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Keywords:

  • Systemic sclerosis;
  • Esophageal involvement;
  • Gastroesophageal reflux;
  • Pulmonary impairment;
  • Interstitial lung disease

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objective

To assess whether esophageal manometric motor disturbances are associated with abnormalities consistent with interstitial lung disease (ILD) on both pulmonary function tests (PFT) and high resolution computerized tomography (HRCT) scans in patients with systemic sclerosis (SSc), during initial evaluation and at 2 years followup.

Methods

Esophageal manometry, PFT, and HRCT scans were performed in 43 consecutive SSc patients. PFT and HRCT scan parameters were compared between patients with severe esophageal motor dysfunction (i.e., aperistalsis and decreased low esophageal sphincter pressure), patients with moderate esophageal motor dysfunction (hypoperistalsis), and patients without esophageal motor dysfunction on manometry.

Results

During initial evaluation of SSc, patients with severe esophageal motor impairment, compared with those with moderate and without esophageal dysmotility, exhibited significantly decreased median values of diffusing capacity for carbon monoxide (DLCO) (68% vs. 94% vs. 104%) and exhibited higher prevalence of evidence for ILD on HRCT scan (57% vs. 27% vs. 18%). At 2 years followup of SSc, patients with severe esophageal motor disturbances, compared with those without, had faster deterioration of DLCO median values (–16% vs. +1%) and higher frequency of ILD on HRCT scan (70% vs. 25%).

Conclusion

Our series underscores a correlation between the degree of esophageal manometric motor disturbances and evidence for ILD on PFT and HRCT scan in SSc patients, suggesting that gastroesophageal reflux (GER) may be one of the contributing factors of ILD in SSc. Our findings further indicate that patients with severe esophageal impairment may require closer followup of lung parameters. In turn, it suggests that aggressive therapy of GER should be initiated in these SSc patients, as it may result in decreased deterioration of pulmonary function.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Systemic sclerosis (SSc) is a systemic inflammatory disorder affecting the skin and other organs, especially the lungs. Prevalence of pulmonary impairment has been reported to be as high as 57% to 86% in patients with SSc(1–10). Pulmonary involvement, principally interstitial lung disease (ILD), is still recognized to be associated with great morbidity and mortality in SSc patients, leading to ventilatory failure, secondary pulmonary hypertension, and cor pulmonale(1, 2, 4–6, 8, 10–23). In a study of a cohort of 264 SSc patients, Altman et al(11) have reported a decreased survival in patients with pulmonary diseases compared with those without (78 ± 17 months SD vs. 108 ± 9 months SD). Bryan et al(12), in 280 SSc patients, have also noted that pulmonary disorders secondary to SSc were the most common cause of death: 21% of the patients (16/76) had died of pulmonary complications at 5 years followup. The pathologic mechanisms of ILD remain unknown in SSc. There is evidence that both cell-mediated and humoral immunity (e.g., proinflammatory and profibrotic cytokines) may play a role in the pathogenesis of ILD(1, 2, 4, 24–28). A causative relationship between ILD and other factors, notably genetic, environmental, and occupational parameters, has further been proposed(2, 4, 29–35).

More recently, esophageal motor disturbances have also been implicated as contributing factors of ILD in patients with SSc(4, 36–40). Both abnormalities of esophageal peristalsis and decreased low esophageal sphincter (LES) pressure may lead to progressive histologic damage of ILD induced by repeated microaspirations of gastric content into the respiratory tract(4, 36–40). The establishment of a causal relationship between esophageal and pulmonary involvement would imply therapeutic consequences, inasmuch as aggressive therapy of gastroesophageal reflux (GER) may decrease both morbidity and mortality related to pulmonary involvement in SSc patients.

