Accepted Manuscript

Esophageal Motor Abnormalities in Patients with Scleroderma: Heterogeneity, RiskFactors, and Effects on Quality of Life

Michael D. Crowell, Sarah B. Umar, W. Leroy Griffing, John K. DiBaise, Brian E.Lacy, Marcelo F. Vela

PII: S1542-3565(16)30615-2DOI: 10.1016/j.cgh.2016.08.034Reference: YJCGH 54890

To appear in: Clinical Gastroenterology and HepatologyAccepted Date: 31 August 2016

Please cite this article as: Crowell MD, Umar SB, Griffing WL, DiBaise JK, Lacy BE, Vela MF,Esophageal Motor Abnormalities in Patients with Scleroderma: Heterogeneity, Risk Factors, and Effectson Quality of Life, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.08.034.

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Esophageal Motor Abnormalities in Patients with Scleroderma: Heterogeneity, Risk Factors,

and Effects on Quality of Life

Michael D. Crowell1, Sarah B. Umar

1, W. Leroy Griffing

2, John K. DiBaise

1, Brian E. Lacy

3, Marcelo

F. Vela1

1Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ

2Division of Rheumatology, Mayo Clinic, Scottsdale, AZ

3Department of Gastroenterology and Hepatology, Hitchcock Medical Center, Dartmouth,

Lebanon, NH

Running Head: Esophageal Motor Abnormalities in Scleroderma

Word Count: 3286 + abstract + 22 references + 3 tables + 1 figure + 1 supplemental table

Corresponding author: Michael D. Crowell, PhD, MACG; Division of Gastroenterology and

Hepatology; Mayo Clinic, 13400 East Shea Blvd, Scottsdale, AZ 85259; 480-301-6990;

Crowell.Michael@mayo.edu

CONFLICT OF INTEREST/STUDY SUPPORT:

A. Guarantor of the article: Michael D. Crowell, Ph.D., MACG, AGAF

B. Specific author contributions: All authors actively participated in the study, contributed to

writing the manuscript, and approved the final draft submitted. Michael D. Crowell was

responsible for study design, data collection, data analysis, and manuscript preparation and

submission. Brian Lacy, John DiBaise, Marcelo Vela, W.L. Griffin, and Sarah Umar participated in

data collection, interpretation of the data and manuscript preparation.

C. Financial support: This project received no financial support

D. Potential competing interests: None

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ABSTRACT (Word count: 257)

BACKGROUND & AIMS. Systemic scleroderma (SSc) is associated with esophageal aperistalsis

and hypotensive esophagogastric junction pressure, although there could be a gradation in

esophageal motor dysfunction. We characterized esophageal motor function by high-resolution

manometry (HRM), and assessed associations between SSc severity, health-related quality of

life (HRQOL), and HRM findings in patients.

METHODS: We performed a prospective study of 200 patients with SSc and 102 patients

without SSc (controls) who underwent HRM at the Mayo Clinic Arizona Rheumatology

Scleroderma Clinic for esophageal manometry, from May 2006 through January 2015. We used

data on integrated relaxation pressure, distal contractile integral and distal latency to classify

esophageal motility disorders according to the Chicago Classification v 3.0. A subset of subjects

(n=122) completed SSc-specific gastrointestinal symptom and HRQOL questionnaires. HRM

findings, symptoms, and HRQOL data were compared among diffuse SSc, limited SSc, and

controls. Categorical variables were compared using the χ2 or Fisher exact test; continuous

variables were compared using Mann-Whitney or Kruskal-Wallis test. Multivariable logistic

regression was used to assess the association between severity of esophageal dysmotility and

baseline clinical factors.

RESULTS: Among patients with SSc, 83 had diffuse SSc (42%) and 117 had limited SSc (58%).

Absent contractility was more frequent in patients with SSc than controls (56% vs 13%; P<.001).

HRM findings varied among the patients: absent contractility (56%) was the most frequent

diagnosis, followed by normal motility (26%), and ineffective esophageal motility (10%). Classic

scleroderma esophagus (esophagogastric junction pressure with absent contractility) was only

observed in 33% of patients (34% with diffuse SSc vs 32% limited SSc) (P=.880). Severe

esophageal dysmotility was associated with disease duration, interstitial lung disease, and

higher gastrointestinal symptom scores (P<.001). HRQOL was decreased in patients with SSc

and severe esophageal dysmotility.

