Clinical characteristics associated with small airways disease in systemic sclerosis

Abstract

Objective:

Pulmonary manifestations of systemic sclerosis are a major cause of morbidity and mortality. Small airways disease can cause dyspnea and pulmonary function test abnormalities. We aimed to determine the prevalence of small airways disease and describe the characteristics associated with small airways disease in a cohort of systemic sclerosis patients.

Methods:

We performed a retrospective cohort study of adults with systemic sclerosis who met American College of Rheumatology/European League Against Rheumatism 2013 classification criteria and were evaluated at our institution between November 2000 and November 2015. Patients with prior lung transplantation were excluded. Small airways disease was defined as the presence of one or more of the following: airway-centered fibrosis on surgical lung biopsy, forced expiratory volume at 25–75% ⩽ 50% on pulmonary function tests, and/or high-resolution computed tomography scan of the chest with bronchiolitis, mosaic attenuation, or air trapping on expiratory views. The primary outcome was small airways disease diagnosis. We performed multivariable logistic regression to determine the association of clinical variables with small airways disease.

Results:

One-hundred thirty-six systemic sclerosis patients were included; 55 (40%) had small airways disease. Compared to those without small airways disease, a significantly greater proportion of those with small airways disease had interstitial lung disease, chronic obstructive pulmonary disease, pulmonary hypertension, and gastroesophageal reflux disease. On multivariable analysis, pulmonary hypertension (odds ratio = 2.91, 95% confidence interval = 1.11–7.65, p-value = 0.03), gastroesophageal reflux disease (odds ratio = 2.70, 95% confidence interval = 1.08–6.79, p-value = 0.034), and anti-topoisomerase I (anti-Scl-70) antibody positivity (odds ratio = 0.42, 95% confidence interval = 0.19–0.93, p-value = 0.033) were associated with diagnosis of small airways disease.

Conclusion:

Small airways disease is prevalent among systemic sclerosis patients; those with pulmonary hypertension or gastroesophageal reflux disease may have a higher risk of small airways disease.

Introduction

Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease characterized by inflammation, vasculopathy, and fibrosis. ¹ Interstitial lung disease (ILD) and pulmonary hypertension (PH) are the two most common pulmonary manifestations of SSc and are a significant cause of morbidity and mortality in this population. Parenchymal lung involvement appears soon after SSc diagnosis and up to 25% of these patients develop the clinically significant disease within 3 years. ² While many patients with SSc have restrictive ventilatory disease due to the presence of ILD, obstruction of the peripheral airways (i.e. small airways disease (SAD)) is a lesser known pulmonary complication of SSc and can contribute significantly to dyspnea and abnormalities on pulmonary function testing (PFTs).^2–4

The small airways are defined as those less than 2 mm in diameter and their obstruction may lead to reduction in airflow, increased airways resistance, gas trapping, and inhomogeneity of ventilation. ⁵ Autopsies in patients with SSc reveal obstructive changes, including atrophy, fibrosis, and variable amounts of inflammation in the smallest bronchi as well as in the bronchioles. ⁶ SAD encompasses a generally poorly understood group of lung diseases that may arise primarily within the small airways or secondarily from disease affecting the bronchi or lung parenchyma. There are several physiological and imaging techniques used to assess the small airways. Autopsy and biopsy remain the most reliable methods for identifying SAD, although noninvasive techniques, such as spirometry and high-resolution computed tomography (HRCT) scan of the chest, have also been utilized to evaluate for and diagnose SAD.^5,7,8

The clinical characteristics associated with SAD in SSc remain unknown. The aims of this study were to determine the prevalence of SAD and to describe the clinical characteristics associated with SAD in a contemporary cohort of adults with SSc.

