Abstract
Objective. To longitudinally evaluate esophageal dysmotility (ED) in patients with limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc).
Methods. We performed a retrospective review of all adult patients with SSc seen between 1995 and 2008. Patients were included if they had undergone 2 or more esophageal transit scintigraphy (ETS) studies at least 1 year apart. Data from 382 ETS studies of 102 patients with SSc were analyzed. Eighty patients had lcSSc and 22 patients had dcSSc. A grading system was used to quantify the degree of esophageal dysfunction, ranging from grade 0 (normal) to grade 3 (severe hypomotility). Change in esophageal motility over time was evaluated and compared between the limited and diffuse subtypes.
Results. Sixty-eight patients (66.7%) had an abnormal ETS study at any time. Of patients with dcSSc, 95.4% had an abnormal ETS study, compared to 58.5% of patients with lcSSc. dcSSc and regurgitation were independent risk factors for ED. There was no association between the presence of anticentromere antibodies or antitopoisomerase (anti-Scl-70) antibodies and an abnormal ETS study. Esophageal motility in patients with dcSSc worsened in 96% of cases compared with only 58.8% in those with lcSSc.
Conclusion. ED is more frequent in patients with dcSSc than in those with lcSSc, and is more likely to deteriorate over time. Given the potential associated risks of erosive esophagitis, Barrett’s esophagus, and esophageal cancer in patients with SSc, routine screening and monitoring for ED is advised.
Systemic sclerosis (SSc) is a chronic, multisystem autoimmune disorder manifested by excessive deposition of connective tissue in the skin and viscera. The inflammation, vascular dysfunction, and excessive fibrosis characteristic of both limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) commonly involve the gastrointestinal (GI) tract1. Esophageal function is affected in up to 90% of patients with SSc1,2,3,4. Symptoms of esophageal dysfunction may include dyspepsia, dysphagia, nausea, or vomiting, which can lead to weight loss, chronic cough, hoarse voice, pharyngitis, laryngospasm, asthma, and recurrent aspiration. Symptoms, however, may be unreliable in estimating the presence and extent of esophageal disease in SSc5. Early diagnosis is important to reduce the risk of complications6.
Esophageal dysfunction in SSc typically occurs within the lower two-thirds of the esophagus as a weakened lower esophageal sphincter (LES) and loss of peristalsis, allowing pathological reflux of acidic gastric contents into the esophagus6,7. Gastroesophageal reflux disease (GERD) may then lead to erosive esophagitis with ulceration, strictures, and fistulae. As a result, patients with SSc are at risk of developing Barrett’s esophagus and esophageal cancer7,8. Routine screening for esophageal dysfunction may be included in the initial evaluation of patients with SSc.
Esophageal transit scintigraphy (ETS) has been shown to be as effective as esophageal manometry in screening patients with esophageal motility disorders9. Using esophageal manometry as the “gold standard,” sensitivities and specificities up to 95% and 96%, respectively, have been reported10,11. As an indicator of esophageal dysmotility (ED) in both early and advanced SSc, ETS has a higher sensitivity than manometry and barium swallows5,12,13,14,15. In patients with SSc, ETS is easy to perform, and yields quantitative information suitable for serial studies to monitor disease progression and treatment efficacy.
Given the limited data evaluating the progression of ED in patients with SSc16,17, the objective of our study was to longitudinally evaluate esophageal motility and risk factors for progression of ED in patients with lcSSc and dcSSc.
MATERIALS AND METHODS
Patients
A total of 382 ETS studies from 102 patients with SSc based on the American Rheumatism Association diagnostic criteria18 were retrospectively reviewed. Every patient with SSc, regardless of whether they had any GI symptoms, had an ETS study ordered on their first visit and yearly thereafter. All patients had 2 or more ETS studies performed at least 1 year apart between January 1995 and December 2008. There were 91 women and 11 men, with a mean age of 51.6 years (range 19–80 yrs) and a mean disease duration of 6.9 ± 5.0 years from their first episode of Raynaud’s phenomenon (Table 1). At the time of the first ETS study, the classification into dcSSc and lcSSc types was based on distribution of skin thickness using the modified Rodnan skin score (MRSS)19, the diffuse cutaneous SSc type with skin tightness involving the trunk and/or proximal extremities. The mean MRSS was 10.4 ± 11.9. Eighty patients had lcSSc and 22 patients had dcSSc. At the time of their initial visit, each patient was tested for antibodies, including anticentromere antibodies (ACA) and anti-Scl-70 antibodies. Thirty-five patients (34.3%) were ACA-positive and 12 (11.8%) were anti-Scl-70 antibody-positive. At the time of their baseline ETS study, 56 patients (54.9%) had heartburn, 42 (41.2%) had regurgitation (defined by the patient-reported return of swallowed food into the mouth), and 6 (5.9%) had dysphagia. At any point during the period in which the patients were followed, 72 patients (70.5%) had heartburn, 58 (56.8%) had regurgitation, and 25 (24.5%) had dysphagia.