CONCLUSION: Although severe dysmotility is more common in patients with SSc than controls,

we observed the so-called scleroderma esophagus in only a third of patients with SSc.

Esophageal motor function appears to be heterogeneous in SSc. Esophageal dysmotility

reduces HRQOL in patients with SSc.

KEY WORDS: High-resolution esophageal manometry; autoimmune disorder; dysphagia; reflux

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Systemic sclerosis (SSc) is an autoimmune disorder that frequently involves multiple

organ systems including the gastrointestinal (GI) tract. Involvement of the GI tract is the third

most frequent manifestation of SSc behind skin changes and Raynaud’s phenomenon, with up

to 90% of patients with SSc experiencing some GI symptom(1, 2). GI involvement in SSc

negatively impacts survival with an attributed mortality rate reported between 6% and 12%(3).

The mechanism by which SSc affects the GI tract is not established, but damage of small

vessels resulting in diffuse collagen deposition with thickening and fibrosis of the skin and

viscera has been suggested(4). Esophageal muscle dysfunction may also be secondary to

neuronal abnormalities that progress to muscle atrophy and loss of motor function in the distal

esophageal body(5). Progression of disease may result in diverse esophageal motor patterns

that may be associated with length or type of SSc(6).

The esophagus is commonly affected in SSc(7). Symptoms of esophageal involvement

include dysphagia, regurgitation and heartburn, and patients with these bothersome symptoms

have a significant decrease in quality of life(8, 9). Few studies have evaluated the association

between severe esophageal dysmotility and quality of life in SSc.

The incidence of dysphagia and gastroesophageal reflux disease in patients with SSc has

been typically associated with esophageal aperistalsis and a hypotensive esophagogastric

junction pressure (hEGJP). In fact, the combination of hEGJP and absent contractility in the

distal esophageal body is commonly referred to as classic scleroderma esophagus. It is unclear

whether aperistalsis is a typical manometric feature of all scleroderma patients, or whether a

gradation in esophageal motor function exists. High-resolution esophageal manometry (HRM)

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provides detailed characterization of motor function, and it has now become the gold standard

for diagnosing esophageal motility disorders(10). HRM provides a unique opportunity to

quantify motor abnormalities in scleroderma patients with greater accuracy and reproducibility

than conventional manometry. Our objectives were 1) to quantify esophageal motor function

using HRM in patients with SSc (Diffuse and Limited); 2) to evaluate the heterogeneity of

esophageal motor abnormalities in SSc compared to controls; 3) to evaluate the associations

between SSc severity and HRM patterns; and 4) to assess the association between esophageal

dysmotility and health-related quality of life in Patients with SSc.

Methods

Patients

Patients with SSc referred from the Mayo Clinic Arizona Rheumatology Scleroderma

Clinic for esophageal manometry between May 2006 and January 2015 were included. The

2013 American College of Rheumatology SSc criteria were used(11). Patients were classified as

having limited (lcSSc) or diffuse cutaneous (dcSSc) systemic disease based on the distribution of

skin involvement according to LeRoy et al(12). Limited disease had skin thickening involving the

extremities distal to the elbows and knees. Diffuse disease had skin thickening involving the

extremities proximally or the trunk. Patients were excluded if they had mixed connective tissue

disease (n=10), were unsubtyped (n=5), or if SSc was not confirmed at a final visit (n = 8).

Complete data were available for 200 patients (lcSSc =117 and dcSSc = 83). Consecutive

patients (n=115) with HRM studies between January and December 2015 were selected as

controls. The intent of the controls was to demonstrate the distribution of esophageal HRM

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patterns that would normally be encountered in consecutive patients from our center. After

excluding those with previous esophageal or gastric surgery (n = 8), hiatus hernia (n = 3), or SSc

(n = 2), 102 patients had complete HRM data. The study was approved by the Mayo Clinic

Institutional Review Board.

