Abstract
Objectives
Pulmonary disease is a common extraarticular manifestation of RA associated with increased morbidity and mortality. No current strategies exist for screening this at-risk population for parenchymal lung disease, including emphysema and interstitial lung disease (ILD).
Methods
RA patients without a diagnosis of ILD or chronic obstructive pulmonary disease underwent prospective and comprehensive clinical, laboratory, functional and radiological evaluations. High resolution CT (HRCT) scans were scored for preclinical emphysema and preclinical ILD and evaluated for other abnormalities.
Results
Pulmonary imaging and/or functional abnormalities were identified in 78 (74%) of 106 subjects; 45% had preclinical parenchymal lung disease. These individuals were older with lower diffusion capacity but had similar smoking histories compared with no disease. Preclinical emphysema (36%), the most commonly detected abnormality, was associated with older age, higher anti-cyclic citrullinated peptide antibody titres and diffusion abnormalities. A significant proportion of preclinical emphysema occurred among never smokers (47%) with a predominantly panlobular pattern. Preclinical ILD (15%) was not associated with clinical, laboratory or functional measures.
Conclusion
We identified a high prevalence of undiagnosed preclinical parenchymal lung disease in RA driven primarily by isolated emphysema, suggesting that it may be a prevalent and previously unrecognized pulmonary manifestation of RA, even among never smokers. As clinical, laboratory and functional evaluations did not adequately identify preclinical parenchymal abnormalities, HRCT may be the most effective screening modality currently available for patients with RA.
Keywords: emphysema, epidemiology, interstitial lung disease, preclinical, rheumatoid arthritis, screening
Rheumatology key messages.
Preclinical parenchymal lung disease is highly prevalent in patients with RA.
Emphysema may be the most common pulmonary manifestation of RA, even amongst never smokers.
HRCT may be the most effective screening modality for RA-associated preclinical parenchymal lung disease.
Introduction
Pulmonary disease accounts for 10–20% of all mortality in patients with RA, second only to cardiovascular disease [1]. While improvements in treatment of articular disease have led to an overall decrease in mortality, age-adjusted mortality rates from RA-associated pulmonary disease have been increasing [2, 3]. Despite this observation, no strategies currently exist for risk stratification, detection or early intervention in patients with RA.
RA-related pulmonary disease can affect different compartments of the lung. Parenchymal lung disease includes both interstitial lung disease (ILD) and emphysema and excludes airway-based diseases, such as asthma, bronchitis, bronchiectasis and broadly defined chronic obstructive lung disease (COPD). Currently, ILD is considered the most common pulmonary manifestation of RA, affecting about 10% of individuals [2, 4]. RA-ILD has a 3-fold increased risk of death compared with RA without ILD [4]. Preclinical disease has been identified in 33–61% of individuals with RA [5–7], 34–57% of whom have radiological evidence of progression after 1.5–2 years of follow-up [8, 9]. The importance of preclinical ILD in autoimmune populations was emphasized in a recent multidisciplinary position paper from the Fleischner Society [10]; this recommended that incidentally detected interstitial lung abnormalities on CT in patients with autoimmune disease should be classified as ‘preclinical ILD’ rather than interstitial lung abnormalities due to the presence of a strong risk factor for progressive disease.
To our knowledge, the prevalence of isolated emphysema in the general RA population has never been reported. Although some studies have investigated the more broadly defined COPD [11], they included assessment of not only emphysema but also airway-based abnormalities, such as chronic bronchitis and often asthma, bronchiectasis and other bronchiolar disorders. The studies that specifically reported isolated parenchyma-based emphysema in patients with RA examined only those with concurrent ILD [12, 13]. When compared with the general population, broadly defined COPD is more common in patients with RA, with an estimated pooled prevalence of 6.2% [14, 15], and is associated with a 47% higher adjusted risk of hospitalization [16]. Patients with RA and COPD have a 10-year mortality of about 60% [17], a prognosis similar to RA-ILD [18]. Research characterizing concurrent RA-ILD and emphysema demonstrated a high prevalence of emphysema at lower pack-years than observed in controls with COPD [12]. Furthermore, emphysema occurs in ∼27% of never smokers with concomitant RA-ILD and is associated with mortality [13]. Identification of patients with preclinical emphysema is important given that incidental emphysema on CT scans performed for non-pulmonary clinical indications in the general population is a strong independent predictor of acute exacerbations of COPD resulting in hospitalization or death [19, 20]. Early identification of emphysema provides opportunities for smoking cessation and early intensive intervention, which can slow disease progression and decrease morbidity and mortality [21–23].
In RA, both emphysema and ILD would be good candidates for effective screening programmes given that both constitute significant public health problems in this population, and both have treatments currently available that are potentially more effective before a patient becomes symptomatic [24]. Unfortunately, screening guidelines for these parenchymal lung diseases in RA patients have not been established. To address the unmet need for early detection of preclinical parenchymal lung disease, this prospective study was designed to screen for preclinical ILD, emphysema and other pulmonary abnormalities in a RA cohort without a prior diagnosis of ILD utilizing a comprehensive assessment. Our hypothesis was that clinical risk factors and functional decrements are associated with preclinical parenchymal lung abnormalities in RA.
Methods
Study design and subjects
Subjects with RA and no history of ILD per patient or physician questionnaire from the Brigham and Women's Hospital RA Sequential Study (BRASS) physician questionnaire were recruited prospectively from November 2016 to December 2019 from the existing BRASS parent cohort for an independent prospective pulmonary substudy (see Supplementary Material, available at Rheumatology online). Subjects with a previous diagnosis of emphysema or COPD per medical record review or BRASS physician questionnaire were excluded for this analysis. This study was approved by the Mass General Brigham Institutional Review Board (protocol number 2016P0000485) and adheres to the principles of the Declaration of Helsinki. All subjects provided written informed consent.