ETS
A 2-part evaluation using ETS was conducted in each patient, in both the upright (sitting) and supine positions. For each study, 0.25 mCi of 99mTc diethylene-triamine-pentaacetic acid was mixed with 10 ml of water. Patients arrived fasting for this study, and were instructed to take the radioactive bolus in their mouth and hold it until instructed to swallow in 1 gulp. A large-field-of-view gamma camera was used, and sequential 64 × 64 images were acquired in the anterior projection at 1 frame/s. Images were stored in a dedicated computer system. Data were analyzed using standard nuclear medicine software for generating time/activity curves from dynamic studies. Regions of interest were drawn for the upper, middle, and lower thirds of the esophagus. The time/activity curve from the upper esophagus was used as the control in assessing the integrity of the radioactive bolus: 1 bolus versus a fragmented bolus. A fragmented bolus invalidated the study. Interpretation was performed by 1 radiologist and was based on visual evaluation of time/activity curves derived from the middle and distal thirds of the esophagus. A study was considered normal (Grade 0) when there was more than 90% emptying of the esophagus in < 15 s. Esophageal transit time was considered mildly delayed (Grade 1) when 50%–90% emptying occurred in 30 s, moderate (Grade 2) when 50%–90% emptying occurred in 60 s, and severe (Grade 3) when < 50% emptying occurred in 60 s.
A patient was determined to have ED if any portion (upright proximal, upright distal, supine proximal, or supine distal) of the ETS revealed dysmotility. Progression of ED was observed and defined as worsening in severity of ED at either the proximal and/or distal esophagus by the end of the patient’s followup period.
Statistical analysis
Chi-square and Fisher’s exact test were used to compare ED rates between the various subgroups. The Wilcoxon rank-sum test was used to analyze the relationship between the number of ETS studies performed, length of followup, MRSS, and ED. Multiple logistic regression analysis was used to assess independent risk factors for ED. A p value < 0.05 was considered significant for all statistical tests.
RESULTS
The number of ETS studies performed was not significantly associated with the presence of ED. Mean ± SD, median, and range for number of ETS studies were similar for patients with and without ED (3.9 ± 1.8, 3.0, 2 to 8; and 3.4 ± 1.8, 3.0, 2 to 8, respectively; p = 0.08). Sixty-eight patients (66.7%) had an abnormal ETS study at any time. A significantly higher proportion of patients with dcSSc had an abnormal ETS study compared to those with lcSSc (95.4% vs 58.8%, respectively; p < 0.01; Table 2). The mean MRSS in patients with an abnormal ETS study was greater (12.5 ± 12.4, range 0–55) for those patients with a normal ETS study (5.9 ± 9.5, range 0–35.3; p < 0.01). There was no association between the presence of ACA or Scl-70 antibodies and an abnormal ETS study. Thirty-four of the 80 patients with lcSSc were ACA-positive. Of those, 20 (58.8%) had an abnormal ETS study compared with 58.7% of the patients who were ACA-negative (p > 0.99). Seven of the 22 patients with dcSSc were Scl-70-positive. All 7 had an abnormal ETS study, compared with 93.3% who were Scl-70-negative (p > 0.99). An abnormal ETS study was associated with the presence of heartburn at any time (p < 0.01) and regurgitation at any time (p < 0.01), but not with dysphagia (p = 0.1). Fifty-five (77.5%) patients taking antireflux medication had an abnormal ETS study, compared with 13 (41.9%) patients who were not (p < 0.01).
Using separate univariate analyses, patients with dcSSc, higher MRSS, the presence of heartburn or regurgitation at any time, and the use of antireflux medication were significantly associated with an abnormal ETS study. However, using multivariate analysis with a multiple logistic regression model, dcSSc and regurgitation at any time were the only independent findings that were significantly associated with an abnormal ETS study. Adjusted odds for an abnormal ETS study among patients with dcSSc were 12.7 times greater (95% CI 1.4–111.1) than for those patients with lcSSc (p = 0.02). Adjusted odds for an abnormal ETS study among patients with regurgitation at any time during followup were 5.8 times greater (95% CI 1.8–18.9) than for patients without regurgitation (p = 0.04).
Serial ETS studies were evaluated for progression of ED. Twenty-one patients (95.5%) with dcSSc had worsening ED on a subsequent ETS study (mean followup = 7.0 years), 1 patient (0.5%) remained unchanged, and none improved. In contrast, 47 patients (58.8%) with lcSSc had worsening ED on a subsequent ETS study (mean followup = 6.8 years), 15 (18.8%) remained unchanged, and 18 (22.5%) had an improved esophageal transit time on a subsequent ETS study (Table 3). Adjusted odds for a worsening ETS study (i.e., ED) among patients with dcSSc were 12.7 times the odds for patients with lcSSc (OR 12.7, 95% CI 1.4–111.1, p = 0.02). Stacked bar graphs illustrating progression of ED in patients with lcSSc and dcSSc are shown in Figure 1. Figure 1 illustrates that the number of patients who obtained serial ETS studies declined over time. However, the proportion of patients with more severe ED increased over time, particularly in the patients with dcSSc.