A subset of 122 patients with SSc completed validated questionnaires including the

UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Scale (GIT) 2.0 and the

Gastrointestinal Symptoms Severity Index (GISSI). The GIT is a validated 34-item questionnaire

measuring the impact of reflux, distention, diarrhea, soilage/fecal incontinence and

constipation on emotional well-being and social functioning in Patients with SSc. The total GIT

score captures the overall burden (severity) of SSc-associated GIT(13). The GISSI is a

multidimensional instrument designed to measure the frequency, severity and bothersomeness

of individual GI symptoms. The GISSI provides subscale scores for GERD/dysphagia, dyspepsia,

constipation, diarrhea/fecal incontinence, urinary incontinence and pelvic floor symptoms(14).

High Resolution Manometry

HRM was completed using a solid-state assembly with 36 circumferential pressure

sensors spaced 1 cm apart and analyzed using ManoView Analysis Software v3.01. (Medtronic

Inc, Shoreview, MN). The HRM protocol included a 5-minute baseline, followed by ten 5-ml

water swallows at 30 second intervals in a supine position. The integrated relaxation pressure

(IRP), distal contractile integral (DCI), and distal latency (DL) were measured and the Chicago

Classification (CC) v 3.0 applied to provide esophageal motility diagnoses(15). Resting

esophagogastric junction (EGJ) pressures were measured during the baseline recording period

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at mean- and end-expiration using the isobaric contour; mean EGJ pressure < 13 mmHg was

considered hypotensive.

Statistical Analysis

Results were presented as mean (95% CI or SD) or median (interquartile range, IQR)

unless otherwise specified. Between-group comparisons were made between SSc-patients by

subtype (dcSSc vs lcSSc) and between SSc and controls for baseline motility and HRM CC v3.0

classifications. To evaluate the association between GI symptoms and severity of SSc, patients

with absent contractility (AC) were compared with Patients with SSc with normal contractility.

Categorical variables were compared using Pearson’s χ2 or Fisher exact test and continuous

variables were compared using Mann-Whitney or Kruskal-Wallis tests, as appropriate.

Multivariable logistic regression was used to assess the association between severity of

esophageal dysmotility and baseline clinical characteristics and predictors. A difference

between groups was considered statistically significant at an alpha value of 0.05.

RESULTS

The total SSc patient group (n = 200) was primarily female (85%) with median (IQR) age of

54 (45-62) years. dcSSc was diagnosed in 83 (42%) and lcSSc in 117 (58%). No differences were

observed between the dcSSc and lcSSc subtypes in age (P = 0.781) or BMI (P = 0.174). The

proportion of females was higher in the lcSSc (91% vs 76%, P = 0.006). The Modified Rodnan

Skin Score (MRSS) was higher (P < 0.001) in dcSSc [19.43 (15.94-22.91) compared with lcSSc

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[7.41 (6.44-8.37)]. Dysphagia (125/200, 63%) and GERD (72/200, 36%) were the primary

indications for HRM and the groups were similar (P = 0.949).

HRM CC v3.0 classifications: SSc Subtype Comparison

CC v3.0 classifications were similar between dcSSc and lcSSc (P = 0.744). However, patients

with SSc in both subgroups showed significant heterogeneity (Figure 1). Absent contractility

(56%) was the most frequent diagnosis, followed by normal motility (26%), and ineffective

esophageal motility (IEM;10%). Other major disorders of peristalsis were found in 9% including

Jackhammer esophagus (JH; 2%), diffuse esophageal spasm (DES; 2%) EGJ outflow obstruction

(EGJOO; 2%), EGJOO plus Jackhammer esophagus (1%) and achalasia (ach; 3%; 1% subtype I, 1%

subtype II, 1% subtype III). HEGJP was observed in 40% (79/200) of patients and was not

different between dcSSc (36/83; 43%) and lcSSc (43/117; 37%; P = 0.380). Importantly, the

classic scleroderma esophagus, defined as ineffective or absent peristalsis along with

hypotensive EGJ pressure was observed in only 33% (66/200; 34% dcSSc vs 32% lcSSc; P =

0.880) of Patients with SSc. In fact, as shown above, esophageal motility was normal in one

fourth of Patients with SSc.

