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Gastroesophageal Reflux Incites Interstitial Lung Disease in Systemic Sclerosis: Clinical, Radiologic, Histopathologic, and Treatment Evidence

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Objectives

Interstitial lung disease (ILD) is currently the main cause of death in systemic sclerosis (SSc) and has an unknown pathogenesis. Gastroesophageal reflux (GER) has been strongly implicated as a cause of ILD in several lung diseases, including SSc-ILD. This review summarizes clinical, radiologic, histopathologic, and treatment aspects of GER in SSc-ILD.

Methods

The PubMed database was searched using the following keywords: “systemic sclerosis, scleroderma, interstitial lung disease, and gastroesophageal reflux.” The research was limited to English-language studies that included SSc patients with ILD.

Results

Pulmonary function tests were related with the presence of GER in several esophageal functional tests (esophageal endoscopy, pH monitoring, and manometric analysis). Regarding the histopathologic data, a pattern called centrilobular fibrosis was described in 21% of 28 lung biopsies, with a bronchocentric distribution and with an intraluminal content resembling gastric fluid. Radiologic evidence of esophageal dilation is very frequent in SSc patients, and consolidation with a patchy distribution was almost exclusively found in SSc patients with centrilobular fibrosis lung pattern. Furthermore, high levels of serum KL-6, a marker of epithelial injury, are indicative of active ILD in SSc disease.

Conclusions

The association of GER with SSc-ILD is strongly supported by several studies. An aggressive treatment for reflux is recommended in all SSc patients with ILD; however, future studies need to be performed to prove a long-term benefit.

Section snippets

Idiopathic Pulmonary Fibrosis

In IPF, there is increasing indirect evidence showing that GER may contribute to pathogenesis in some or all cases. Tobin and colleagues were the first to document a high prevalence of reflux in IPF, present in 16 of 17 patients, which was, however, associated with typical reflux symptoms in only 25% of cases (26). In a larger prospective study of 65 IPF patients, undergoing 24-hour pH monitoring and esophageal manometry (27), reflux was present in 87%, with reflux to the proximal esophagus in

Bronchoalveolar Lavage Fluid

The measurement of pepsin and bile acids in BALF has been used mainly to detect GER in children with pulmonary symptoms (31, 32). Farrell and colleagues analyzed BALF for the presence of pepsin in 33 children with GER and compared the results to asymptomatic control subjects (31). Pepsin levels were significantly higher in patients than in the control group, with a high degree of sensitivity (80%) and specificity (100%) to detect pulmonary aspiration. All control asymptomatic subjects were

Histopathologic Data

Chronic inflammation of bronchioles (“diffuse aspiration bronchiolitis”) caused by recurrent aspiration of foreign particles was described in 0.6% of nearly 5000 consecutive autopsies (32). The mean age of the patients autopsied was greater than 80 years and clinical correlations demonstrated an association with neurologic disorders, dementia, and cardiovascular diseases. Histologic findings were characterized by a lymphoplasmacytic cellular infiltration in the bronchioles and a high incidence

Radiologic Data

In a retrospective study that analyzed tomographic evidence of esophageal dilation in 25 SSc patients, a prevalence of 80% having a diameter ranging from 12 to 40 mm was found (45). None of these patients had significant esophageal symptoms, revealing that tomographic observation of esophageal dilation could be a useful tool to detect this common feature of SSc and may perhaps prevent future consequences such as ILD. In a larger and controlled study (46), more than 100 SSc patients and controls

Others

The incitation of the immune response by GER might be initiated in lung epithelial cells, acting as an immunologic trigger as demonstrated by Imokawa and coworkers more than a decade ago (47). They showed that tissue factor, which is known to be increased in lung fibrosis, was mainly produced by type II pneumocytes from IPF and SSc-ILD patients (47). Epithelial injury incited by GER or other mechanisms might contribute to the abnormal fibroproliferative repair processes seen in SSc-ILD and

Long-Term Follow-Up

So far, only 1 study has compared immunosuppressive treatment for lung fibrosis with an exclusive and aggressive GFR treatment in SSc-ILD (43). Eighteen SSc patients with NSIP lung pattern (surgical lung biopsy) were treated with monthly cyclophosphamide (0.5-1 g/m2, IV) for 12 months and compared with 4 SSc patients with isolated CLF treated with high-dose proton pump inhibitor and prokinetic medications also for 1 year. Lung function parameters were comparable between groups at baseline and

Summary

  • 1

    In SSc-ILD, substantially reduced PFTs were associated with the presence of GER (esophageal endoscopy, pH monitoring, and manometry)

  • 2

    The lung histologic pattern of CLF that is related to GER was observed in SSc patients with ILD

  • 3

    A central and patchy distribution of the lesions on HRCT is suggestive of a GER pathogenesis

  • 4

    In active SSc-ILD, the presence of several specific markers suggests that GER might damage epithelial cells

  • 5

    The value of aggressive antireflux treatment in SSc-ILD patients merits

Conclusion

An association of GER with SSc-ILD and IPF has been observed in several distinct studies over the past 20 years (Table 3). Recently, prospective esophageal function analyses together with radiographic and histologic evidence have supported this strong correlation and have identified GER as a potential villain in the pathogenesis of ILD, especially in those patients with NSIP and CLF. Furthermore, GER warrants aggressive treatment in all patients with proven ILD, including SSc-ILD.

We encourage

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    Richard Silver receives grant support from Actelion, Bristol Myers Squibb, Boehringer Ingelheim, and United Therapeutics and acts as Speakers bureau for Actelion, Genentech, and Takeda.

    Romy Beatriz Christmann and Athol Wells have no conflicts of interest to disclose.

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