Abstract
Rationale: Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD.
Objectives: To characterize GER (acid and nonacid) in patients with SSc with and without ILD.
Methods: Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance–pH monitoring off–proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th–75th percentile).
Measurements and Main Results: Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24–71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score ≥ 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5–15] vs. 5.2 [1.5–11]), higher (P < 0.01) number of acid (41 [31–58] vs. 19 [10–23]) and nonacid (25 [20–35] vs. 17 [11–19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31–54] vs. 15 [8–22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r2 = 0.637) and proximal (r2 = 0.644) esophagus.
Conclusions: Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.
The mechanisms leading to interstitial lung disease (ILD) are poorly understood. Gastroesophageal reflux (GER) disease (GERD) has been previously associated with several airway manifestations. Abnormal acid GER has also been implicated as a risk factor for ILD.
Patients with systemic sclerosis (SSc) with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.
The mechanisms leading to ILD are poorly understood. Cell-mediated and humoral immunity, genetic, environmental, and occupational factors may play a role in the pathogenesis of ILD (10–14). Risk factors for ILD include cigarette smoking (15), exposure to metal and wood dust (16), and, in recent years, abnormal acid gastroesophageal reflux (GER) (17). GER disease (GERD) is associated with pulmonary diseases, including chronic bronchitis, bronchiectasis, recurrent pneumonia, chronic cough, and asthma (18–20). Animal (21) and human (22, 23) studies suggest that pulmonary fibrosis can occur after repeated aspiration of small amounts of gastric contents over long periods of time. Until recently, diagnosis and therapy of GERD has focused on gastric acid as the main monitoring parameter and treatment target. The limited benefit of acid-suppressive therapy in controlling pulmonary manifestations potentially associated with GERD has raised questions on the causal relationship between reflux and pulmonary fibrosis (24, 25). Conventional pH monitoring is limited to detecting only acid refluxing from the stomach into the esophagus, and proton pump inhibitors suppress acid, but have limited effect in preventing gastric content from refluxing back into the esophagus (26).
In recent years, combined impedance and pH monitoring allowed detecting GER independent of pH in clinical settings. Combined multichannel intraluminal impedance–pH monitoring can identify both acid (refluxate with pH < 4) and nonacid reflux (refluxate with pH > 4), as well as proximal extent of reflux episodes (27).
The aim of our study was to explore the association of GER and pulmonary fibrosis in patients with SSc with and without pulmonary fibrosis, and to compare these findings to those from healthy controls.
Some of the results of these studies have been previously reported in the form of an abstract (28).
Between June 2004 and March 2008, consecutive patients diagnosed with SSc, presenting to the out-patient unit of Clinical Immunology Division of the University Hospital at Genoa (Italy), were prospectively enrolled in the study. The diagnosis of SSc was based on criteria of the American College of Rheumatology (29). Patients with other connective tissue disorders were not included. Exclusion criteria were: history of thoracic, esophageal, or gastric surgery; presence of peptic stricture and duodenal or gastric ulcer on upper endoscopy; diabetes mellitus; and malignancy. In women of childbearing age, pregnancy was excluded by urine analysis. Patients with SSc enrolled in the present study were not treated with immunosuppressants or vasodilator drugs. Patients were asked to discontinue any medication that would influence esophageal motility and acid-suppressive therapy at least 30 days before the start of the examination. During the washout period, patients were allowed to use an oral antacid on an as-needed basis for the relief of heartburn. During the same period, 48 volunteers without any symptoms, disease, or history of surgery were enrolled in the study.
The study protocol was approved by the local ethics committee and performed according to the Declaration of Helsinki. All participants gave written, informed consent before entering the study.
Initial standardized evaluation of organ involvement of SSc included: (1) digital pitting scars; (2) arthralgia or arthritis; (3) cardiac impairment, assessed by both electrocardiogram and echocardiography; and (4) kidney involvement, assessed by biochemical analysis and echography. Patients underwent biochemical analysis and autoantibody screening tests (anti-Scl 70 antibody and anti-centromere antibody). At the time of ambulatory impedance–pH monitoring, a second investigator completed a structured questionnaire, including: a careful history of pulmonary symptoms (i.e., cough and dyspnea); GER symptoms (i.e., heartburn and regurgitation); medications; and tobacco use. Height and weight were also recorded.