The subset of 122 Patients with SSc who completed validated questionnaires did not

significantly differ from the full SSc patient sample. The subsample included 47 patients with

dcSSc [79% female, aged 59 (50-68) yrs, BMI 23.05 (20.70-26.51) kg/m2] and 75 patients with

lcSSc [92% female, aged 61 (50-68) yrs, BMI 23.37 (20.45-27.77) kg/m2]. The groups were not

significantly different in gender, age, BMI or symptoms. The duration of SSc was significantly

longer in patients with lcSSc vs dcSSc in this sample [8 (3.5-15.5) yrs vs 4 (1-8) yrs; P = 0.003].

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There were no differences between the groups in the primary indication for the HRM study or

the HRM findings (Supplementary Table 1).

SSc versus Controls Comparison

The dcSSc and lcSSc subtypes were not substantially different and the data were combined

for comparison with the clinical control group. Patient characteristics and HRM measures are

shown in Table 1. The SSc group included more females and was slightly younger with a lower

BMI. Dysphagia and GERD were the primary indications for HRM in both groups, but more

patients with SSc were referred for dysphagia.

Significant differences were observed between patients with SSc and controls in CC v3.0

classifications (Table 1). AC was more frequently observed in patients with SSc (56% vs 13%),

whereas normal motility (26% vs 44%) was more frequent in controls. IEM (10% vs 22%) was

more frequent in controls likely because the AC criteria were more frequently observed in SSc.

Other major disorders were more frequent in controls, but were not uncommon in Patients

with SSc. In particular DES and EGJOO with DES were more frequently observed in the controls.

Interestingly, achalasia (6% vs 2%) was observed more often in the SSc group in these samples.

Not unexpectedly, weak peristalsis defined as AC or IEM was more common in the Patients with

SSc. Hypotensive esophagogastric resting pressure was observed more frequently in SSc, but

did not reach statistical significance (P = 0.075).

Gastrointestinal Symptoms and Quality of Life in SSc

Severity of Esophageal Dysmotility and Gastrointestinal Symptoms in SSc

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The association between GI symptoms and severity of esophageal dysmotility was assessed

in patients with SSc with AC (n = 65) compared with patients with SSc with normal contractility

(n = 37) with the GISSI. The AC group and normal group were similar in mean (SD) age [59 (13)

vs 57 (13) years; P = 0.586] and BMI [23.26 (4.36) vs 25.20 (5.98) kg/m2; P = 0.108). The AC

group included more females compared with the normal group [60 (92%) vs 27 (73%); P =

0.017]. No significant differences were noted in MRSS between the AC and normal group [12.08

(7.96) vs 14.89 (12.69); P = 0.306].

Patients with SSc with AC reported more severe heartburn (P = 0.003), dysphagia (P =

0.039), and chest pain (P = 0.021) (Table 2). Dyspeptic symptoms were also more frequent and

severe in patients with SSc with AC including abdominal pain (P = 0.022), abdominal discomfort

(P = 0.020), early satiety (P < 0.001), inability to finish a normal meal (P < 0.001), persistent

fullness (P < 0.001), diminished appetite (P = 0.002), and bloating (P = 0.032). The use of acid

suppression (92% vs 76%; P = 0.033) and prokinetic (11% vs 0%; P = 0.046) medications was

higher in patients with AC compared to those with normal esophageal motor function.

Esophagitis on EGD was also more frequent in AC patients (31% vs 16%; P = 0.033).

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Severity of Esophageal Dysmotility and Quality of Life in SSc

The association between GI symptoms, QoL, and severity of esophageal dysmotility was

further assessed in patients with SSc with AC compared with patients with SSc with normal

contractility using the GIT. On the GIT subscales for GI symptom severity, patients with SSc with

AC reported more severe Reflux (P < 0.001), Distention/Bloating (P = 0.007), Diarrhea (P =

0.031), and Fecal Soilage (P < 0.001), but not Constipation (P = 0.693) compared with patients

with normal esophageal motor function (Table 3). The GIT HRQOL Social subscale was more

impaired in the AC group compared with the normal SSc group (P = 0.043) and there was a

marginal difference for the GIT Emotional subscale (P = 0.074). The GIT total score was

significantly worse in the group with more compromised esophageal motility (P < 0.001). The

GIT findings did not change substantially after adjusting for acid suppression and prokinetic use.