Methods

Participants

We performed a retrospective cohort study of adults with SSc who were evaluated at Columbia University Irving Medical Center (CUIMC) between November 2000 and November 2015. Data were extracted from the electronic medical record (EMR). SSc patients were identified by International Classification of Diseases Clinical Modification, 9th Revision (ICD-9) code 710.1 and SSc diagnosis was confirmed by chart review. ⁹ Patients were included if they were at least 18 years of age and met American College of Rheumatology/European League Against Rheumatism 2013 Classification Criteria for SSc. ¹⁰ Patients were excluded if they had previously undergone lung transplantation, were deceased, or did not have either one of PFTs, HRCT, or surgical lung biopsy. This study was approved by the Institutional Review Board (#AAAR4202) at Columbia University Irving Medical Center.

Primary outcome

The primary outcome was diagnosis of SAD, which was defined as the presence of at least one of the following: (1) airway-centered fibrosis on surgical lung biopsy, defined as fibrosis of the respiratory bronchioles and peribronchiolar interstitium, ¹¹ (2) forced expiratory flow (FEF) at 25–75% ⩽ 50% predicted on the most recent set of PFTs,^12–14 and (3) HRCT findings of bronchiolitis (defined as centrilobular micronodules, bronchial wall thickening, and/or bronchiolar dilatation), mosaic attenuation, or air trapping on expiratory views.

Covariates

The following covariates were extracted from the EMR: age, sex, smoking status, comorbid diagnoses, immuno-modulators at the time of data collection (azathioprine, oral corticosteroids, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, rituximab, tacrolimus), other medications at the time of data collection (inhaled corticosteroids, inhaled bronchodilators, and proton-pump inhibitors (PPIs)), and history of positive autoantibodies (antinuclear antibody (ANA), anti-centromere antibody (ACA), anti-topoisomerase I (anti-Scl-70) antibody (ATA), and anti-RNA polymerase III antibody (ARA)) at any time during disease course. Comorbidities of interest included ILD, PH, chronic obstructive pulmonary disease (COPD), asthma, gastroesophageal reflux disease (GERD), gastroparesis (defined by gastric emptying study as ⩾ 10% of the meal remaining in the stomach after 4 h), and esophageal dysmotility (defined by esophagram). ILD was defined radiographically by the presence of a combination of honeycombing, reticular changes, traction bronchiectasis, and ground-glass opacification on HRCT interpreted by expert thoracic radiologists at CUIMC. PH was defined as mean pulmonary arterial pressure ⩾ 25 mmHg on right heart catheterization, or estimated pulmonary artery systolic pressure > 40 mmHg on transthoracic echocardiogram. ¹⁵ Diagnosis of GERD was confirmed by chart review of documented diagnosis and/or use of proton-pump inhibitor. Diagnoses of COPD (documented spirometry with post-bronchodilator FEV1 (forced expiratory volume)/FVC (forced vital capacity) ratio < 0.7) and asthma (documented airflow obstruction in spirometry with FEV1/FVC ratio < 0.7) were confirmed by chart documentation.

Statistical approach

We compared baseline characteristics between patients with and without SAD. Categorical variables were compared using chi-square test and Fisher’s exact test as appropriate. For continuous variables, means and standard deviations (SDs) were computed if data were normally distributed, and medians and interquartile ranges if data were skewed. Differences in means were calculated using the Student’s t test and differences in medians were compared using the Wilcoxon rank-sum test. We performed univariate analyses to evaluate the relationship between covariates of interest and SAD. We then performed multivariable logistic regression to determine which covariates were independently associated with SAD. All of the covariates that attained a p-value ⩽ 0.05 in the univariate analyses were included in the final logistic regression model, as were age, sex, and smoking status. We also performed a sensitivity analysis in which we excluded patients who were diagnosed with SAD solely based on HRCT findings, given that mosaic attenuation may also be seen on HRCT in those with PH. All analyses were performed using STATA version 13.1 (College Station, TX, USA).

Results

Of the 153 charts reviewed, 136 patients met inclusion criteria. Of the 136 participants with SSc included in this study, the majority were female (88%) and the mean age was 61 (SD = 16) years at the time of analysis (Table 1). The majority of patients had the limited cutaneous subtype (77%). GERD was the most common comorbidity identified (56%), followed by ILD (48%), PH (25%), and esophageal dysmotility (14%). Only 3% of patients were diagnosed with COPD and 3% with asthma. No patients had gastroparesis. Thirty-four percent were taking mycophenolate mofetil, 27% oral corticosteroids, 24% bronchodilators, 17% hydroxychloroquine, and 11% inhaled corticosteroids. Of the patients with available serologies, 93% (119/127) were positive for ANA, 38% for ACA (48/125), 24% for ATA (29/121), and 19% (15/78) for ARA. Forty percent met criteria for SAD.