These findings prompted us to conduct this prospective study: first, to assess whether manometric motor disturbances of the esophagus are associated with abnormalities of parameters on both pulmonary function tests (PFT) and high resolution computerized tomography (HRCT) scans of the lungs during initial evaluation of SSc, and, second, to evaluate whether manometric motor disturbances of the esophagus are predictive factors of pulmonary impairment (i.e., deterioration of parameters on PFT and HRCT of the lungs) at 2 years followup of SSc.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patient population

Forty-three consecutive patients with a definite diagnosis of SSc were included in the study. The criteria for diagnosis of SSc were based on American College of Rheumatology (formerly the American Rheumatism Association) criteria(41). All patients were seen at the University of Rouen medical center, as either inpatients or outpatients, between 1997 and 1999. There were 6 men and 37 women, with a median age of 59 years (range 33–79 years); the median duration of the disease, considered to have existed from the onset of Raynaud's phenomenon, was 6 years (range 0.5–24 years). Patients were grouped according to the criteria of LeRoy et al(42); 10 patients (23.26%) had diffuse cutaneous SSc (dcSSc) and 33 (76.74%) had limited cutaneous SSc (lcSSc). No patients with SSc had other connective tissue disorders or a history of liver or digestive diseases, diabetes mellitus, esophageal or gastric surgery, or vagotomy. None of the women were pregnant.

The 43 patients had an initial standardized evaluation of organ involvement, which resulted in the detection of systemic complications related to SSc, i.e., (a) digital pitting scars, (b) arthralgia or arthritis, and (c) cardiac impairment, assessed by both electrocardiogram and echocardiography. All patients also underwent biochemical analysis, including erythrocyte sedimentation rate (ESR) (mm/hour), creatine kinase (CK) (units/liter), serum urea (mmoles/liter), and creatinine (μmoles/liter). Autoantibody screening tests (anti-Scl 70 antibody and anticentromere antibody) were performed.

Esophageal investigations

All patients underwent esophageal manometry and endoscopy during initial evaluation of SSc.

Esophageal manometry.

Medication that might affect esophageal dysmotility (cisapride, metoclopramide, calcium channel antagonist) was discontinued at least 72 hours prior to manometry. After a 12-hour overnight fast, the manometric probe catheter was introduced through the nose and positioned within the stomach. During monitoring, patients remained in a supine position, and care was taken to avoid any factors that could have disturbed their tranquility.

Esophageal manometry was performed with a tube assembly (4.5 mm outer diameter; Synectics Medical, Stockholm, Sweden) consisting of 8 polyvinyl catheters (0.8 mm internal diameter). Recording lumens were perfused with distilled water via a low-compliance pneumohydraulic apparatus (0.5 ml/minute) from a pressurized reservoir. Esophageal pressure values from external pressure transducers (Gould Statham P23 ID, Oxnard, CA) were digitized as 8-bit data with a frequency of 5 Hz/channel and stored on the hard disk of an IBM PC computer.

For the esophageal manometric tracings, the recording chart was analyzed to determine LES pressure and esophageal motor function (i.e., characteristics of peristalsis). With the 4 distal side holes of the manometric tube spaced radially 1 cm apart at 90°, LES pressure was recorded by a stationary pull-through (0.5 increment every 30 seconds); mean LES pressure was calculated as the average obtained from these 4 distal holes. The manometric tube was further positioned to monitor esophageal peristaltic motility, using the 4 proximal side holes located at 3, 8, 13, and 18 cm above the LES; patients were asked to perform 20 dry swallows (at 30-second intervals) and 10 wet swallows (5 ml of water, at 30-second intervals). Tubular esophageal function was analyzed for peak contraction pressure, duration of contractions, coordination, and propagation velocity after voluntary deglutition; both amplitude and duration of esophageal contractions were calculated as the average of the values obtained during the 10 wet swallows and the 20 dry swallows separately.

Both visual and computerized analyses were performed by 2 of the authors (Drs. Marie and Ducrotté) who are experienced in esophageal chart assessment. One (Dr. Ducrotté) was blinded to the patients' clinical symptoms and test results. After analysis, the patients were classified according to Hurwitz's criteria(43) for the degree of esophageal involvement on manometry, i.e., 11 had normal esophageal motility (stage I), 6 had uncoordinated peristalsis with normal pressure wave amplitude (stage II), 5 had uncoordinated peristalsis with low pressure wave amplitude (stage III), and 21 had both aperistalsis and decreased LES pressure (stage IV).

After analysis, esophageal motor disorders were found to be divided among the SSc patients as follows: severe (stage IV; n = 21); moderate (stages II and III; n = 11); normal (stage I; n = 11).

Esophageal endoscopy.