Predictors of Severity of Esophageal Dysmotility in SSc

In univariate analyses length of SSc diagnosis (< 0.001), the presence of interstitial lung

disease (P=0.004), and pulmonary hypertension (P = 0.048) were significantly associated with

esophageal dysmotility; no such association was found for myopathy (P = 1.00), renal disease (P

= 1.00), or diabetes mellitus (P = 0.534). No significant associations were observed between SSc

antibodies and severity of esophageal dysmotility including anti-scl-70 (P = 0.545),

anticentromere (ACA) (P = 0.197), or anti-RNA polymerase antibody (P = 0.387). The use of acid

suppression (92% vs 76%; P = 0.033) and prokinetic medications (11% vs 0%; P = 0.046) were

more frequently reported in AC patients compared to those with normal esophageal motility.

No other associations were found between medication used to treat of SSc and esophageal

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dysmotility; specifically use of calcium channel blockers and severity of esophageal dysmotility

(nifedipine; P = 1.00 or amlodipine; P = 0.281). No association was found between hEGJP and

use of nifedipine (P = 0.095) or amlodipine (P = 1.00). Smoking history was not associated with

esophageal dysmotility. No association was found between esophageal dysmotility and

Raynaud’s (P = 0.620), but Raynaud’s was present in 95% of Patients with SSc in this sample.

In multivariable logistic regression the length of SSc diagnosis [1.18 (1.08, 1.33); P < 0.001],

the presence of interstitial lung disease [8.15 (2.60, 30.42); P < 0.001], and the GIT total scores

[7.22 (1.95, 35.01); P < 0.001] were positive predictors of the severity of esophageal dysmotility

as measured by AC compared with normal esophageal motor function even after controlling for

age, gender, and BMI. The Reflux/Dysphagia subscale of the GIT was most strongly associated

with esophageal dysmotility [4.93 (2.07, 13.92); P < 0.001).

DISCUSSION.

Classic teaching suggests that sclerodermatous involvement of the esophagus (classic

scleroderma esophagus) leads to hEGJP and absent contractility in the distal esophageal

body(7). Thus, many clinicians may assume that these abnormalities are found in most or all

Patients with SSc, and they may also interpret a normal esophageal manometry as evidence

against a diagnosis of scleroderma. In contrast, but consistent with the hypothesis of

heterogeneous esophageal motor function in SSc, HRM revealed significant variability in distal

smooth muscle esophageal contractile patterns in our scleroderma cohort, which is the largest

reported to date. Absent contractility (56%) was the most frequent diagnosis, followed by

normal motility (26%), and IEM (10%). Other major disorders were observed; Jackhammer

esophagus (2%), DES (2%) EGJ outflow obstruction (2%), EGJOO plus Jackhammer esophagus

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(1%) and achalasia (3%). Hypotensive basal EGJ pressure was observed in 40% of Patients with

SSc. The classic SSc esophageal motor pattern was only observed in a third of Patients with SSc.

These findings contrast with those of a smaller HRM study (n = 28) that only included patients

with ‘scleroderma esophagus’ motor patterns (16). In that study 15 of 28 patients were found

to have a hypotensive LES while all had complete absence of peristalsis in the mid-to-distal

esophageal body. A direct comparison to this study is difficult as patients were not grouped into

limited or diffuse categories, skin changes were based on 1980 American College of

Rheumatology guidelines, and Chicago classification for HRM was not used(16). Based upon our

findings showing “scleroderma esophagus” in only one third of Patients with SSc, we see little

value in using this term, which we believe should be abandoned. Instead, we favor instituting

measures to address this form of dysmotility when present in patients with dysphagia with or

without scleroderma. In addition, we would like to highlight the importance of educating

clinicians about the fact that the absence of aperistalsis and hEGJ does not rule out

scleroderma.

