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- PATIENTS AND METHODS
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.
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- PATIENTS AND METHODS
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.