Table 1.

Baseline demographics and clinical characteristics.

	Total (N = 136)	SAD (n = 55)	No SAD (n = 81)	p-value
Age, mean (SD)	61 (16)	62 (15)	61 (17)	0.58
Sex				0.28
Female	120 (88%)	51 (93%)	69 (85%)
Male	16 (12%)	4 (7%)	12 (15%)
Smoking status				<0.001
Never smoker	92 (68%)	33 (60%)	59 (73%)
Former smoker	32 (24%)	10 (18%)	22 (27%)
Current smoker	12 (9%)	12 (22%)	0 (0%)
Pulmonary function tests
Spirometry and diffusion capacity, mean (SD), N = 101
FEF 25–75%	74 (36)	57 (36)	92 (32)	<0.001
FEV1 %	73 (23)	68 (22)	78 (24)	0.08
FVC %	74 (24)	73 (24)	75 (23)	0.78
FEV1/FVC ratio	90 (14)	88 (16)	93 (13)	0.15
DLCO	44 (22)	41 (20)	47 (23)	0.22
Lung volumes, mean (SD), N = 69
TLC, absolute	3.96 (1.35)	3.94 (1.15)	3.99 (1.58)	0.89
TLC, percent predicted	78 (23)	78 (20)	78 (27)	0.93
RV, absolute	1.46 (0.81)	1.42 (0.58)	1.50 (1.02)	0.70
RV, percent predicted	78 (37)	77 (24)	79 (49)	0.78
RV/TLC, absolute	0.37 (0.09)	0.37 (0.08)	0.37 (0.10)	0.70
Comorbid diagnoses
Interstitial lung disease	65 (48%)	32 (58%)	33 (41%)	0.046
Chronic obstructive pulmonary disease	4 (3%)	4 (7%)	0 (0%)	0.03
Asthma	4 (3%)	1 (2%)	3 (4%)	0.67
Pulmonary hypertension	34 (25%)	20 (36%)	14 (17%)	0.01
Gastroesophageal reflux disease	76 (56%)	40 (73%)	36 (44%)	0.001
Esophageal dysmotility	19 (14%)	11 (20%)	8 (10%)	0.10
Immunomodulators at the time of data collection
Azathioprine	2 (2%)	1 (2%)	1 (2%)	0.77
Oral corticosteroids	37 (27%)	17 (31%)	20 (25%)	0.42
Cyclophosphamide	0 (0%)	0 (0%)	0 (0%)	1.00
Hydroxychloroquine	18 (17%)	6 (15%)	12 (19%)	0.56
Methotrexate	3 (3%)	1 (2%)	2 (3%)	0.81
Mycophenolate mofetil	36 (34%)	13 (31%)	23 (37%)	0.56
Rituximab	1 (1%)	1 (2%)	0 (0%)	0.22
Tacrolimus	3 (3%)	2 (5%)	1 (2%)	0.34
Scleroderma characteristics
Subtype, N = 119				0.72
Diffuse	27 (23%)	11 (24%)	16 (22%)
Limited	92 (77%)	34 (76%)	58 (78%)
Skin thickening, N = 119	57 (48%)	25 (56%)	32 (43%)	0.19
Raynaud, N = 119	106 (89%)	43 (96%)	63 (85%)	0.08
Digital ulcers, N = 119	45 (38%)	16 (36%)	29 (39%)	0.69
Telangiectasias, N = 119	57 (48%)	28 (62%)	29 (39%)	0.02
Other medications at the time of data collection
Inhaled corticosteroids	15 (11%)	7 (13%)	8 (10%)	0.60
Inhaled bronchodilators	32 (24%)	19 (35%)	13 (16%)	0.01
Positive autoantibodies
Antinuclear antibody, N = 127	119 (93%)	50 (93%)	69 (93%)	0.58
Anti-centromere antibody, N = 125	48 (38%)	21 (39%)	27 (38%)	0.92
Anti-topoisomerase I (anti-Scl-70) antibody, N = 121	29 (24%)	10 (19%)	19 (28%)	0.25
Anti-RNA polymerase III antibody, N = 78	15 (19%)	7 (19%)	8 (20%)	0.95

