The subjects were 144 females (69.2%), the age at entry was 59.25 ± 13.16 years, and 46.8% had a history of smoking (Table 1). The age of RA onset was 51.31 ± 15.26 years and disease duration was 7.94 ± 9.31 years. Anti-CCP antibody and RF were positive in 85.9% and 84.1% of the subjects, respectively; and there was usage of MTX and glucocorticoids in 65.3% and 75.4% of the subjects, respectively. Twenty-one patients (10.1%) displayed respiratory symptoms (e.g., cough). The mean interval between HRCT scans obtained before and during biologic therapy was 3.26 years. The patients underwent sequential HRCT scans for the following reasons: follow-up or screening for chest abnormalities without respiratory manifestations (n = 120; 58%), new/worsened symptoms (n = 46; 22%), new/worsened radiographic findings (n = 37; 18%) and abnormal laboratory findings (n = 19; 9%).
Prevalence of pulmonary abnormalities prior to initiation of biologic therapy
Pulmonary abnormalities were found in 146 of the 208 patients (70.2%): ILD (38.9%), nodular lesions (21.6%), and AD (55.3%) (Table 2). The most common ILD lesions were reticular pattern (20.2% of all patients), honeycombing (6.7%), GGO (6.3%), and consolidation (7.7%). Regarding nodular lesions, nodular pattern was observed in 14.4% and small nodular pattern in 12.0% of all patients. Regarding AD, bronchiolitis was observed in 40.4% and bronchiectasis in 41.3%. An area of low attenuation was detected in 13.0% of patients. Commonly, several pulmonary lesions coexisted in the same individual.
The agreement rate and the kappa statistic between the two evaluators regarding detection of lesions were 0.90 and 0.52, respectively.
Cluster analysis of the patterns of existence of pulmonary abnormalities
Because many individuals had several pulmonary lesions, we examined the patterns of their occurrence by cluster analysis, in which clusters were determined according to the presence or absence of the 20 lesions. Six clusters were identified (Fig. 1A): cluster 1, no pulmonary abnormalities; cluster 2, bronchiolitis alone; cluster 3, AD + curved linear opacity; cluster 4, AD; cluster 5, AD + nodular lesions; and cluster 6, AD + ILD (reticular pattern). Of note, AD was found in most patients with pulmonary abnormalities (clusters 2-6) suggesting that AD is a shared pulmonary abnormality in patients with pulmonary lesions.
Change in pulmonary abnormalities during biologic therapy
During the observation period (3.3 ± 2.6 years), in 92 patients the pulmonary abnormalities showed change: new lesions developed in 68, lesions improved without development of new lesions or worsening of pre-existing abnormalities in 4, and pre-existing abnormalities worsened without the development of new lesions in 20.
As shown in Table 2, the incidence of any new pulmonary lesion was 10.5/100 person-years (PY). The incidence of ILD, nodular lesions, and AD was 7.0, 2.2, and 4.3/100 PY, respectively. The most common new abnormalities in ILD were GGO (3.2/100 PY) and consolidation (2.3/100 PY), and those in AD were bronchiolitis (2.3/100 PY) and bronchiectasis (2.0/100 PY).
There was much variation in the frequencies of worsening and improving lesions among the 20 lesions (Suppl. Table 1). For GGO and consolidation, some lesions worsened whereas others improved; however, some reticular pattern lesions and worsened, but few improved. Some honeycomb lesions worsened, and none improved. Lesions with small nodular pattern and AD including bronchiolitis and bronchiectasis worsened, but rarely improved.
Regarding evaluation of change in a lesion between the initial and subsequent scan, the agreement rate and the kappa statistic were 0.83 and 0.65, respectively.
Patterns of newly emerging pulmonary abnormalities
To examine the emergence pattern of the pulmonary lesions, we conducted a cluster analysis of newly developed lesions in all 208 patients. New lesions formed clusters rather than developing at random. As shown in Fig. 1B, we identified seven clusters: cluster 1, no pulmonary abnormalities; cluster 2, nodular pattern; cluster 3, curved linear opacity; cluster 4, bronchiectasis; cluster 5, consolidation; cluster 6, bronchiolitis; and cluster 7, GGO.
Impact of pre-existing pulmonary lesions on development of new abnormalities
We examined whether the pre-existence of pulmonary abnormalities affected the development of new lesions. As shown in Fig. 2, new pulmonary abnormalities (especially ILD) frequently developed in patients with pre-existing diseases, particularly in those with nodular lesions and AD. The incidence of pulmonary lesions was 4.86/100 PY, which was lower than the incidence of pulmonary lesions (13.5/100 PY) in patients with pre-existing pulmonary abnormalities (Table 2). However, not all pulmonary lesions developed in patients with pre-existing lesions. GGO and consolidation frequently developed in patients with pre-existing disease, whereas curved linear opacity and bronchiolitis occurred in patients without pulmonary lesions (Table 2).
Development of pulmonary abnormalities in patients without pre-existing pulmonary abnormalities
We attempted to determine the developmental pathways of pulmonary abnormalities in RA. First, to identify which lesions appear as initial abnormalities in RA, we examined the pulmonary lesions that developed in patients with no pre-existing abnormalities.
Of 62 patients without pulmonary abnormalities, 11 patients (17.7%) developed a total of 23 new lesions. The most frequent lesions were bronchiolitis (n = 6; 54.5% of patients with new lesions), curved linear opacity (n = 4; 36.4%) and bronchiectasis (n = 3; 36.4%) (Fig. 1C). A heat map of the lesions suggested that the initial pulmonary abnormalities were bronchiolitis with curved linear opacity/bronchiectasis (Fig. 1C). Taken together, bronchiolitis and curved linear opacity were the initial lesions.
Development of pulmonary abnormalities in patients with pre-existing pulmonary abnormalities
We also examined the pulmonary lesions that developed in patients with pre-existing abnormalities. Of 146 patients with pulmonary abnormalities, 57 patients (39%) developed a total of 92 new abnormalities. A variety of pulmonary lesions developed in these patients. A cluster analysis of new abnormalities in patients with pre-existing lesions identified five clusters: cluster 1, no pulmonary abnormalities; cluster 2, AD with bronchiectasis/bronchial wall thickening; cluster 3, bronchiolitis; cluster 4, consolidation; and cluster 5, GGO (Fig. 1D).
The heat map shows that clusters 2 and 3 emerged in patients with pre-existing AD, which suggests that AD induces other AD as a complex form of AD. Cluster 4 (consolidation) and cluster 5 (GGO) also developed in patients with pre-existing AD. Taken together, we consider that AD induces a variety of pulmonary abnormalities, including further progression of AD.
Correlation between pre-existing and newly emerging lesions
To examine the correlation between pre-existing and new pulmonary lesions, we performed a checkerboard analysis of pre-existing and newly emerging lesions (Suppl. Table 2). Note that many individuals had or developed several lesions.
Figure 3A shows the results of the checkerboard analysis. There are several correlations between the pre-existing and new lesions. There was a strong correlation of each of pre-existing honeycomb, reticular pattern, small nodular lesion, bronchiolitis, and bronchiectasis with new development of GGO.
The above relationships are summarized diagrammatically in Fig. 3B, which outlines the development pathways of pulmonary abnormalities in RA.