Esophageal endoscopy was carried out in order to disclose mucosal abnormalities related to GER. Mucosal damage of the esophagus was classified according to Savary-Miller's classification(44): grade 0, no lesion; grade 1, single or multiple erosions on a single fold, with erosions that may be primarily erythematous; grade 2, multiple erosions affecting multiple folds, with erosions that may be confluent; grade 3, multiple circumferential erosions; grade 4, ulcer and/or stricture; grade 5, endobrachyesophagus or “Barrett's esophagus.”

In our population, esophageal endoscopy demonstrated mucosal abnormalities related to GER in 17 patients (39.53%). Esophageal mucosal abnormalities were as follows: grade 0, n = 26; grades 1 and 2, n = 9; grades 3 and 4, n = 7; grade 5, endobrachyesophagus or “Barrett's esophagus,” n = 1.

Comparison of esophageal manometric and endoscopic findings.

Comparison between endoscopic findings related to GER and esophageal manometric data was performed, in order to demonstrate a correlation between the severity of esophageal mucosal abnormalities and manometric motor dysfunction and, in turn, to demonstrate that hypoperistalsis or aperistalsis associated with decreased LES pressure predisposes to GER, as previously shown(45).

Pulmonary tests

Pulmonary involvement was systematically investigated, during initial evaluation of SSc in all patients, by chest radiographs, HRCT scan of the lungs, and PFT.

Eighteen of the 43 patients who entered in the study between 1997 and 1999 had a minimal 2-year period of followup from SSc diagnosis; these 18 patients further underwent pulmonary investigations at 2 years followup of SSc, i.e., PFT and HRCT scan of the lungs. Lung tests were not performed in the 25 remaining patients, whose duration of SSc from diagnosis was less than 2 years.

Pulmonary function tests.

The following PFT parameters were assessed: vital capacity (VC), forced vital capacity (FVC), total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV), forced expiratory volume in 1 second (FEV1), and forced expiratory volume in 1 second as percentage of vital capacity (FEV1/VC [%]). VC, FVC, and FEV1 were measured by spirometry (using a water-sealed spirometer) and FRC by a plethysmographic method. The diffusing capacity for carbon monoxide (DLCO) was obtained by the single-breath method. Data were expressed as percentages of predicted values; the predicted values for each subject, based on sex, age, height, and weight, were obtained from standard tables(46). Lung function was considered abnormal when volumes were less than 80% of predicted values or when DLCO was less than 70% of the value predicted.

HRCT of the lungs.

HRCT of the lungs was performed in the SSc patients in order to disclose radiographic abnormalities related to ILD(4), i.e., (a) parenchymal micronodules (<7 mm in diameter), nodules (7–20 mm in diameter), and masses (>20 mm in diameter); (b) linear opacities, i.e., septal lines (representing thickened interlobular septa) and nonseptal lines; (c) irregularity of the interfaces between peripheral pleura and aerated lung parenchyma, defined as nodular opacities (i.e., subpleural micronodules) or small lines perpendicular to the pleura; (d) ground-glass opacities, defined as areas of minimal to marked attenuation in which the bronchi and vessels remain visible; (e) honeycombing, defined as areas of cystic spaces with thickened walls; (f) traction bronchiectases or bronchiolectases, recognized on the basis of dilatation and abnormal depiction of the airways in the peripheral portion of the lungs; and (g) architecture distortion, determined as the displacement of fissures, bronchi, and vessels. Both prone and supine scans were carried out in order to rule out radiologic interstitial changes due to hypostasis or hypoventilation.

Comparison of pulmonary and esophageal involvement

Pulmonary parameters, evaluated by PFT and HRCT scan of the lungs, were compared between patients with severe esophageal impairment (stage IV), patients with moderate esophageal impairment (stage II or III), and patients without esophageal impairment (stage I) on manometry, during the initial evaluation of SSc.

Moreover, comparison of pulmonary manifestations (assessed by PFT and HRCT scan of the lungs) was also performed between patients with severe (stage IV; n = 10) and moderate or normal (stage I, II, or III; n = 8) esophageal motor dysfunction on manometry, at 2 years followup of SSc.