Scleroderma may result in diverse esophageal motor patterns that may be associated

with duration of disease or type of SSc(6, 17, 18). Roman et al. reported esophageal body

dysmotility in 14 of 14 dcSSc compared with 19 of 35 of lcSSc. Kimmel and colleagues reported

absent contractility in a higher proportion of dcSSc compared with lcSSc, but the differences did

not reach statistical significance (p=0.08). Other studies have been limited by small sample size

and the use of conventional esophageal manometry. We found no significant differences in CC

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v3.0 motility diagnoses and particularly no differences in the proportion with absent vs normal

contractility between patients with dcSSc and lcSSc.

Heterogeneous findings demonstrating variable effects of SSc on the esophagus is

clinically important, as patients with presumed scleroderma may be misdiagnosed if HRM does

not show the “classic” findings of aperistalsis and a hEGJP. The underlying cause of this variable

penetrance is not clear. Our analysis does not show a clear relationship with age, gender, or

BMI. As well, there does not appear to be any relationship to serologic markers, prior SSc

medication treatment or involvement of other organ systems other than the lung. The study by

Tang et al., more esophageal dysmotility in Patients with SSc with Raynaud’s than those without

(16). In our study, the relationship between Raynaud’s and HRM findings was not significant,

but nearly all our SSc sample had Raynaud’s.

We further evaluated the heterogeneity of esophageal motor abnormalities by

comparing patients with SSc to consecutive controls. Absent contractility was far more frequent

in patients with SSc compared with controls (56% vs 13%), whereas normal motility (26% vs

44%) was more frequently observed in controls. The classic scleroderma esophagus pattern of

hypotensive esophagogastric junction and absent distal esophageal contractility was not

observed in the consecutive controls. Major disorders of peristalsis was found more frequently

in controls, but were not uncommon in Patients with SSc.

Patients with SSc with compromised esophageal motility reported more severe heartburn,

dysphagia, and chest pain symptoms on the GISSI and more severe reflux on the GIT than

patients with SSc with the normal contractile pattern. Dyspeptic and lower GI symptoms were

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also more frequent and severe in patients with SSc with AC on both the GISSI and the GIT,

which might suggest more diffuse GI tract involvement in patients with SSc with severe

esophageal dysfunction.

Progression of GI involvement in SSc has been associated with worsening GI symptoms and

decreased HRQOL(19). Consistent with these reports, we found that more severe esophageal

dysfunction was associated with decreased condition-specific HRQOL. The GIT Social subscale

showed more impairment in the AC group compared with the normal SSc group and a trend

was observed for more impact on the GIT Emotional subscale. The GIT total score was

significantly worse in the group with more compromised esophageal motility. The total GIT

score reflects the overall burden (severity) of SSc-associated GIT and has been shown to have

high sensitivity for upper GI involvement in SSc(20).

In our study, the length of SSc diagnosis, the presence of interstitial lung disease, and the

GIT total scores were positive predictors of the severity of esophageal dysmotility as measured

by AC compared with normal esophageal motor function. No significant associations were

found for subtype of SSc, Modified Rodnan Skin Score (MRSS), SSc antibodies, or medications.

Similar to the findings of earlier reports(21, 22), our study did not show any correlation

between GI involvement and SSc subtype.

The current study was strengthened by the larger sample size, prospective data collection, a

well-established and carefully characterized scleroderma patient sample, the inclusion of a

clinical control group of consecutive patients, and the use of validated condition-specific,

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patient-reported symptom and QoL measures. Additionally, the study was strengthened by the

use of the most current high-resolution manometry methods and the CC v3.0 diagnostic

criteria. The study may be limited by the inclusion of patients referred specifically for upper GI

symptoms for manometry testing in a tertiary center and a predominantly Caucasian

population in the Southwestern United States that may not be representative of all SSc

populations. Even though the overall sample size was large, comparisons between CC v3.0

classifications often involved limited sample sizes.

Conclusions

Distal esophageal contractile patterns were heterogeneous among Patients with SSc. While

the most prevalent observation in Patients with SSc was absent contractility in the distal

esophageal body, the so-called scleroderma esophagus, characterized by hEGJP and absent

contractility, was seen in only a third of the scleroderma patients in our cohort. Thus, the

absence of this so-called scleroderma esophagus should not be used as evidence against a

diagnosis of scleroderma. Length of SSc diagnosis and the presence of interstitial lung disease

predicted more severe esophageal dysfunction. GI symptoms were more severe in patients

with SSc with absent contractility. When present, esophageal motor dysfunction negatively

impacts quality of life in Patients with SSc.