Water-perfused manometry was performed using a 4.5-mm polyvinyl catheter (Synectics Medical, Stockholm, Sweden) with eight capillary ports perfused via a low-compliance pneumohydraulic apparatus at 0.5 ml/minute. Esophageal pressure values were recorded at 5 Hz/channel, digitized, and stored on a personal computer.
Patients were studied after an overnight fast of at least 8 hours. After transnasal passage of the catheter into the stomach, the lower esophageal sphincter (LES) was located by station pull-through technique using the four distal, radially oriented side holes. Mean LES pressure was calculated as the average of the four measurements at midrespiration. The catheter was then positioned for esophageal peristalsis testing with the four proximal side holes located at 5, 10, 15, and 20 cm above the LES, and patients were asked to swallow 10 liquid (5-ml water) boluses, 20–30 seconds apart.
Esophageal motility parameters included: LES pressure and relaxation; peak contraction amplitude; duration of contraction; and coordination and propagation velocity of swallows. Contraction amplitude and duration were calculated as the average of 10 liquid swallows, the peristaltic success as percentage of normal contractions.
Final manometric findings were reported according the Spechler and Castell criteria (30)
The ambulatory multichannel intraluminal impedance and pH monitoring system (Sleuth, Sandhill Scientific, Inc., Highland Ranch, CO) included a portable data logger and a catheter with one antimony pH electrode and eight impedance rings.
The methodology of probe calibration, catheter placement, patient instruction, and performance of the study have been previously described (31). On the monitoring day, subjects ate three standardized meals during the examination period, as previously reported (32).
GER episodes were identified and classified as acid (nadir, pH < 4), weakly acidic (nadir, pH 4–7), and weakly alkaline (nadir, pH > 7), according to previously reported criteria (33). Weakly acidic and weakly alkaline reflux were grouped together as nonacid reflux episodes (nadir, pH > 4).
Impedance and pH data was used to define: number and type of reflux episodes; acid exposure (reflux time [min] and reflux percent time); proximal extent (reflux reaching 15-cm impedance site). Meal periods were excluded for the analysis.
Total 24-hour esophageal acid exposure (%) was defined as the total time below pH 4 divided by the time of monitoring. Total distal esophageal acid exposure (i.e., % time pH < 4) less than 4.2% over 24 hours was considered normal (34, 35).
Impedance–pH data from the 48 healthy volunteers studied in ambulatory conditions served as normal values.
Pulmonary involvement was investigated as part of the initial evaluation of SSc in all patients, and included: chest radiographs; pulmonary high-resolution computer tomography (HRCT) scan; and pulmonary function test (PFT).
FVC and FEV curves were determined in a constant-volume plethysmograph (Sensor Medics 28000; Sensor Medics, Yorba Linda, CA). A 10-second, single-breath DlCO test (Morgan, Kent, UK) was carried out. Pulmonary function was considered abnormal if volumes were less than 80% of predicted values and/or when DlCO was less than 75% of predicted value (36, 37).
HRCT scanning (CT Lightspeed; GE, Milwaukee, WI) of the lungs was performed to identify abnormalities related to ILD (38, 39). Pointedly, 1.25-mm-thick slices (200 mAs, 120 kV, 1 s/slice) performed at the end of inspiration were obtained from apex to base with a table increment of 10 mm according to a high-resolution algorithm, selecting only high frequencies (Bone algorithm). All examinations were filmed with two window levels (300–30 and 1,600–500 Hounsfield units) for review.
HRCT scans were read independently by experienced radiologists in random order without knowledge of the patients group status. The parenchymal abnormalities were scored according to Warrick and colleagues (40). A cut-off score of 7 was required to consider HRCT abnormalities in SSc as predictive of pulmonary disease (HRCT score ≥ 7 = positive; HRCT score < 7 = negative) (41).
Reflux parameters were compared between patients with (HRCT score ≥ 7) and without (HRCT score < 7) pulmonary impairment.