Statistical analysis

Statistical analyses were performed, using StatXact version 3.0 (Cytel Software Corporation, Cambridge, MA) and StatView version 5.0 (SAS Institute Inc., Cary, NC).

For group comparisons involving binary data, we used either the chi-square test or Fisher's exact test, depending on the sample size (n > 5 and n ≤ 5, respectively). Comparisons involving continuous data were performed using the Mann–Whitney test. Comparisons of continuous outcomes between subgroups of patients with SSc were made by the Kruskal–Wallis test when the number of patient subgroups was above 2. The results were regarded as significant when the P value was less than 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Esophageal manometric involvement and general clinical data

As shown in Table 1, there were no significant differences between patients with severe esophageal dysfunction, patients with moderate esophageal dysfunction, and patients with normal esophageal function with respect to median age (59 years vs. 52 years vs. 59 years, respectively; P = 0.821) and median SSc duration (6 years vs. 4 years vs. 6 years, respectively; P = 0.484).

Table 1. Clinical characteristics and biochemical findings of SSc patients with normal and disturbed esophageal motility on manometry*
 Esophageal manometric involvementP
Stage I (n = 11)Stage II/III (n = 11)Stage IV (n = 21)
  • *

    SSc = systemic sclerosis; lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; CK = creatine kinase; ESR = erythrocyte sedimentation rate. Except where indicated, values are median (range).

Clinical parameters
 Age, years59 (35–79)52 (33–77)59 (33–79)0.821
 SSc duration, years6 (1–24)4 (1–22)6 (0.5–24)0.484
 SSc subtype27.27% of lcSSc30.30% of lcSSc42.42% of lcSSc0.274
20% of dcSSc10% of dcSSc70% of dcSSc
 Arthralgia/arthritis36.36%9.09%33.33%0.268
 Digital pitting scars54.55%63.64%57.14%0.903
 Cardiac dysfunction0%0%0%1
Biochemical parameters
 Increased CK0%0%19.05%0.164
 ESR, mm/hour11 (2–24)10 (7–52)15 (4–32)0.664
 Serum urea, mmoles/liter6.1 (2.1–8.6)5.7 (3.6–12.7)5.3 (3.3–6.7)0.215
 Serum creatinine, μmoles/liter64.5 (59–100)68 (47–141)69 (51–91)0.737
 Anticentromere antibody54.55%63.64%52.38%0.827
 Anti-Scl 70 antibody9.09%18.18%33.33%0.523

We also failed to show any statistically significant difference between SSc subtypes and the degree of esophageal manometric dysfunction (P = 0.274) (Table 1). According to esophageal manometric impairment, patients with lcSSc were divided as follows: stage I, 27.27% (n = 9/33); stages II and III, 30.30% (n = 10/33); stage IV, 42.42% (n = 14/33). Patients with dcSSc were divided as follows: stage I, 20% (n = 2/10); stages II and III, 10% (n = 1/10); stage IV, 70% (n = 7/10).

Moreover, as illustrated in Table 1, the prevalence of systemic manifestations related to SSc was similar in patients with severe, moderate, and normal esophageal manometric findings, as follows: arthralgia or arthritis (33.33% vs. 9.09% vs. 36.36%), digital pitting scars (57.14% vs. 63.64% vs. 54.55%), and cardiac dysfunction (0% vs. 0% vs. 0%).

Finally, biochemical data did not differ among the 3 subgroups of patients for ESR, CK levels, and both serum urea and creatine values (Table 1). Prevalence of anticentromere antibody (52.38% [n = 11/21] vs. 63.64% [n = 7/11] vs. 54.55% [n = 6/11], respectively; P = 0.827) and anti-Scl 70 antibody (33.33% [n = 7/21] vs. 18.18% [n = 2/11] vs. 9.09% [n = 1/11], respectively; P = 0.523) was also similar in SSc patients with severe, moderate, and normal manometric esophageal involvement.