SAD: small airways disease; SD: standard deviations; FEF: forced expiratory flow; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffusing capacity for carbon monoxide; TLC: total lung capacity; RV: residual volume.

Of the 55 participants with SAD (Table 1), 93% were female and 40% were either current or former smokers. There were no significant differences in age or sex between those with and without SAD. A greater proportion of patients with SAD than those without were current smokers (22% vs 0%, p-value < 0.01) and had comorbid ILD (58% vs 41%, p-value = 0.046), COPD (7% vs 0%, p-value = 0.03), PH (36% vs 17%, p-value = 0.01), and GERD (73% vs 44%, p-value = 0.001).

The majority of patients with SAD met only 1 of the 3 SAD criteria, most commonly the PFT criterion (Table 2). Eleven percent met both the PFT and HRCT criteria, while only 4% met both the biopsy and HRCT criteria. There were no patients diagnosed by all three modalities.

Table 2.

Percentage of participants meeting each diagnostic criterion for SAD.

SAD diagnostic criteria	N = 55
PFTs	32 (58%)
HRCT	25 (45%)
Biopsy	6 (11%)
PFTs only	26 (47%)
HRCT only	17 (31%)
Biopsy only	4 (7%)
PFTs + HRCT	6 (11%)
PFTs + Biopsy	0 (0%)
HRCT + Biopsy	2 (4%)
HRCT + Biopsy + PFTs	0 (0%)

SAD: small airways disease; PFT: pulmonary function test; HRCT: high-resolution computed tomography.

In univariate analyses, the following comorbidities and medications were positively associated with a diagnosis of SAD: ILD (odds ratio (OR) = 2.02, 95% confidence interval (CI) = 1.01–4.06, p-value = 0.047), PH (OR = 2.73, 95% CI = 1.23–6.06, p-value = 0.01), GERD (OR = 3.33, 95% CI = 1.59–6.97, p-value = 0.001), and use of bronchodilators (OR = 2.76, 95% CI = 1.22–6.22, p-value = 0.01; Table 3). ATA positivity was inversely associated with a diagnosis of SAD (OR = 0.48, 95% CI = 0.27–0.87, p-value = 0.02). The multivariable-adjusted logistic regression model included age, sex, smoking status, ILD, PH, GERD, use of bronchodilators, and ATA positivity. Comorbid PH (OR = 2.91, 95% CI = 1.11–7.65, p-value = 0.03), GERD (OR = 2.70, 95% CI = 1.08–6.79, p-value = 0.034), and ATA positivity (OR = 0.42, 95% CI = 0.19–0.93, p-value = 0.033) remained statistically significantly associated with a diagnosis of SAD (Table 3). In a multivariable-adjusted sensitivity analyses in which we excluded patients who were diagnosed with SAD solely based on HRCT findings (N = 119), comorbid PH (OR = 3.81, 95% CI = 1.25–11.62, p-value = 0.019) and GERD (OR = 3.18, 95% CI = 1.08–9.41, p-value = 0.036) were statistically significantly associated with SAD.

Table 3.

Univariate and multivariable odds of small airways disease in relation to selected clinical covariates.