Differences in proportions were compared using the Chi-square or Fisher's exact test, depending on the sample size. Manometric data are expressed as mean (range) value. Because reflux monitoring values were not normally distributed, results are reported as median and percentile values (median [25th–75th percentile; 95th percentile]). Differences between groups were assessed using Kruskal-Wallis and/or Mann-Whitney tests. The correlation between the severity of pulmonary fibrosis and reflux parameters was calculated using the Spearman correlation. For statistical significance, α was set at 0.05.
Between June 2004 and March 2008, 40 consecutive patients (35 female; median age, 53 yr; age range, 24–71 yr; median body mass index, 23 kg/m2) diagnosed with SSc, and 48 healthy volunteers (27 females; median age, 44 yr; age range, 22–77 yr; body mass index, 23 kg/m2; range 16–34) were included in the study. According to the established criteria (42), 25 patients had limited cutaneous SSc and 15 had diffuse cutaneous SSc. The median duration of the disease (starting at the onset of Raynaud's phenomenon) was 5 years (range, 1–16 yr).
In the HRCT, 18 patients (45%) had a positive pulmonary fibrosis score (HRCT score ≥ 7; Group A) and 22 had a negative pulmonary fibrosis score (HRCT score < 7; Group B). There were no differences between groups with respect to age, disease duration, SSc subtypes, GERD symptoms, or PFT findings. Detailed demographic and characteristics of patients with normal and abnormal HRCT score are summarized in Table 1.
Demographic and Clinical Parameters | Group A HRCT+ | Group B HRCT− | P Value |
|---|---|---|---|
| Patients, n | 18 | 22 | |
| Female patients, n | 17 | 18 | ns |
| Median age, yr | 53.4 (37–67) | 50.9 (27–71) | ns |
| Median body mass index | 23.8 (19–32) | 23 (17–28) | ns |
| Median SSc duration, yr | 5.5 (1–16) | 5.7 (2–16) | ns |
| Percentage SSc subtype | ns | ||
| lcSS | 61 | 64 | ns |
| dcSSc | 39 | 36 | |
| Tobacco use, % | 11 | 14 | ns |
| Median DlCO, % | 81 (50–114) | 94 (72–108) | ns |
| Median FVC, % | 97 (74–117) | 102 (77–130) | ns |
| Median FEV, % | 88 (72–118) | 98 (62–125) | ns |
| Arthralgia/arthritis, % | 28 | 36 | ns |
| Digital pitting scars, % | 61 | 50 | ns |
| Cardiac dysfunction, % | 0 | 0 | 1 |
| Kidney dysfunction, % | 0 | 0 | 1 |
| Esophageal symptoms (i.e., heartburn/regurgitation), % | 55 | 45 | ns |
| Pulmonary symptoms (i.e., cough and dyspnea), % | 44 | 36 | ns |
| Anti-centromere antibody, % | 55 | 64 | ns |
| Anti-Scl 70 antibody, % | 28 | 36 | ns |
| Patients ANA and anti-Scl 70 negative, n | 3 | 0 | ns |
Patients in Group A had lower LES resting pressure median (range) values (13.7 [8–19] vs. 19.1 [6–28]; P < 0.01) and lower distal contraction amplitude (58.9 [20–150] vs. 77.8 [20–150]; P < 0.01) compared with patients in Group B. LES relaxation duration, residual pressure, and proximal contraction amplitudes (75.6 [30–130] vs. 86.1 [40–150]; P = ns) were normal in both groups.
The prevalence of hiatal hernia was similar in the two groups (33% versus 36%; P = ns). Details on esophageal motility findings are summarized as shown in Table 2.
Manometric Patterns | Group A HRCT+ (%) | Group B HRCT− (%) | P Value |
|---|---|---|---|
| Normal peristaltis | 45 | 55 | ns |
| Distal esophageal spasm | 0 | 0 | 1 |
| Nutcracker esophagus | 0 | 0 | 1 |
| Ineffective esophageal motility | 55 | 45 | ns |
| Abnormally low LES pressure | 22 | 13 | ns |
In Group A, 15 of 18 (83%) patients had an abnormal distal acid exposure compared with 13 of 22 (59%) patients in Group B (P < 0.001). Total, upright, and recumbent percent time below pH 4 was significantly higher in Group A compared with Group B and healthy volunteers (10.3 [7.5–15; 19] vs. 5.2 [1.5–11; 13] vs. 0.7 [0–1.4; 4.2]; P < 0.001) (Figure 1).