Data collection
All subjects underwent a comprehensive assessment that included a history and physical exam with Disease Activity Score 28-joint count CRP (DAS28-CRP) assessment by a trained physician, high-resolution CT (HRCT) of the chest if one had not been performed for clinical indications within 6 months of the study visit, self-administered respiratory questionnaires, full pulmonary function tests, a 6-min walk test and blood sampling (see Supplementary Material, available at Rheumatology online). Obstruction, restriction and diffusion abnormalities were defined by American Thoracic Society criteria [25]. Data on rheumatoid nodules on exam, Sharp–van der Heijde (SvH) scores from hand radiographs, Multi-Dimensional Health Assessment Questionnaire (MDHAQ) scores and ever medication use were obtained from the BRASS registry.
HRCT image evaluation
HRCT scans were scored for emphysema by a senior thoracic radiologist (R.R.G.) according to the modified Goddard scoring system with scores of 0 categorized as absent, 1–7 as mild, 8–15 as moderate and 16–24 as severe [26, 27]. Images were also evaluated for preclinical ILD via a previously described sequential reading method for interstitial lung abnormalities [5, 28]. The presence of other pulmonary abnormalities was noted, including bronchiectasis, lung nodules, cystic lung disease, infection, pleural disease, mediastinal lymphadenopathy and small airways disease. Additional incidental non-pulmonary radiographic abnormalities were also noted based on safety and clinical radiologist reads (see Supplementary Material, available at Rheumatology online).
Statistical analysis
Cross-sectional analyses comparing presence vs absence of preclinical parenchymal abnormalities were conducted with Fisher’s exact tests and the Wilcoxon rank-sum tests. Data are reported as n (%) or median (interquartile range). Ninety-five per cent CIs of sample proportions were determined by the Wilson–Brown method. Unadjusted and multivariable logistic regression analyses were performed to assess the strength of association (odds ratio [OR]) between preclinical emphysema and variables that were significantly associated with the outcome in bivariate comparisons. Subgroup analyses were performed comparing preclinical emphysema and preclinical ILD with no parenchymal lung disease and were performed excluding individuals with clinical CTs (see Supplementary Material, available at Rheumatology online). Receiver operating characteristic curves were generated to determine the performance characteristics of those predictors of preclinical parenchymal lung disease with statistically significant associations (see Supplementary Material, available at Rheumatology online). Statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA), Stata version 16.1 (StataCorp, College Station, TX, USA) and Prism version 9.2.0 (GraphPad Software, San Diego, CA, USA). P-values <0.05 were considered statistically significant.
Results
One hundred and nine subjects completed a baseline study visit (Supplementary Fig. S1, available at Rheumatology online). Three were excluded from this analysis due to a known COPD diagnosis. Research HRCTs were performed in 92% (n = 97). No clinical CTs were performed for respiratory symptoms (see Supplementary Material and Supplementary Table S1, available at Rheumatology online). Baseline characteristics of all subjects are provided in Table 1. Subjects were older (63 years), predominantly female (78%) and white (96%), with a median RA duration of 17 years and an ever-smoking rate of 45%.
Table 1.
Characteristics of subjects with RA with or without preclinical parenchymal lung disease (emphysema and/or ILD)
| Characteristic | Total (n = 106) | No parenchymal lung disease (n = 58; 55%) | Preclinical parenchymal lung disease (n = 48; 45%) | P-value |
|---|---|---|---|---|
| Demographics | ||||
| Age, median (IQR), years | 63 (55, 71) | 58 (50, 68) | 67 (59, 72) | 0.002 |
| Male sex, n (%) | 23 (22) | 13 (22) | 10 (21) | 1.00 |
| White race, n (%) | 102 (96) | 55 (95) | 47 (98) | 0.62 |
| BMI, median (IQR), kg/m2 | 26 (23, 30) | 25 (22, 30) | 26 (23, 30) | 0.72 |
| Ever smoker, n (%) | 48 (45) | 23 (40) | 25 (52) | 0.24 |
| Current smoker, n (%) | 5 (5) | 4 (7) | 1 (2) | 0.37 |
| Pack-years, median (IQR) | 9 (3, 17) | 5 (1, 16) | 12 (8, 18) | 0.10 |
| RA characteristics | ||||
| RA duration, median (IQR), years | 18 (11, 31) | 17 (11, 30) | 20 (12, 32) | 0.50 |
| Rheumatoid nodules, n (%) | 4 (4) | 2 (3) | 2 (4) | 1.00 |
| CRP, median (IQR), mg/l | 1.6 (0.6, 5.1) | 1.5 (0.6, 4.4) | 2.3 (0.8, 5.3) | 0.26 |
| CCP+, n (%) | 64 (60) | 34 (59) | 30 (63) | 0.70 |
| CCP titre, median (IQR), U/ml | 70 (1, 340) | 31 (2, 279) | 143 (1, 340) | 0.18 |
| RF+, n (%) | 62 (58) | 34 (59) | 28 (58) | 1.00 |
| RF titre, median (IQR), IU/ml | 30 (15, 109) | 23 (15, 95) | 37 (15, 177) | 0.55 |
| RF+ and CCP+, n (%) | 56 (53) | 28 (48) | 28 (58) | 0.33 |
| DAS28-CRP, median (IQR) | 2.1 (1.5, 3.0) | 2.0 (1.4, 2.8) | 2.1 (1.7, 3.0) | 0.26 |