Comparison of esophageal manometric and endoscopic abnormalities at initial evaluation of SSc

We observed a marked correlation between esophageal motor disturbances and endoscopic mucosal abnormalities (P = 0.024). Endoscopy disclosed the following mucosal abnormalities in the esophagus, according to Savary-Miller's criteria(44): grades 1 and 2 (n = 7), grades 3 and 4 (n = 6), and endobrachyesophagus or “Barrett's esophagus” (n = 1) in patients with severe (stage IV) esophageal motor impairment; grades 3 and 4 (n = 1) and grades 1 and 2 (n = 1) in patients with moderate (stage II or III) esophageal motor dysfuntion; and grades 1 and 2 (n = 1) in patients with normal (stage I) esophageal manometry.

Comparison of esophageal manometric involvement and pulmonary parameters during initial evaluation of SSc

At the time of initial evaluation, 13 SSc patients had clinical pulmonary symptoms, i.e., 10 patients had dry cough (stage IV, n = 6; stages II and III, n = 1; stage I, n = 3), and 3 patients complained of both dry cough and dyspnea on exertion (stage IV, n = 3). In 4 of these 13 patients, cough was also nocturnal (stage IV, n = 4).

Comparison of esophageal involvement and PFT data.

The characteristics of PFT findings in the 3 subgroups of patients are shown in Table 2.

Table 2. Pulmonary function test data as a function of manometric esophageal findings in patients with systemic sclerosis*
 Esophageal manometric involvementP
Stage I (n = 11)Stage II/III (n = 11)Stage IV (n = 21)
  • *

    Values are median (range), P values were determined by Mann–Whitney tests. FVC = forced vital capacity; VC = vital capacity; TLC = total lung capacity; RV = residual volume; FRC = functional respiratory capacity; FEV1 = forced expiratory volume in 1 second; FEV1/VC = forced expiratory volume in 1 second as % of vital capacity; DLCO = carbon monoxide diffusing capacity with single-breath method; C dyn = dynamic compliance; SaO2 = arterial blood saturation in oxygen.

FVC %103.45 (87.57–134.40)102.13 (11.7–144.44)94.14 (11.17–149.81)0.505
VC %99.00 (77.13–143.54)100.30 (85.38–126.77)93.55 (60.54–147.65)0.630
TLC %96.78 (69.70–116.85)102.30 (79.72–112.73)88.81 (58.00–139.50)0.422
RV %68.47 (50.53–125.16)69.48 (48.70–147.12)81.62 (20.00–135.96)0.184
FRC %92.65 (58.11–142.70)98.85 (67.29–111.83)98.32 (50.00–194.80)0.529
FEV1 %91.91 (62.50–148.60)102.99 (65.18–118.86)95.27 (65.80–149.50)0.578
FEV1/VC %79.29 (63.55–99.00)76.09 (59.54–81.60)77.40 (65.00–86.00)0.101
DLCO %103.70 (46.69–109.00)93.57 (55.00–110.76)68.00 (7.05–110.07)0.048
C dyn 1/kpa1.60 (0.69–0.9)0.85 (1.10–2.47)1.20 (0.7–1.9)0.07
SaO2 %98 (95–99)98 (96–99)97 (93–98)0.477

Only the median value of DLCO was significantly lower in SSc patients with severe esophageal manometric impairment compared with patients with moderate and without esophageal dysfunction (68% vs. 93.57% vs. 103.70%, respectively; P = 0.048). Other PFT parameters, i.e., values of VC, FVC, TLC, FRC, RV, FEV1, and FEV1/VC (%), also tended to be lower in SSc patients with severe esophageal manometric involvement, although not significantly so.

Comparison of esophageal involvement and pulmonary HRCT scan data.

HRCT scanning of the lungs showed evidence for ILD in 17 patients with SSc (39.53%). HRCT findings consistent with ILD included parenchymal micronodules or nodules in 9 patients (52.94%), linear opacities in 14 patients (82.35%), irregularity of the interfaces in 8 patients (47.06%), ground-glass opacities in 7 patients (41.18%), honeycombing in 4 patients (23.53%), traction bronchiectases or bronchiolectases in 4 patients (23.53%), and architecture distortion in 2 patients (11.76%). The 4 patients with radiologic honeycombing underwent bronchoalveolar lavage fluid analysis; 3 patients had both lymphocyte and neutrophil alveolitis, whereas the remaining patient had neutrophil alveolitis.

As illustrated in Table 3, the prevalence of ILD was higher in patients with severe esophageal manometric impairment than in patients with moderate and without esophageal motor disturbances (57.14% vs. 27.27% vs. 18.18%, respectively; P = 0.037).