Figure 1. Distal esophageal acid exposure time (AET) expressed as the percentage of time below pH 4 in healthy volunteers (n = 48) and in patients with systemic sclerosis (SSc) with normal (n = 22) and abnormal (n = 18) high-resolution computer tomography (HRCT) score. Bars indicate median values. Box plots indicate median, 25th–75th percentile; whiskers, 5th–95th percentile.
[More] [Minimize]The total (acid and nonacid) number of reflux episodes was higher in Group A compared with Group B and healthy volunteers (P < 0.001) (Figure 2).
Figure 2. Number and types of gastroesophageal reflux in healthy volunteers (n = 48) and in patients with SSc with normal (n = 22) and abnormal (n = 18) high-resolution computer tomography (HRCT) score. Box plots indicate median, 25th–75th percentile; whiskers, 5th–95th percentile.
[More] [Minimize]More reflux episodes reached the proximal esophagus (42.5 [31–54; 114]) in patients from Group A than from Group B (15 [8–22; 44]; P < 0.001) and healthy volunteers (9 [4–17; 30]; P < 0.001), as shown in Figure 3. In addition, the percentage of total reflux episodes reaching the proximal measuring site was higher in patients from Group A (65.5%) than in those from Group B (47%; P < 0.01) and healthy volunteers (33%; P < 0.001).
Figure 3. Number of reflux episodes reaching the proximal esophagus in healthy volunteers (n = 48) and in patients with SSc with normal (n = 22) and abnormal (n = 18) high-resolution computer tomography (HRCT) score. Box plots indicate median, 25th–75th percentile; whiskers, 5th–95th percentile. LES = lower esophageal sphincter.
[More] [Minimize]There was a good correlation between the degree of pulmonary fibrosis (HRCT score) and total number of reflux episodes in both distal (r2 = 0.637; P < 0.001) and proximal (r2 = 0.644; P < 0.001) esophagus (Figures 4A and 4B).
Figure 4. (A) Correlation between the degree of pulmonary fibrosis (high-resolution computer tomography [HRCT] score) and total number of reflux episodes in the distal (r2 = 0.637, P < 0.001) esophagus. (B) Correlation between the degree of pulmonary fibrosis (HRCT score) and total number of reflux episodes in the proximal (r2 = 0.644; P < 0.001) esophagus. LES = lower esophageal sphincter.
[More] [Minimize]In the present study, we noted lower LES resting pressures, lower esophageal contraction amplitudes, higher frequency of GER episodes (both acid and nonacid), and a higher frequency of reflux episodes reaching the proximal esophagus in patients with SSc and ILD compared with patients with SSc without ILD. These findings suggest that patients with SSc and ILD have more extensive esophageal involvement, leading to more severe GER.
Esophageal involvement is frequent in SSc, occurring in 50–90% of patients (43–46). Esophageal findings related to SSc include low LES pressure and smooth muscle dysfunction (i.e., uncoordinated pressure waves and reduced or absent peristalsis) predisposing to GER (45, 46). Current manometric findings are consistent with those observed by Marie and colleagues (43) in 43 patients with SSc. Manometry, PFT, and HRCT scans found lower DlCO and higher prevalence of ILD on HRCT scan in patients with severe esophageal motor impairment compared with those with moderate and without esophageal dysmotility, once again suggesting an association between the degree of esophageal manometric motor disturbances and ILD (43). The reduced LES pressure in our patients with SSc with ILD indicates an incompetent antireflux barrier, leading to aspiration of gastric content into the lungs, as reported by Yarze and colleagues (47). Furthermore, it has been suggested that the increased respiratory workload in patients with ILD could contribute to GER by increasing the transdiaphragmatic gradient (48). Unfortunately, current methodology (i.e., conventional manometry) didn't allow us to assess this parameter.