DISCUSSION
The GI tract is affected in 75%–90% of patients with SSc, with the esophagus being the most frequently involved portion1,2,3,4,20. Although studies have shown that up to 90% of patients with SSc have ED, many of these patients are asymptomatic4,5,21. In our study, the proportion of patients with ED by ETS was found to be 66.7%. Common esophageal manifestations in SSc include motility abnormalities, GERD, Barrett’s esophagus, adenocarcinoma, infectious esophagitis, and drug-induced esophagitis, with complications of GERD also including erosive esophagitis, bleeding, and stricture formation20. Patients with SSc who develop ED may develop early satiety, regurgitation of food, progressive weight loss, malnutrition, or impaction of food. In addition, ED in patients with SSc may correlate with the presence of interstitial lung disease (ILD)22. Proposed progression of GI involvement in SSc includes vascular damage (grade 0), neurogenic impairment (grade 1), and myogenic dysfunction, with the replacement of normal smooth muscle by collagenous fibrosis and atrophy (grade 2)2.
In accordance with previous published studies, we found that ED was more frequent and severe in patients with dcSSc than in those with lcSSc15,22,23,24,25,26. Those studies also demonstrated that ED was more frequent and severe in patients who are anti-Scl-70 antibody-positive and ACA-negative. Interestingly, however, and in contrast to these data, we found that in our patient population there was no association between the presence of anti-Scl-70 antibody or ACA and the finding of an abnormal ETS study. Multivariate analysis revealed that in addition to having diffuse subtype, the symptom of regurgitation was the only independent finding that was significantly associated with ED. Our patients who were taking antireflux medication were more likely to have an abnormal ETS study, suggesting that these patients were more symptomatic and had more severe esophageal involvement. A recent study by Pakozdi, et al demonstrated that although longterm therapy with lansoprazole aided in reducing gastroesophageal symptoms in patients with SSc, there was no beneficial effect in preventing the progression of ED27.
Prior to our study, there were limited published data evaluating the progression of esophageal dysfunction in patients with SSc. Baron and Arzoumanian longitudinally followed 19 patients with progressive SSc by ETS over 3 to 5 years. They noted a gradual deterioration of esophageal transit at both 20 s and 10 min. Deterioration occurred in 58.5% of followup ETS studies in patients at 20 s, and in 48% of patients at 10 min16. Dantas, et al studied the progression of esophageal involvement by manometry on 2 occasions with a median interval of 40 months in 17 females with SSc compared to 14 healthy females17. The LES pressure and amplitude of contractions in the esophageal body were lower in patients with SSc than in controls. In 16 of the 17 patients with SSc, no difference in LES pressure, esophageal contraction amplitude, duration, or velocity was observed between the first and second manometric evaluation. In only 1 patient with SSc, the distal esophageal contractions deteriorated from peristaltic to completely absent along with a decline in the LES pressure.
Our retrospective study included a larger sample of 102 patients with SSc. Our protocol with our patients with SSc has been to obtain a baseline ETS study at the initial evaluation, then on a yearly basis to monitor for ED, regardless of the presence of symptoms. Twenty-one out of 22 of our patients with dcSSc had deterioration of their ETS study compared to 47 out of 80 patients with lcSSc. Fifteen patients with lcSSc had no change in their ETS study on sequential examination, and interestingly, 18 patients with lcSSc showed improvement on subsequent ETS evaluation. These data help to provide important prognostic information to patients with SSc, suggesting that the vast majority of patients with dcSSc will have deterioration in esophageal involvement, whereas esophageal involvement in patients with lcSSc is not progressive in all cases. As patients with SSc are at risk of developing erosive esophagitis, Barrett’s esophagus, and esophageal cancer as a consequence of GERD secondary to ED, the results also suggest that routine sequential monitoring for esophageal dysfunction should be performed in all patients with SSc.
Our study is limited by its retrospective design and the lack of a control group for comparison. Patients were followed for varying durations, and although an attempt was made to obtain yearly ETS studies, the number of ETS studies performed varied from patient to patient. Medications known to alter esophageal function, such as calcium channel blockers and metoclopramide, were not taken into consideration.
Esophageal abnormalities are frequently found in patients with SSc. ED appears to be more frequent and severe in patients with dcSSc than in patients with lcSSc. Although prior data suggest that autoantibody status, particularly the presence of anti-Scl-70 antibody, is associated with ED, our results were not in accordance. ED is likely to deteriorate in most if not all patients with dcSSc, and may not be progressive in patients with lcSSc. Given the potential associated comorbidities, routine initial screening and serial monitoring for ED should be a part of the evaluation of patients with SSc. In this regard, ETS is a useful diagnostic tool to evaluate esophageal function and to monitor the severity of esophageal involvement in SSc5.
- Accepted for publication December 16, 2011.