| SvH score, median (IQR) | 6 (0, 30) | 4 (1, 28) | 7 (0, 32) | 0.81 |
| MDHAQ score, median (IQR) | 0.3 (0, 0.7) | 0.2 (0, 0.7) | 0.5 (0, 0.8) | 0.47 |
| Abatacept current, n (%) | 11 (10) | 5 (9) | 6 (13) | 0.54 |
| Methotrexate current, n (%) | 58 (55) | 32 (55) | 26 (54) | 1.00 |
| TNF-α inhibitors current, n (%) | 46 (43) | 27 (47) | 19 (40) | 0.56 |
| Rituximab current, n (%) | 3 (3) | 2 (3) | 1 (2) | 1.00 |
| Steroids current, n (%) | 22 (21) | 11 (19) | 11 (23) | 0.64 |
| Pulmonary characteristics | ||||
| Cough (self-reported), n (%) | 34 (32) | 14 (24) | 20 (42) | 0.06 |
| Dyspnoea (self-reported), n (%) | 8 (8) | 4 (7) | 4 (8) | 1.00 |
| Abnormal pulmonary exam, n (%) | 10 (10) | 4 (7) | 6 (13) | 0.34 |
| FEV1, median (IQR), % predicted | 99 (90, 113) | 100 (93, 115) | 97 (85, 110) | 0.31 |
| FVC, median (IQR), % predicted | 102 (90, 114) | 103 (93, 117) | 99 (86, 114) | 0.22 |
| FEV1/FVC, median (IQR) | 77 (73, 82) | 77 (73, 81) | 77 (71, 82) | 0.51 |
| TLC, median (IQR), % predicted | 103.5 (91.5, 113) | 102 (92, 111) | 105 (90, 114) | 0.78 |
| DLCO, median (IQR), % predicted | 80 (70, 88) | 83 (73, 89) | 77 (66, 86) | 0.04 |
| Obstruction, n (%) | 11 (10) | 4 (7) | 7 (15) | 0.34 |
| Restriction, n (%) | 8 (8) | 3 (5) | 5 (11) | 0.46 |
| Diffusion defect, n (%) | 23 (22) | 8 (14) | 15 (33) | 0.03 |
| 6MWD, median (IQR), m | 468 (389, 549) | 501 (394, 564) | 441 (377, 521) | 0.14 |
| SGRQ score, median (IQR) | 7 (2, 16) | 7 (2, 13) | 10 (2, 21) | 0.22 |
| Preclinical ILD, n (%) | 16 (15) | NA | 16 (33) | NA |
| Preclinical emphysema, n (%) | 38 (36) | NA | 38 (79) | NA |
| Preclinical ILD + emphysema, n (%) | 6 (6) | NA | 6 (13) | NA |
| Bronchiectasis, n (%) | 23 (22) | 7 (12) | 16 (33) | 0.01 |
| Goddard emphysema score, median (IQR) | 0 (0, 5) | NA | 6 (2, 12) | NA |
Data missing: 6MWD (n = 1), CCP (n = 2), CRP/DAS28-CRP (n = 1), DLCO (n = 3), FEV1 and FVC (n = 1), pulmonary exam (n = 4), RF (n = 3), SvH score (n = 22), SGRQ score (n = 2), TLC (n = 2). 6MWD: 6-min walk distance; CCP: cyclic citrullinated peptide; CCP+: CCP values above upper limit of normal; DAS28-CRP: Disease Activity Score-28-CRP; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ILD: interstitial lung disease; IQR: interquartile range; IU: international units; MDHAQ: multidimensional health assessment questionnaire; NA: not applicable; RF+: RF values above upper limit of normal; SGRQ: St George’s Respiratory Questionnaire; SvH: Sharp–van der Heijde; TLC: total lung capacity; U: units.
Overall, 74% (95% CI: 64%, 81%) of subjects had imaging and/or functional abnormalities (Fig. 1). Sixty-five per cent (95% CI: 56%, 73%) had imaging abnormalities, most commonly emphysema (36%) followed by pulmonary nodules (27%), bronchiectasis (22%) and preclinical ILD (15%) (for bronchiectasis data, see Supplementary Material, available at Rheumatology online). Only six individuals had concurrent evidence of both preclinical emphysema and preclinical ILD (see Supplementary Material, available at Rheumatology online). Representative HRCT images of preclinical parenchymal diseases identified in this study are displayed in Fig. 2. Thirty-two per cent (95% CI: 24%, 42%) of subjects had functional abnormalities, most commonly a diffusion defect (22%), followed by obstructive (10%) and restrictive (8%) ventilatory impairments. Incidental non-pulmonary radiographic abnormalities are presented in the Supplementary Material and Supplementary Table S2, available at Rheumatology online.
Fig. 1.
Counts of imaging and functional abnormalities identified in subjects with RA
(A) Counts of any imaging abnormality, functional decrement or the combination of both. (B) Counts of types of pulmonary imaging abnormalities identified. (C) Counts of preclinical parenchymal abnormalities. (D) Counts of abnormalities identified on pulmonary function testing. Data missing: diffusing capacity of the lung for carbon monoxide (n = 3); forced expiratory volume in 1 s and forced vital capacity (n = 1); total lung capacity (n = 2). ILD: interstitial lung disease.
Fig. 2.
Representative images of preclinical parenchymal pulmonary abnormalities identified in subjects with RA
(A, B) Preclinical emphysema. (C, D) Preclinical interstitial lung disease.
Preclinical parenchymal lung disease
Forty-eight (45%; 95% CI: 36%, 55%) subjects had preclinical emphysema and/or preclinical ILD on HRCT (Table 1). These individuals were significantly older with a trend towards increased cumulative pack-years; however, there were no differences by sex, smoking or RA disease characteristics, including duration of disease, current disease activity or immunosuppressive therapy (both current and ever use). Functionally, those with preclinical parenchymal disease had a lower percentage predicted diffusing capacity of the lung for carbon monoxide (%DLCO) and a diffusion defect, but no difference in spirometry. There was a trend towards increased cough but no difference in dyspnoea. Individuals with preclinical parenchymal lung disease were more likely to have bronchiectasis.