Despite a lower distal esophageal contraction amplitude, patients with SSc with ILD did not have a higher prevalence of abnormal motility patterns compared with patients without ILD. Indeed, about half of patients with and without pulmonary involvement were classified as having ineffective esophageal motility (30). This finding could be related to a type-2 error, although this suggests that factors others than esophageal motor abnormalities contribute to the pathogenesis of pulmonary fibrosis.
Several studies have reported on the role of GER in various respiratory disorders (18–20, 22, 48–51). To our knowledge, our study is the first investigating the association of acid and nonacid GER on pulmonary findings in patients with SSc. We prospectively collected impedance–pH monitoring, PFT, and HRCT data in a carefully defined group of unselected patients with SSc off acid-suppressive therapy, a group representative of the general SSc population. Although lung biopsy remains the gold standard to diagnose ILD, HRCT is currently regarded as the reference among noninvasive procedures (38, 39). It allows precise analysis of lung parenchyma and lung volume. Recent studies in patients with SSc with lung involvement underscored that pulmonary abnormalities on HRCT correlate well with lung histology findings (52).
The mechanisms leading to ILD remain poorly understood. Current concepts implicate epithelial–fibroblast interactions as a result of repeated insults to the lung parenchyma by a noxious stimulus over a long period of time, causing pulmonary fibrosis (53). Recent studies implicate microaspiration of gastric contents into the lungs as the trigger mechanism inducing pulmonary parenchymal lesions, suggesting that GER therapy could improve symptoms and PFT parameters (18–20, 43, 48). However, using conventional pH monitoring allowed only detection of acid GER. Using combined impedance–pH monitoring, we observed that patients with pulmonary involvement had more reflux episodes—both acid and nonacid—in the distal and proximal esophagus, enhancing the risk of microaspiration into the lungs. Finding an increased number of nonacid reflux episodes is important, and a possible explanation why acid suppression alone might not be sufficient to prevent progression of ILD. This is supported by studies documenting abnormal levels of pepsin and bile acids in bronchoalveolar lavage fluid of patients with pulmonary disease (54–57). The good correlation between the degree of pulmonary fibrosis (HRCT score) and number of proximal and distal reflux episodes reinforces the role of GER in the development and/or progression of pulmonary fibrosis. Our results are consistent with the findings of Raghu and colleagues (48) in 65 patients with interstitial pulmonary fibrosis, showing a high prevalence of abnormal distal esophageal acid exposure compared with a control group of 133 patients with intractable asthma.
The relationship between esophageal and lung manifestations could be due to concomitant involvement of internal organs, resulting in ILD and fibrosis of esophageal smooth muscle. In the present study, clinical characteristics of SSc were similar in patients with SSc with and without pulmonary impairment. This suggests that the correlation between the frequency of GER and severity of lung impairment may not be an expression of a more advanced SSc with higher degree and extent of generalized fibrosis. Further studies are necessary to clarify the cause–effect relationship of the association of GER in patients with SSc with ILD.
Although the vast majority of patients with SSc had abnormal acid GER, only 50% reported typical GERD symptoms. This is consistent with previous reports indicating that patients with SSc report GER symptoms less frequently, despite an increased frequency of abnormal esophageal acid exposure (58), and studies in patients with pulmonary reflux manifestations, in which only 50% of patients suspected of pulmonary aspiration reported a history of “heartburn” (59). We did not observe statistical differences in GER symptoms between patients with SSc with and without ILD (Table 1). These findings indicate that GERD is “silent” in most patients with SSc, and suggest that reflux monitoring should be performed independent of reflux symptoms to adequately address treatment for GER.
In conclusion, current data indicate that patients with SSc with pulmonary fibrosis have more extensive esophageal involvement compared with patients with SSc without pulmonary fibrosis. The increased number of reflux episodes could be the consequence of a more pronounced esophageal involvement in these patients; on the other hand, GER could be responsible for the development of pulmonary fibrosis. The observations on nonacid reflux and proximal extent of reflux episodes imply that reflux-reducing, and not only acid-suppressive therapies, should be included in studies aimed at testing whether or not the development of ILD in patients with SSc can be prevented by treating GER.
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