Table 3. Lung HRCT scan data as a function of manometric esophageal findings in patients with systemic sclerosis*
 Esophageal manometric involvementP
Stage I (n = 11)Stage II/III (n = 11)Stage IV (n = 21)
  • *

    HRCT = high resolution computerized tomography; ILD = interstitial lung disease. P values were determined by Mann–Whitney tests.

ILD prevalence18.18%27.27%57.14%0.037
Abnormalities consistent with ILD
 Parenchymal micronodules0%4.65%16.28%0.079
 Linear opacities4.65%4.65%23.26%0.179
 Irregularity of the interfaces0%4.65%13.95%0.139
 Ground-glass opacities2.33%0%13.95%0.087
 Honeycombing0%0%9.30%0.099
 Bronchiectases/bronchiolectases2.33%0%6.98%0.418

Moreover, HRCT abnormalities were more numerous in patients with severe esophageal involvement (Table 3). According to esophageal manometric impairment, HRCT therefore depicted the following signs of ILD: parenchymal micronodules or nodules (n = 7), linear opacities (n = 10), irregularity of the interfaces (n = 6), ground-glass opacities (n = 6), honeycombing (n = 4), traction bronchiectases or bronchiolectases (n = 3), and architecture distortion (n = 2) in 12 patients with severe motor dysfunction; parenchymal micronodules or nodules (n = 2), linear opacities (n = 2), and irregularity of the interfaces (n = 2) in 3 patients with moderate motor involvement; and linear opacities (n = 2), ground-glass opacities (n = 1), and traction bronchiectases or bronchiolectases (n = 1) in 2 patients with normal motility.

Comparison of esophageal manometric involvement and pulmonary parameters at 2 years followup of SSc

Characteristics of SSc patients. Pulmonary investigations were carried out in 18 consecutive patients at 2 years followup of SSc. These were 18 women. Seven patients (38.89%) had dcSSc and 11 (61.11%) had lcSSc. All 18 SSc patients again underwent both PFT and HRCT scan of the lungs. The course of PFT parameters and HRCT findings was compared in patients with (stage IV; n = 10) and without (stages I, II, and III; n = 8) severe esophageal motor disturbances on manometry.

Comparison of esophageal involvement and PFT data.

Patients with severe esophageal motor dysfunction (stage IV) had a markedly faster decrease of DLCO median values compared with other patients (stages I, II, and III) (–16.04% vs. +1.47%, respectively; P = 0.022). As shown in Table 4, other PFT data, i.e., values of VC, FVC, TLC, FRC, RV, FEV1, and FEV1/VC (%), were similar in these 2 subgroups of patients.

Table 4. Pulmonary function test data at 2-year followup as a function of manometric esophageal findings in patients with systemic sclerosis*
 Esophageal manometric involvementP
Stage I/II/III (n = 8)Stage IV (n = 10)
  • *

    Value at 2-year followup (%) − value at initial evaluation (%). FVC = forced vital capacity; VC = vital capacity; TLC = total lung capacity; RV = residual volume; FRC = functional respiratory capacity; FEV1 = forced expiratory volume in 1 second; FEV1/VC = forced expiratory volume in 1 second as % of vital capacity; DLCO = carbon monoxide diffusing capacity with single-breath method; C dyn = dynamic compliance. P values were determined by Mann–Whitney tests.

FVC+0.09%−3.65%0.386
VC+0.76%+0.17%0.656
TLC+0.31%−2.50%0.656
RV+25.21%−25.25%0.093
FRC−8.26%−8.29%0.657
FEV1−2.98%+0.98%0.858
FEV1/VC−2.66%−0.51%0.374
DLCO+1.47%−16.04%0.022
C dyn+29.33%−5.88%0.179
Comparison of esophageal involvement and pulmonary HRCT scan data.

HRCT scan of the lungs revealed ILD appearance in 9 patients with SSc.

The prevalence of ILD was higher in patients with severe esophageal manometric disturbances compared with other patients (70% [n = 7/10] vs. 25% [n = 2/8]).