Preclinical emphysema
The thirty-eight subjects (36%; 95% CI: 27%, 45%) with preclinical emphysema were significantly older and had a median Goddard emphysema score of 8 (moderate disease) (Table 2). They did not have a significantly different smoking history, but there was a trend towards increased cumulative pack-years among ever smokers. They had significantly higher cyclic citrullinated peptide (CCP) titres, but there were no differences in other RA disease characteristics or immunosuppressive medications (both current and ever use). Functionally, subjects with preclinical emphysema were more likely to have a diffusion defect and trends towards lower %DLCO and reduced forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio. These individuals were also more likely to have bronchiectasis. In unadjusted logistic regression, preclinical emphysema was associated with increased odds of having a diffusion defect (OR 3.03; 95% CI: 1.17, 7.87; P = 0.02). This association persisted with adjustment for age (P = 0.04) and/or bronchiectasis (P = 0.02) but was attenuated with adjustment for CCP (P = 0.09) and in a model including all three covariates (OR 2.74; 95% CI: 0.92, 8.15; P = 0.07). Comparison of characteristics of subjects with preclinical emphysema with those without any preclinical parenchymal lung disease including preclinical ILD (n = 58) resulted in attenuation of the statistically significant association with CCP titre (P = 0.06) despite a persistent large absolute difference in medians (31 vs 181 U/ml); otherwise, all other statistically significant associations remained unchanged (Supplementary Table S3, available at Rheumatology online).
Table 2.
Characteristics of subjects with RA with or without preclinical emphysema
| Characteristic | Preclinical emphysema (n = 38; 36%) | No emphysema (n = 68; 64%) | P-value |
|---|---|---|---|
| Demographics | |||
| Age, median (IQR), years | 67 (60, 73) | 59 (52, 69) | 0.003 |
| Male sex, n (%) | 9 (24) | 14 (21) | 0.81 |
| White race, n (%) | 37 (97) | 65 (96) | 1.00 |
| BMI, median (IQR), kg/m2 | 27 (23, 30) | 25 (22, 30) | 0.65 |
| Ever smoker, n (%) | 20 (53) | 28 (41) | 0.31 |
| Current smoker, n (%) | 1 (3) | 4 (6) | 0.65 |
| Pack-years, median (IQR) | 12 (7, 18) | 6 (2, 14) | 0.09 |
| RA characteristics | |||
| RA duration, median (IQR), years | 22 (12, 32) | 16 (11, 29) | 0.37 |
| Rheumatoid nodules, n (%) | 2 (5) | 2 (3) | 0.62 |
| CRP, median (IQR), mg/l | 2.4 (1.0, 5.3) | 1.5 (0.6, 4.4) | 0.15 |
| CCP+, n (%) | 26 (68) | 38 (56) | 0.22 |
| CCP titre, median (IQR), U/ml | 181 (5, 340) | 24 (1, 279) | 0.04 |
| RF+, n (%) | 24 (63) | 38 (56) | 0.54 |
| RF titre, median (IQR), IU/ml | 43 (15, 139) | 22 (15, 102) | 0.30 |
| RF+ and CCP+, n (%) | 24 (63) | 32 (47) | 0.16 |
| DAS28-CRP, median (IQR) | 2.1 (1.6, 3.0) | 2.0 (1.4, 2.8) | 0.38 |
| SvH score, median (IQR) | 8 (0, 39) | 4 (0, 26) | 0.30 |
| MDHAQ score, median (IQR) | 0.4 (0, 0.8) | 0.2 (0, 0.7) | 0.98 |
| Abatacept current, n (%) | 3 (8) | 8 (12) | 0.74 |
| Methotrexate current, n (%) | 23 (61) | 35 (51) | 0.42 |
| TNF-α inhibitors current, n (%) | 16 (42) | 30 (44) | 1.00 |
| Rituximab current, n (%) | 1 (3) | 2 (3) | 1.00 |
| Steroids current, n (%) | 8 (21) | 14 (21) | 1.00 |
| Pulmonary characteristics | |||
| Cough (self-reported), n (%) | 16 (42) | 18 (26) | 0.13 |
| Dyspnoea (self-reported), n (%) | 3 (8) | 5 (7) | 1.00 |
| Abnormal pulmonary exam, n (%) | 5 (14) | 5 (7) | 0.31 |
| FEV1, median (IQR), % predicted | 96 (85, 109) | 100 (92, 115) | 0.22 |
| FVC, median (IQR), % predicted | 98 (87, 114) | 103 (92, 118) | 0.29 |
| FEV1/FVC, median (IQR) | 75 (70, 81) | 78 (73, 82) | 0.09 |
| TLC, median (IQR), % predicted | 105 (92, 114) | 102 (91, 113) | 0.65 |
| DLCO, median (IQR), % predicted | 77 (64, 87) | 82 (73, 88) | 0.06 |
| Obstruction, n (%) | 6 (16) | 5 (7) | 0.20 |
| Restriction, n (%) | 3 (8) | 5 (8) | 1.00 |
| Diffusion defect, n (%) | 13 (35) | 10 (15) | 0.03 |
| 6MWD, median (IQR), m | 440 (366, 530) | 478 (392, 558) | 0.31 |
| SGRQ score, median (IQR) | 7 (2, 18) | 7 (2, 16) | 0.71 |
| Preclinical ILD, n (%) | 6 (16) | 10 (15) | 1.00 |
| Bronchiectasis, n (%) | 13 (34) | 10 (15) | 0.03 |
| Goddard emphysema score, median (IQR) | 8 (4, 12) | NA | NA |
Data missing: 6MWD (n = 1), CCP (n = 2), CRP/DAS28-CRP (n = 1), DLCO (n = 3), FEV1/FVC (n = 1), pulmonary exam (n = 4), RF (n = 3), SvH score (n = 22), SGRQ score (n = 2), TLC (n = 2). 6MWD: 6-min walk distance; CCP: cyclic citrullinated peptide; CCP+: CCP values above upper limit of normal; DAS28-CRP: Disease Activity Score-28-CRP; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ILD: interstitial lung disease; IQR: interquartile range; IU: international units; MDHAQ: multidimensional health assessment questionnaire; NA: not applicable; RF+: RF values above upper limit of normal; SGRQ: St George’s Respiratory Questionnaire; SvH: Sharp–van der Heijde; TLC: total lung capacity; U: units.
