC and the increase in the FEV1/FVC ratio. Additional studies are warranted to confirm air trapping/hyperinflation as a mechanism of progression in RA-AWD, which, in turn, may impact the choice of interventions to be tested in the management of this condition.
 
AUTHOR CONTRIBUTIONS
 
The authors confirmed contribution to the paper as follows: study conception and design MLBS, CAM, MVYS, KB, RAK, BGB, LKD; data collection MLBS, CAM, FEA, LKD; analysis and interpretation of results MLBS, CAM, AP, RHN, RAA, BGB, LKD; draft manuscript preparation MLBS, CAM, MVYS, KB, ACMR, AP, RHN, FEA, RAA, RAK, BGB, LKD. All authors reviewed the results and approved the final version of the manuscript. Both MLBS and LKD contributed equally.
 
CONFLICTS OF INTEREST
 
The authors have no conflicts of interest to declare.
 
REFERENCES
 
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