Furthermore, according to esophageal manometric impairment, HRCT revealed the following signs of ILD: parenchymal micronodules or nodules (n = 5), linear opacities (n = 7), irregularity of the interfaces (n = 6), ground-glass opacities (n = 6), honeycombing (n = 4), traction bronchiectases or bronchiolectases (n = 4), and architecture distortion (n = 3) in 7 patients with severe motor dysfunction; and parenchymal micronodules or nodules (n = 1), linear opacities (n = 1), and irregularity of the interfaces (n = 1) in 2 patients with moderate or normal motor involvement.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Esophageal involvement is frequent in SSc, occurring in as many as 50% to 90% of patients(37, 40, 43, 47–53). Esophageal impairment related to SSc is characterized by low pressure in the LES and dysfunction of smooth muscle motor activity (i.e., uncoordinated pressure waves and reduced or absent peristalsis) and predisposes to prolonged GER(37–40, 45, 52). It is still recognized to be associated with high morbidity in SSc patients, as motor dysfunction and GER may lead(37, 40, 51–53) to (a) inability to ingest sufficient calories (due to esophageal ulcers and strictures), resulting in weight loss and malnutrition and, at later stages, in both cachexia and electrolyte disturbances, and (b) endobrachyesophagus or “Barrett's esophagus” with its accompanying potential for adenocarcinoma degeneration.

Recently, many investigators have reported that GER may be one of the initiating factors of a variety of respiratory disorders, e.g., asthma, bronchiectasis, and recurrent acute pneumonia(45, 54–70). They have implicated microaspirations of gastric content into the lungs as the trigger mechanism in inducing pulmonary parenchymal lesions and have further noted that GER therapy could potentially improve symptoms and PFT parameters in these patients(54–70). Similarly, esophageal motor disturbances have also been postulated as favoring parameters of ILD(61–64, 69). However, few investigators have previously explored the relationship between esophageal and lung manifestations in patients with SSc, and the results of these series are conflicting(36, 38, 39, 71). Troshinsky et al(71), in a series of 39 SSc patients, have further found that PFT parameters tended to be similar in patients with abnormal or normal GER (evaluated by 24-hour intraesophageal pH recording).

Our prospective series is, to our knowledge, the first to have investigated the influence of esophageal motor impairment on both PFT and pulmonary HRCT parameters in patients with SSc. We considered a sample of 43 consecutive SSc patients without any prior selection based on clinical presentation (notably, digestive or pulmonary manifestations), which tends to be representative of the entire SSc population. In our experience, we have observed a correlation between both pulmonary and esophageal dysfunction during initial evaluation of SSc. We have demonstrated that patients with severe esophageal motor disturbances on manometry (associating both absent peristalsis and decreased LES pressure) experienced more numerous pulmonary alterations compared with other patients, i.e., marked lower median values of DLCO on PFT (P = 0.048) and both higher prevalence and degree of ILD changes on HRCT scan of the lungs (P = 0.037).

Our findings therefore confirm 3 previous PFT series' data in patients with SSc(36, 38, 39). Denis et al(36), in a manometric study of 24 SSc patients, have observed that only dynamic compliance values on PFT were significantly reduced in SSc patients with both absent peristalsis and decreased LES pressure on esophageal manometry. Lock et al(39), in another manometric trial of 43 SSc patients, have also reported an association between the degree of esophageal motor dysfunction and PFT abnormalities; values of TLC, FVC, and FEV1 were lower in the group of patients with abnormal esophageal motility. Finally, Johnson et al(38), in a series of 13 SSc patients, have found a correlation between the severity of both GER and pulmonary manifestations; there was a correlation between the marked decrease of DLCO levels on PFT and the degree of both direct (24-hour intraesophageal pH monitoring) and indirect (99mTc sulfur colloid aspiration scan) evidence for GER(38).

In the present series, the second main finding was a relationship between the degree of esophageal manifestations and the faster deterioration of lung manifestations at 2 years followup of SSc. Our study is the first to have investigated the influence of esophageal motor dysfunction on pulmonary parameters at 2 years followup of 18 SSc patients. Because SSc duration from diagnosis was less than 2 years, 25 patients did not undergo lung tests; thus, a selection bias in the 18 SSc patients at 2 years followup due to loss of initial randomness could be excluded. SSc patients with severe esophageal manometric involvement compared with other patients had a markedly faster decrease of DLCO median values on PFT and a higher prevalence (70% vs. 25%) and severity of ILD on HRCT scan of the lungs.