Eighteen (47%) of the 38 subjects with preclinical emphysema were never smokers, representing a prevalence of emphysema in never smokers of 31% (95% CI: 21%, 44%; Table 3). Never smokers with emphysema were younger and had a higher %DLCO than smokers with emphysema; however, their median Goddard emphysema score (7) did not significantly differ from smokers with emphysema (9). There were no significant differences in RA-specific disease characteristics or in pulmonary symptoms although there was a trend towards lower St George’s Respiratory Questionnaire scores in never smokers. The morphology of emphysema in never smokers differed from smokers, as there was a higher proportion of panlobular destruction and a lower proportion of centrilobular destruction (Supplementary Fig. S2, available at Rheumatology online). There was no difference in the distribution of emphysema between never and ever smokers except a trend towards extension of emphysema below the main carina in ever smokers (Supplementary Table S4, available at Rheumatology online).
Table 3.
Characteristics of subjects with RA and preclinical emphysema stratified by smoking status for never smokers (N=58) and ever smokers (N=48)
| Characteristic | Never Smokers with Preclinical emphysema N=18 (31%) | Ever Smokers with Preclinical emphysema N=20 (42%) | P-value |
|---|---|---|---|
| Demographics | |||
| Age, median (IQR), years | 65 (59, 68) | 71 (63, 76) | 0.02 |
| Male sex, n (%) | 5 (28) | 4 (20) | 0.71 |
| White race, n (%) | 18 (100) | 19 (95) | 1.00 |
| BMI, median (IQR), kg/m2 | 26 (24, 31) | 28 (23, 29) | 0.81 |
| Current smoker, n (%) | NA | 1 (5) | NA |
| Pack-years, median (IQR) | NA | 12 (8, 18) | NA |
| RA characteristics | |||
| RA duration, median (IQR), years | 24 (15, 32) | 18 (11, 30) | 0.62 |
| Rheumatoid nodules, n (%) | 1 (6) | 1 (5) | 1.00 |
| CRP, median (IQR), mg/l | 2.5 (1.2, 4.9) | 2.3 (0.7, 5.8) | 0.86 |
| CCP+, n (%) | 11 (61) | 15 (75) | 0.30 |
| CCP titre, median (IQR), U/ml | 110 (1, 340) | 340 (12, 340) | 0.28 |
| RF+, n (%) | 10 (56) | 14 (70) | 0.31 |
| RF titre, median (IQR), IU/ml | 28 (15, 77) | 48 (21, 192) | 0.26 |
| RF+ and CCP+, n (%) | 10 (56) | 14 (70) | 0.31 |
| DAS28-CRP, median (IQR) | 2.0 (1.6, 2.8) | 2.3 (1.7, 3.1) | 0.42 |
| SvH score, median (IQR) | 20 (3, 33) | 6 (0, 52) | 0.64 |
| MDHAQ score, median (IQR) | 0.3 (0, 1.0) | 0.4 (0, 0.6) | 0.95 |
| Abatacept current, n (%) | 1 (6) | 2 (10) | 1.00 |
| Methotrexate current, n (%) | 9 (50) | 14 (70) | 0.32 |
| TNF-α inhibitors current, n (%) | 6 (33) | 10 (50) | 0.34 |
| Rituximab current, n (%) | 0 (0) | 1 (5) | 1.00 |
| Steroids current, n (%) | 5 (28) | 3 (15) | 0.44 |
| Pulmonary characteristics | |||
| Cough (self-reported), n (%) | 5 (28) | 11 (55) | 0.11 |
| Dyspnoea (self-reported), n (%) | 1 (6) | 2 (10) | 1.00 |
| Abnormal pulmonary exam, n (%) | 2 (11) | 3 (15) | 1.00 |
| FEV1, median (IQR), % predicted | 97 (87, 109) | 96 (76, 105) | 0.48 |
| FVC, median (IQR), % predicted | 103 (89, 113) | 95 (86, 113) | 0.46 |
| FEV1/FVC, median (IQR) | 78 (73, 82) | 74 (69, 77) | 0.10 |
| TLC, median (IQR), % predicted | 107 (91, 112) | 103 (94, 115) | 0.72 |
| DLCO, median (IQR), % predicted | 85 (71, 90) | 71 (60, 78) | 0.02 |
| Obstructive spirometry, n (%) | 1 (6) | 5 (25) | 0.18 |
| Restrictive spirometry, n (%) | 3 (17) | 0 0 | 0.10 |
| Diffusion defect, n (%) | 5 (28) | 8 (40) | 0.50 |
| 6MWD, median (IQR), m | 471 (397, 522) | 434 (363, 550) | 1.00 |
| SGRQ score, median (IQR) | 5 (0, 13) | 12 (5, 23) | 0.07 |
| Preclinical ILD, n (%) | 1 (6) | 5 (25) | 0.18 |
| Bronchiectasis, n (%) | 5 (28) | 8 (40) | 0.51 |
| Goddard emphysema score, median (IQR) | 7 (4, 12) | 9 (5, 12) | 0.48 |
Data missing: CCP (n = 1), DLCO (n = 1), pulmonary exam (n = 2), RF (n = 1), SGRQ score (n = 1), SvH score (n = 6), TLC (n = 1). 6MWD: 6-min walk distance; CCP: cyclic citrullinated peptide; CCP+: CCP values above upper limit of normal; DAS28-CRP: Disease Activity Score-28-CRP; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ILD: interstitial lung disease; IU: international units; MDHAQ: multidimensional health assessment questionnaire; NA: not applicable; RF+: RF values above upper limit of normal; SvH: Sharp–van der Heijde; SGRQ: St George’s Respiratory Questionnaire; TLC: total lung capacity; U: units.