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Figure Legends.

Figure 1. HRM CC v3.0 Esophageal Diagnosis

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Society for Diseases of the Esophagus / I.S.D.E 2013;26:197-203.

17. Roman S, Hot A, Fabien N, et al. Esophageal dysmotility associated with systemic sclerosis: a

high-resolution manometry study. Diseases of the esophagus : official journal of the International

Society for Diseases of the Esophagus / I.S.D.E 2011;24:299-304.

18. Vischio J, Saeed F, Karimeddini M, et al. Progression of esophageal dysmotility in systemic

sclerosis. The Journal of rheumatology 2012;39:986-91.

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19. Khanna D. Health-related quality of life: a primer with focus on scleroderma. Scleroderma Care

Res 2006;3:3-13.

20. Bae S, Allanore Y, Furst DE, et al. Associations between a scleroderma-specific gastrointestinal

instrument and objective tests of upper gastrointestinal involvements in systemic sclerosis. Clinical and

experimental rheumatology 2013;31:57-63.

21. Abu-Shakra M, Guillemin F, Lee P. Gastrointestinal manifestations of systemic sclerosis.

Seminars in arthritis and rheumatism 1994;24:29-39.

22. Kimmel JN, Carlson DA, Hinchcliff M, et al. The association between systemic sclerosis disease

manifestations and esophageal high-resolution manometry parameters. Neurogastroenterology and

motility : the official journal of the European Gastrointestinal Motility Society 2016.

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Table 1. SSc vs clinical control patient characteristics and HRM CC v3.0 Esophageal Diagnosis (Diffuse vs

Limited Patients with SSc combined).

SSc (n = 200) Controls (n = 102) P-value

Age; median (IQR) yrs 53 (46-65) 58 (45-68) 0.062

BMI; median (IQR) kg/m2 23.70 (20.80-28.07) 26.99 (23.14-29.77 < 0.001

Female; n(%) 169 (85) 66 (65) <0.001

Primary Indication <0.001

Chest Pain; n(%) 3 (2) 11 (11)

Dysphagia; n(%) 125 (63) 36 (35)

GERD; n(%) 72 (36) 36 (35)

Other; n(%) 0 (0) 19 (19)

HRM CC 3.0 Diagnosis < 0.001*

Normal; n(%) 51 (26) 45 (44)

Absent Contractility; n(%) 112 (56) 13 (13)

IEM; n(%) 19 (10) 22 (22)

**Other Major; n(%) 18 (9) 22 (22)

EGJOO; n(%) 3 (2) 2 (2)

Jackhammer; n(%) 4 (2) 4 (4)

EGJOO + JH; n(%) 1 (1) 1 (1)

EGJOO + DES 0 (0) 3 (3)

DES; n(%) 4 (2) 7 (7)

Achalasia; n(%) 6 (4) 2 (2)

hEGJ; n(%) 79 (40) 29 (28) 0.075

Classic SSc; n(%) 66 (33) 0 (0) N/A

* Fischer’s exact test between SSc subtype and HRM diagnoses Normal, Absent Contractility, IEM, and Other

Major.

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** Statistical comparisons were not made between groups for Other Major subcategories due to small sample

sizes.

** IQR – interquartile range; BMI – body mass index; GERD – gastroesophageal reflux disease; EGJP –

esophagogastric basal pressure; IRP – integrated relaxation pressure; DL – distal latency; DCI – distal contractile

integral; IEM – ineffective esophageal motility; EGJOO – esophagogastric junction outflow obstruction; DES – distal

esophageal spasm; hEGJ – hypotensive esophagogastric junction resting pressure.