The pathologic mechanisms of ILD remain unknown in SSc. In the present series, 2 hypotheses are possible for the findings of significantly more frequent ILD in SSc patients with severe esophageal impairment.

First, ILD may be, at least in part, a complication of esophageal motor disturbances and associated GER. Although our study does not offer direct evidence that aspiration occurred, it suggests that GER may be one of the predisposing factors, as our patients with severe esophageal motor dysfunction had higher prevalence of evidence for ILD, both during initial evaluation and at 2 years followup, on PFT and on HRCT of the lungs—ILD changes on HRCT being further localized predominantly in pulmonary lower lobes. SSc-related esophageal impairment may result in repeated microaspirations of acid gastric content into the lungs, leading to histologic lesions of ILD, because LES weakness results in a loss of the prime barrier against GER and absence of peristalsis leads to prolonged GER due to impaired esophageal clearance (4, 36–40, 45, 52). In this instance, because we observed a marked correlation between the degree of esophageal motor disturbances and endoscopic mucosal abnormalities, we did not include a 24-hour pH measurement as a direct proof of GER in the initial evaluation of our SSc patients. Our data are therefore in accordance with previous series suggesting that ILD may be a complication of GER(61–64, 69). Although many investigators have remarked that aspiration pneumonia does not cause definite remodeling of lung parenchymal structure and subsequent fibrosis, Mays et al(61), using barium radiography, have noted an increased prevalence of GER (54% vs. 8.5%) in patients with ILD compared with those without. Moreover, Tobin et al(69), in 17 patients with biopsy-proven interstitial pulmonary fibrosis, have recently found that these patients had increased esophageal acid exposure (using intraesophageal pH recording) compared with control subjects; these authors(69) have therefore concluded that acid reflux may be a contributing factor in the pathogenesis of ILD.

Second, the relationship between esophageal and lung manifestations may also be due to a concomitant involvement of internal organs in the SSc process, resulting in ILD and fibrosis of esophageal smooth muscle. However, in this instance, we failed to find differences between SSc patients with severe esophageal motor dysfunction and those without, with respect to (a) median age at onset, (b) median SSc duration, (c) SSc subsets, and (d) other concomitant systemic complications of SSc, i.e., prevalence of digital pitting scars, joint and muscle manifestations, cardiac impairment (assessed by electrocardiogram and echocardiography), and renal involvement (as shown by similar values of both serum urea and creatinine levels). We therefore suggest that the observed correlation between the severity of esophageal motor disturbances and lung impairment, i.e., both decreased DLCO values on PFT and evidence for ILD on HRCT scan, may not be an expression of a more advanced SSc with both higher degree and extent of generalized fibrosis in our patients.

In conclusion, our series underscores a correlation between the severity of esophageal motor disturbances on manometry and evidence for ILD (i.e., marked deterioration of PFT parameters and both prevalence and degree of abnormalities consistent with ILD on HRCT) in SSc patients, suggesting that repeated microaspirations of gastric content into the lungs may be one of the contributing factors of ILD in SSc. From a practical point of view, our findings highlight the usefulness of esophageal manometry during initial evaluation of SSc in objectively defining the characteristics of motor disorders, particularly concerning the degree of esophageal dysfunction, that may influence both management and choice of medical therapy in patients. In turn, SSc patients with severe esophageal impairment (i.e., aperistalsis and decreased LES pressure) may require closer followup of both clinical and paraclinical (PFT and HRCT) lung parameters. In our experience, all patients with severe or moderate esophageal motor dysfunction have been given prokinetic therapy (i.e., domperidone or cisapride); these SSc patients may have required a more aggressive therapy of GER associating prokinetic and proton pump inhibitor, which may have resulted in decreased frequency of insidious and widespread lung damage related to GER. In turn, it is questionable whether therapy of GER in SSc patients with severe esophageal motor involvement would improve or stop the course of ILD or prevent ILD onset. Our series therefore requires further multicenter, prospective, and randomized trials with a larger number of patients with SSc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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