When stratified by severity of preclinical emphysema (Supplementary Table S5, available at Rheumatology online), subjects with moderate or severe emphysema (Goddard score ≥8) compared with mild or no emphysema were significantly older and more likely to have a cough and had a trend towards less likely to be taking steroids. They were also more likely to have higher CCP titres, a lower FEV1/FVC ratio, comorbid bronchiectasis, and a trend towards a lower %FEV1 and %DLCO. In a model adjusting for bronchiectasis, the effect of moderate or severe emphysema on cough remained significant (P = 0.03), but the association with FEV1/FVC ratio was attenuated (P = 0.09).
Preclinical interstitial lung disease
Sixteen subjects (15%; 95% CI: 10%, 23%) had preclinical ILD (Table 4). Although not statistically significant, those with preclinical ILD tended to be older with a history of smoking and tended to have higher CCP and RF titres. There was no association between preclinical ILD and sex, RA disease characteristics, medications including methotrexate (both current and ever use), cough, dyspnoea, an abnormal pulmonary exam or any functional abnormalities. Comparison of characteristics of subjects with preclinical ILD with those without any preclinical parenchymal lung disease including those with preclinical emphysema (n = 58) resulted in an emergence of an association with age (P = 0.03) (Supplementary Table S3, available at Rheumatology online). Of the 16 with preclinical ILD, nine (56%) had subpleural changes, while seven (44%) had mixed subpleural and centrilobular changes. Those with subpleural changes were more likely to be ever smokers when compared with those with mixed changes (100% vs 33%; P = 0.01).
Table 4.
Characteristics of subjects with RA with or without preclinical interstitial lung disease
| Characteristic | Preclinical ILD (n = 16; 15%) | No ILD (n = 90; 85%) | P-value |
|---|---|---|---|
| Demographics | |||
| Age, median (IQR), years | 66 (58, 74) | 62 (54, 70) | 0.18 |
| Male sex, n (%) | 3 (19) | 20 (22) | 1.00 |
| White race, n (%) | 16 (100) | 86 (96) | 1.00 |
| BMI, median (IQR), kg/m2 | 26 (23, 31) | 26 (22, 30) | 0.73 |
| Ever smoker, n (%) | 10 (63) | 38 (42) | 0.18 |
| Current smoker, n (%) | 0 (0) | 5 (6) | 1.00 |
| Pack-years, median (IQR) | 10 (1, 13) | 9 (3, 18) | 0.60 |
| RA characteristics | |||
| RA duration, median (IQR), years | 18 (12, 27) | 18 (11, 32) | 0.75 |
| Rheumatoid nodules, n (%) | 1 (6) | 3 (3) | 0.49 |
| CRP, median (IQR), mg/l | 1.8 (0.7, 4.2) | 1.6 (0.6, 5.1) | 0.81 |
| CCP+, n (%) | 10 (63) | 54 (60) | 1.00 |
| CCP titre, median (IQR), U/ml | 264 (1, 340) | 56 (1, 319) | 0.31 |
| RF+, n (%) | 10 (63) | 52 (58) | 0.79 |
| RF titre, median (IQR), IU/ml | 40 (15, 319) | 29 (15, 99) | 0.39 |
| RF+ and CCP+, n (%) | 10 (63) | 46 (51) | 0.43 |
| DAS28-CRP, median (IQR) | 1.8 (1.6, 2.7) | 2.1 (1.5, 3.0) | 0.86 |
| SvH score, median (IQR) | 4 (0, 21) | 6 (0, 31) | 0.58 |
| MDHAQ score, median (IQR) | 0.6 (0, 0.7) | 0.2 (0, 0.7) | 0.43 |
| Abatacept current, n (%) | 3 (19) | 8 (9) | 0.37 |
| Methotrexate current, n (%) | 7 (44) | 51 (57) | 0.42 |
| TNF-α inhibitors current, n (%) | 7 (44) | 39 (43) | 1.00 |
| Rituximab current, n (%) | 0 (0) | 3 (3) | 1.00 |
| Steroids current, n (%) | 4 (25) | 18 (20) | 0.74 |
| Pulmonary characteristics | |||
| Cough (self-reported), n (%) | 6 (38) | 28 (31) | 0.77 |
| Dyspnoea (self-reported), n (%) | 1 (6) | 7 (8) | 1.00 |
| Abnormal pulmonary exam, n (%) | 1 (6) | 9 (10) | 1.00 |
| FEV1, median (IQR), % predicted | 100 (84, 110) | 99 (90, 115) | 0.82 |
| FVC, median (IQR), % predicted | 94 (86, 111) | 103 (92, 114) | 0.23 |
| FEV1/FVC, median (IQR) | 81 (73, 83) | 77 (73, 81) | 0.16 |
| TLC, median (IQR), % predicted | 99 (81, 110) | 104 (94, 113) | 0.29 |
| DLCO, median (IQR), % predicted | 80 (68, 83) | 80 (71, 88) | 0.41 |
| Obstruction, n (%) | 2 (13) | 9 (10) | 0.67 |
| Restriction, n (%) | 2 (13) | 6 (7) | 0.32 |
| Diffusion defect, n (%) | 4 (29) | 19 (21) | 0.51 |
| 6MWD, median (IQR), m | 461 (397, 541) | 469 (389, 549) | 0.96 |
| SGRQ score, median (IQR) | 12 (5, 26) | 7 (2, 16) | 0.16 |
| Preclinical emphysema, n (%) | 6 (38) | 32 (36) | 1.00 |
| Bronchiectasis, n (%) | 4 (25) | 19 (21) | 0.75 |
| Goddard emphysema score, median (IQR) | 0 (0, 5) | 0 (0, 5) | 1.00 |
Data missing: 6MWD (n = 1), CCP (n = 2), CRP/DAS28-CRP (n = 1), DLCO (n = 3), FEV1/FVC (n = 1), pulmonary exam (n = 4), RF (n = 3), SvH score (n = 22), SGRQ score (n = 2), TLC (n = 2). 6MWD: 6-min walk distance; CCP: cyclic citrullinated peptide; CCP+: CCP values above upper limit of normal; DAS28-CRP: Disease Activity Score-28-CRP; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ILD: interstitial lung disease; IQR: interquartile range; IU: international units; MDHAQ: multidimensional health assessment questionnaire; NA: not applicable; RF+: RF values above upper limit of normal; SGRQ: St George’s Respiratory Questionnaire; SvH: Sharp–van der Heijde; TLC: total lung capacity; U: units.