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Table 2. Gastrointestinal Symptom Severity Index in SSc with Normal vs Absent Contractility

HRM Comparisons - Subset

Normal Absent Contractility

Mean Std Dev Mean Std Dev P-Value

Abdominal Pain 2.17 3.29 3.92 4.14 0.022

Abdominal Discomfort 2.92 3.78 4.88 4.32 0.020

Dysphagia 1.17 2.38 2.43 3.66 0.039

Chest Pain 2.36 3.55 4.26 4.46 0.021

Nausea 2.47 3.50 2.11 3.26 0.609

Vomiting 0.31 1.33 0.77 2.10 0.178

Diminished Appetite 2.06 3.21 4.48 4.38 0.002

Early Satiety 1.94 3.15 5.88 4.52 <0.001

Unable to finish meal 2.08 3.37 5.25 4.53 <0.001

Bloating 2.97 4.53 4.80 4.95 0.032

Heartburn 3.72 3.57 6.18 4.33 0.003

Belching 2.06 3.55 2.71 3.99 0.400

Early Fullness 2.39 3.60 5.62 4.32 <0.001

Regurgitation 1.56 3.19 2.48 3.73 0.195

Cough 3.19 3.35 3.51 3.86 0.671

Asthma 1.72 3.55 1.03 2.58 0.309

*GISSI symptom scores range from 0 – 14 points; higher scores indicated increased symptom severity.

** Includes score for all patients that reported the symptom – zeros included

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Table 3. UCLA GIT 2.0 - Patients with SSc with AC compared with Patients with SSc with normal

contractility

Normal Absent Contractility

Mean Std Dev Mean Std Dev P-Value

GIT REFLUX 0.43 0.58 0.89 0.60 < 0.001

GIT DISTENTION 0.73 0.86 1.23 0.86 0.007

GIT SOILAGE 0.14 0.43 0.63 0.93 < 0.001

GIT DIARRHEA 0.63 0.28 0.77 0.38 0.031

GIT SOCIAL 0.23 0.45 0.41 0.52 0.043

GIT EMOTIONAL 0.39 0.72 0.67 0.78 0.074

GIT CONSTIPATION 0.67 0.55 0.71 0.53 0.693

GIT TOTAL 0.42 0.41 0.76 0.50 < 0.001

*UCLA SCTC GIT 2.0 scores range from 0 – 3; 0 indicates better health and 3 worse health

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Supplemental Table 1. Diffuse vs Limited SSc patient characteristics and HRM summary measures

SSc Diffuse (n= 47) SSc Limited (n = 75) P-value

Age; median (IQR) yrs 59 (50-68) 61 (50-68) 0.954

BMI; median (IQR) kg/m2 23.05 (20.70-26.51) 23.37 (20.45-27.77) 0.651

Female; n(%) 37 (79) 67 (92) 0.052

Length SSc Dx; yrs 4 (1-8) 8 (3.5-15.5) 0.003

Primary Indication 0.930

Chest Pain; n(%) 1 (1) 2 (2)

Dysphagia; n(%) 30 (64) 46 (61)

GERD; n(%) 16 (35) 28 (37)

HRM CC 3.0 Diagnosis 0.233*

Normal; n(%) 20 (43) 16 (22)

Absent Contractility; n(%) 21 (45) 42 (57)

IEM; n(%) 3 (6) 7 (9)

**Other Major; n(%) 3 (6) 10 (13)

EGJOO; n(%) 1 (2) 5 (7)

Jackhammer; n(%) 2 (4) 2 (1)

EGJOO + JH; n(%) 0 (0) 1 (1)

DES; n(%) 1 (1) 3 (3)

Achalasia I; n(%) 0 (0) 1 (1)

hEGJ; n(%) 18 (38) 26 (35) 0.703

Classic SSc; n(%) 12 (26) 24 (32) 0.542

* Fischer’s exact test between SSc subtype and HRM diagnoses Normal, Absent Contractility, IEM, and Other

Major.

** Statistical comparisons were not made between groups for Other Major subcategories due to small sample

sizes.

** IQR – interquartile range; BMI – body mass index; GERD – gastroesophageal reflux disease; EGJP –

esophagogastric basal pressure; IRP – integrated relaxation pressure; DL – distal latency; DCI – distal contractile

integral; IEM – ineffective esophageal motility; EGJOO – esophagogastric junction outflow obstruction; DES – distal

esophageal spasm; hEGJ – hypotensive esophagogastric junction resting pressure.