	Unadjusted odds ratio (95% CI)	p-value	Adjusted odds ratio (95% CI)	p-value
Age	1.02 (0.98–1.07)	0.12	1.01 (0.99–1.04)	0.33
Sex	2.21 (0.68–7.27)	0.19	1.89 (0.41–8.61)	0.41
Smoking status
Never smoker	Reference	—	—	—
Ever smoker	1.42 (0.67–3.00)	0.36	1.62 (0.62–4.18)	0.32
Comorbid diagnoses
Interstitial lung disease	2.02 (1.01–4.06)	0.047	2.19 (0.88–5.44)	0.093
Chronic obstructive pulmonary disease	—	—	—	—
Asthma	0.48 (0.05–4.75)	0.53	—	—
Pulmonary hypertension	2.73 (1.23–6.06)	0.01	2.91 (1.11–7.65)	0.030
GERD	3.33 (1.59–6.97)	0.001	2.70 (1.08–6.79)	0.034
Esophageal dysmotility	2.28 (0.85–6.11)	0.10	—
Immunomodulators at the time of data collection
Azathioprine	1.51 (0.09–24.86)	0.77	—	—
Oral corticosteroids	1.36 (0.64–2.93)	0.43	—	—
Cyclophosphamide	—	—	—	—
Hydroxychloroquine	0.73 (0.25–2.12)	0.56	—	—
Methotrexate	0.74 (0.07–8.47)	0.81	—	—
Mycophenolate mofetil	0.78 (0.34–1.79)	0.56	—	—
Rituximab	—	—	—	—
Tacrolimus	3.10 (0.27–35.32)	0.36	—	—
Medications at the time of data collection
Inhaled corticosteroids	1.33 (0.45–3.90)	0.60	—	—
Inhaled bronchodilators	2.76 (1.22–6.22)	0.01	2.04 (0.78–5.37)	0.15
Positive serologic findings
Antinuclear antibody	0.52 (0.19–1.43)	0.21	—	—
Anti-centromere antibody	0.66 (0.38–1.16)	0.15	—	—
Anti-topoisomerase I (anti-Scl-70) antibody	0.48 (0.27–0.87)	0.02	0.42 (0.19–0.93)	0.033
Anti-RNA polymerase III antibody	0.71 (0.49–1.02)	0.07	—	—

CI: confidence interval; GERD: gastroesophageal reflux disease; RNA: ribonucleic acid.

Discussion

We found that SAD had a prevalence of 40% in this cohort of adults with SSc. GERD and PH were associated with a higher multivariable-adjusted odds of SAD, while ATA positivity was associated with a lower multivariable-adjusted odds of SAD. Older studies have analyzed ventilation heterogeneity in SSc patients, with conflicting results.^16–20 Some have reported a high prevalence of SAD in those with SSc, suggesting that the peripheral airways may be an initial site of lung involvement, while others have found that SAD is uncommon and not characteristic of pulmonary disease in SSc.^16,18,21,22 A more recent study by Ostojic and Vujovic aimed to assess the relationship between SAD, which they defined as maximal expiratory flow at 25% of the FVC < 60% predicted, and certain clinical characteristics in patients with SSc. SAD was present in 67% of their SSc cohort and was associated with large airway obstruction. However, only 69 patients were included in that study and the authors did not perform multivariable analyses to evaluate the associations between SAD and clinical features of SSc. ²³ Our findings complement that study by demonstrating that SAD in SSc is both prevalent and associated with common comorbid conditions in these patients.

Esophageal reflux has been associated with development of SSc-ILD with evidence of impaired esophageal peristalsis and lower esophageal sphincter function. ²⁴ More severe esophageal dysfunction is correlated with more severe interstitial changes and reduced lung diffusion capacity. ²⁵ Lung transplant patients with GERD have a higher prevalence of bronchiolitis obliterans syndrome, a disease of the small airways that reflects chronic allograft rejection.^26,27 These patients experience progressive dyspnea, cough, recurrent infection, and progressive airflow limitation on PFTs. The potential mechanisms underlying GERD-induced airway hyper-reactivity include micro-aspiration of acid into the airways with subsequent induction of an inflammatory response, bronchoconstriction, and stimulation of acid-sensitive receptors in the esophageal wall. ²⁸ It is possible that such mechanisms may similarly contribute to the underlying pathogenesis of SAD in SSc patients with GERD.