Discussion
We describe a high prevalence of preclinical parenchymal lung disease in RA (45%) among subjects without known ILD or COPD. This was primarily driven by a previously unreported significant burden of preclinical emphysema (36%) unrelated to smoking history. Preclinical ILD (15%) was less common than previous reports but higher than what has been observed in the general population and other at-risk populations, such as smokers [29]. This suggests that emphysema may be the most common pulmonary manifestation of RA. To the best of our knowledge, this is the most comprehensive prospective study of preclinical parenchymal lung disease in patients with RA and the first to examine isolated emphysema in a RA population. HRCT may be the most effective currently available screening tool for early detection of parenchymal lung disease in RA.
The high prevalence of preclinical emphysema in patients with RA is novel and may have direct clinical relevance. Although no prior studies have investigated isolated parenchyma-based emphysema in RA, there are data suggesting that RA is associated with an increased risk for more broadly defined incident COPD (hazard ratio 1.52–2.61) inclusive of airways disease and that the risk of developing airway-based obstructive lung disease is highest among males, smokers and those with severe RA [11, 30–32]. In our study, subjects with RA and emphysema were older, but there was no association with male sex, RA severity or smoking history. Of significance, our subjects were more likely to have a diffusion defect on functional testing, and those with moderate or severe emphysema were more likely to have a cough. Although it is not clear at what point a patient with preclinical emphysema becomes symptomatic or has increased risk of disease progression or complications, our results suggest that some of these individuals were already symptomatic and functionally impaired. The importance of early diagnosis of emphysema is underscored by reports that patients with RA and broadly defined COPD have an increased rate of hospitalization and 10-year mortality compared with COPD patients without RA and that incidental emphysema on CT scans in the general population was a strong independent predictor of COPD exacerbations resulting in hospitalization or death [16, 17, 19, 20]. More studies are needed to identify non-invasive methods to recognize preclinical emphysema in the RA population and to define the threshold of clinically relevant disease.
In our study, the presence of preclinical emphysema in subjects with RA was not associated with a history of smoking, and almost half of the emphysema identified occurred in never smokers. Stated differently, nearly one out of three never smokers in our cohort with RA had preclinical emphysema, which to our knowledge has not been previously reported. Never smokers with emphysema were younger and had higher %DLCO measurements than ever smokers. Otherwise, there were no other significant differences in RA-specific or pulmonary-specific characteristics—most notably emphysema severity by Goddard score—between the subgroups with emphysema stratified by smoking history. An interesting difference between never and ever smokers with emphysema was that never smokers predominantly had panlobular emphysematous morphology, possibly associated with immune aetiologies [33], while ever smokers were more likely to have the classic smoking-related centrilobular morphology.
We found that a significant proportion of never smokers with preclinical emphysema were younger and had a different radiographic morphology than their ever-smoking counterparts suggesting that RA may be an independent risk factor for emphysema. Never smokers with RA may have a different mechanism by which emphysematous destruction of alveoli occurs, especially given that COPD has been linked to chronic inflammation, autoimmunity and the presence of citrullinated peptides, as well as being associated with incident RA [34–36]. It is possible that RA predisposes patients to the development of emphysema or, alternatively, that RA pathogenesis may start in the lungs at inflamed mucosae [36, 37]. Increased CCP titres noted in our subjects with preclinical emphysema further support this hypothesis. As smoking is a well-documented risk factor for emphysema and has also been associated with increased disease activity in RA and the development of CCP [38, 39], we want to strongly emphasize the importance of smoking cessation in this population.
Preclinical ILD has been previously shown to have prevalence of 33–61% with disease progression noted in up to 57% of patients with RA [5–9]. Previous studies have suggested several risk factors, including older age, male sex, smoking history, RA disease activity and positive serologies for CCP or RF [5, 40, 41]. Substantial heterogeneity exists among these studies in the populations studied, sample size, diagnostic criteria for preclinical ILD and imaging modality employed, with an overwhelming majority utilizing retrospective analyses of clinically indicated chest imaging. Our prospective screening study suggests that preclinical ILD is less prevalent than previously reported and cannot be reliably identified by symptoms, physical exam, or laboratory or pulmonary function test abnormalities. We propose that HRCT may be the only reliable clinical screening tool currently available to identify preclinical ILD in patients with RA. Future studies should focus on identifying more sensitive markers of disease in addition to risk factors for progressive disease given the possible benefits of early intervention, especially with the recent availability of antifibrotic medications to treat progressive fibrotic ILD in individuals with autoimmune diseases such as RA [42].