Approximately 28% (range = 9.4%–42%) of patients with SSc are ATA positive. ²⁹ ATA is highly specific for SSc (90%–100%) and is associated with the diffuse cutaneous subtype. ³⁰ ATA positivity has been linked to an increased risk of ILD and poor prognosis; however, titers of ATA and serial ATA measurements do not predict extent of fibrosis or degree of pulmonary impairment.^31–35 To our knowledge, the relationship between ATA and SAD has not been previously evaluated. Our findings suggest that ATA positivity may be negatively associated with SAD, although 5% of patients with SAD and 15% of patients without SAD were missing ATA; thus, this association should be evaluated further in future prospective studies, particularly given ATA’s strong positive association with SSc-ILD.

Patients with SSc and PH may have a higher risk of SAD. SAD has been reported in multiple case series of patients with PH.^36,37 It has been hypothesized that increased production of cytokines and growth factors in the pulmonary vasculature in PH causes concurrent proliferation of the small airways. ³⁸ Meyer et al. ³⁶ demonstrated limitations in end expiratory airflow and premature airway closure, leading to a reduction in vital capacity in patients with severe PH. A subsequent series reported that FEF 25–75% did not differ between patients with significantly different mean pulmonary artery pressures, suggesting that airflow limitation may occur through mechanisms independent of the severity of PH. ³⁶ Novel lung function tests, including impulse oscillometry and sulfur hexafluoride-multiple-breath-washout, have been utilized to identify ventilation heterogeneity in those with PH. ³⁹ The presence of SAD in SSc patients with PH has unclear prognostic and therapeutic implications. The significance of SAD in these patients should be explored further. ³⁹

Our findings have important implications for the clinical care of SSc patients. It can be difficult to diagnose SAD, as 70% of the peripheral airways need to be affected in order to detect a clinically meaningful decline in FEF 25–75%. ¹² In our study, SAD was commonly diagnosed by noninvasive means—primarily by PFTs, followed by HRCT. These modalities could be used to screen SSc patients for SAD, particularly those with respiratory symptoms unexplained by known pulmonary pathology. ⁵ Furthermore, we found that patients with SAD were more likely to be active smokers and to have comorbid COPD. SSc patients should therefore be informed about this additional risk of smoking and be counseled on smoking cessation. Those with SAD have poorer COPD control and more exacerbations, and thus warrant close management and tailoring of therapy. ¹²

There are some limitations of our study. First, it was retrospective, which raises concern for residual confounding. Second, we did not capture the timing of diagnosis of comorbidities or SAD during the course of a patient’s SSc. Understanding the timeline of onset of these comorbidities in relation to SAD onset could yield important pathophysiological insights. Third, there is considerable heterogeneity between prior studies of SAD regarding which test (e.g. lung biopsy, PFTs, or HRCT) is used to define SAD and which is the most accurate for the detection of small airways dysfunction. Therefore, we incorporated all three tests into our definition of SAD. Moreover, FEF_25–75 is dependent on the FVC and therefore changes in FVC will affect the portion of the flow-volume curve examined. For example, FEF_25–75 may be falsely normal in patients with ILD due to low FVC, likely underestimating the true prevalence of SAD in this study. Associations of SAD with clinical outcomes such as hospitalizations, death, and longitudinal change in lung function were not assessed, and the prognostic implications of SAD remain poorly understand. Finally, some patients had missing serologic data, although data on prevalence of comorbidities were complete.

To our knowledge, this is the largest cohort study to evaluate the comorbidities associated with SAD in patients with SSc. We have shown that SAD is prevalent among patients with SSc, is positively associated with PH and GERD in these patients, and is negatively associated with ATA positivity. Understanding the role of the small airways in SSc is increasingly important, as it may lead to a more tailored approach to the assessment and treatment of these patients, with the goal of improving respiratory symptoms, lung function, and quality of life. Noninvasive methodologies for identifying SAD, including PFTs and HRCT, should be used to evaluate for SAD if patients exhibit otherwise unexplained respiratory symptoms. Those with PH and GERD should be closely monitored for symptoms of SAD and should be treated if necessary. Further studies of risk factors for and outcomes of SAD in patients with SSc are warranted to facilitate improved SAD detection and treatment.