Our study has several limitations. (i) It is possible that there is selection bias. Healthier subjects that were already part of BRASS may have been more likely to participate, which may underestimate the prevalence of preclinical emphysema and ILD. Furthermore, as subjects had a median duration of RA of 17 years, our study may have excluded individuals who developed symptomatic parenchymal lung disease earlier in their disease course and may have further biased the study towards a healthier population. Alternatively, subjects at higher risk for parenchymal lung disease or with symptoms may have self-selected for this study, possibly overestimating the prevalence of lung disease. (ii) Although this would be the largest prospective screening study in RA published to date, our small number of subjects with preclinical ILD may have resulted in an underpowered study to find true associations; however, it is notable that our study suggests the prevalence may be less than previously reported in the literature. Future research studies may require enrolment of larger sample size to have the power to identify associations. (iii) A portion of subjects may have had a history of COPD that was not reflected in the electronic medical record/physician questionnaire or a history of ILD that was not reflected on patient/physician reports who would be misclassified as having undiagnosed parenchymal lung disease. (iv) As a single centre study with a predominantly white and female cohort, the generalizability of our results may be limited, especially in the absence of external validation. Nevertheless, the BRASS parent cohort from which our subjects were recruited has reasonable generalizability to other RA populations, as the median age (57 years), proportion female (82%), new-onset RA (20%) and high functional status (82%) are very similar to RA patients in the Consortium of Rheumatology Researchers of North America (CORRONA) registry (59 years, 75%, 20% and 88%, respectively) [43, 44]. Similarly, about 62% of BRASS subjects are seropositive, which is similar to what has been reported in other RA studies [45, 46].
In summary, the results of this study indicate that there is a high prevalence of preclinical parenchymal lung disease in RA. Emphysema was the most prevalent, even among never smokers, perhaps making it the most common pulmonary manifestation of RA. As clinical, laboratory and functional testing were not associated with preclinical ILD, HRCT may be the most effective screening modality currently available to detect the spectrum of parenchymal lung disease in RA. Further studies are required to establish the clinical significance of these preclinical parenchymal abnormalities, to determine the optimal approach to detect undiagnosed disease, and to characterize the subset of patients who progress and may benefit from early intervention.
Supplementary Material
Acknowledgements
We offer our sincere thanks to the patients with RA who participated and to the staff of BRASS and the Arthritis Center at Brigham and Women’s Hospital for their efforts in this study.
Funding: This work was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [F32 HL151132 to A.J.E.; R01 HL111024, R01 HL135142, and R01 HL130974 to H.H.; and K23 HL119558 and R03 HL148484 to T.J.D.]; the National Cancer Institute at the National Institutes of Health [R01 CA203636 and U01 CA209414 to H.H.]; the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health [K23 AR069688 and R03 AR075886 to J.A.S.]; and the Rheumatology Research Foundation [Career Development Bridge Funding Award: R Bridge Award to J.A.S. BRASS is funded by grants from Bristol Myers Squibb, Amgen, Crescendo Bioscience, and Sanofi/Regeneron.
Disclosure statement: J.A.S. reports personal fees from Bristol Myers Squibb, Amgen, Janssen, Optum and Gilead, unrelated to this study. R.R.G. reports research support from Cannon Inc. H.H. reports grant funding from Canon Medical System, Inc. and Konica-Minolta, Inc. and personal fees from Mitsubishi Chemical, Inc. and Canon Medical System, Inc., unrelated to this study. C.K.I. reports funding from CRICO/Risk Management Foundation of the Harvard Medical Institutions and IBM. P.F.D. participates in clinical trials sponsored by Genentech and Bristol Myers Squibb. M.E.W. reports grant funding from Amgen, Bristol Myers Squibb, Sanofi and Eli Lilly; personal fees from Amgen, Bristol Myers Squibb, Sanofi, Eli Lilly, Abbvie, Arena Pharmaceuticals, GlaxoSmithKline, Horizon Therapeutics, Pfizer, Novartis, Roche and Corevitas; and other funding from Scipher Medicine, Can-Fite Biopharma, Inmedix and VersaPharm, unrelated to this study. N.A.S. reports grant funding from Bristol Myers Squibb, Sanofi, Amgen, Crescendo Bioscience, Eli Lilly and Mallinckrodt Pharmaceuticals and personal fees from Bristol Myers Squibb, unrelated to this study. I.O.R. reports grant funding from Genentech, unrelated to this study. T.J.D. reports grant funding and other support from Bristol Myers Squibb and Genentech and personal fees from Boehringer Ingelheim and LEK Consulting, unrelated to this study. A.J.E., E.J.M., P.H., S.P., E.A.F., W.X., M.L.F., M.P., A.Z. and A.M. have nothing to disclose.
Contributor Information
Anthony J Esposito, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
Jeffrey A Sparks, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Ritu R Gill, Department of Radiology, Beth Israel Deaconess Medical Center.
Hiroto Hatabu, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Eric J Schmidlin, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Partha V Hota, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Sergio Poli, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Elaine A Fletcher, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Wesley Xiong, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Michelle L Frits, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Christine K Iannaccone, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Maria Prado, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Alessandra Zaccardelli, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Allison Marshall, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Paul F Dellaripa, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Michael E Weinblatt, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Nancy A Shadick, Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital.
Ivan O Rosas, Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA.
Tracy J Doyle, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Data availability statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. Data are available on reasonable request from the corresponding author after approval from the BRASS Scientific Advisory Board.
Supplementary data
Supplementary data are available at Rheumatology online.
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Supplementary Materials
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. Data are available on reasonable request from the corresponding author after approval from the BRASS Scientific Advisory Board.