Abstract
Introduction:
In this study we assessed high-resolution manometry (HRM) findings in patients with dermatomyositis and polymyositis.
Methods:
From 2008 to 2015, we performed a cross-sectional study of myositis patients. A survey of esophageal symptoms and HRM data were analyzed and compared among different clinical and serologic groups.
Results:
Twenty-four (45%) of the 53 patients included in the study had manometric involvement that was not correlated with any esophageal symptom (P = 0.8). Failed waves (34% vs. 0%, P = 0.004) and decreased upper esophageal sphincter pressure (50 vs. 70 mm Hg, P = 0.03) were more common in polymyositis than in dermatomyositis patients. Jackhammer esophagus was more common in anti–TIF1-γ patients (30% vs. 9%, P = 0.04), and lower esophageal sphincter involvement (47% vs. 25%, P = 0.03) was more prevalent in patients with the antisynthetase syndrome.
Conclusions:
Esophageal involvement is common in myositis patients, but it correlates poorly with esophageal symptoms. Specific clinical and serologic groups have different manometric features.
Keywords: autoantibodies, dermatomyositis, dysphagia, esophageal involvement, high-resolution manometry, polymyositis
Idiopathic inflammatory myopathies (IIM) are autoimmune systemic diseases characterized by variable skeletal muscle, skin, and lung involvement.1 Dysphagia has been reported in 32%–84% of IIM patients, mainly as a reflection of the inflammation of the skeletal muscle of the pharynx and the upper third of the esophagus.2 Interestingly, some investigators have described involvement of the lower part of the esophagus. This part of the gastrointestinal tract is comprised of smooth muscle, which is not the usual target of the inflammatory response in IIM,3–5 but it is commonly involved in other autoimmune diseases, such as systemic sclerosis.6
High-resolution esophageal manometry (HRM) is a new method to assess esophageal motility using a catheter that contains more pressure-recording channels than conventional manometry (between 20 and 36). These channels, spaced at 1-cm intervals, provide higher spatial resolution to detect motor abnormalities limited to a short segment of the esophagus.7 The normal values for HRM have been well defined in both American and European populations.8–12 Chicago Classification v3.0, released in 2015, was developed to categorize esophageal motility disorders utilizing HRM.9
Although the highest incidence of dysphagia (65%–86%) has been reported in inclusion-body myositis (IBM), 30%–60% of polymyositis (PM) and 18%–20% of dermatomyositis (DM) patients have this manifestation of the disease.13,14 Although dysphagia in DM and PM responds better to treatment than in IBM,14 esophageal involvement has been less studied in these 2 diseases.
In this study we examined the HRM findings and the esophageal symptoms among clinical and serologic groups of patients with DM and PM.
METHODS
Patients.
From November 2008 to January 2015, a sample of consecutive patients from the Vall d’Hebron Hospital myositis cohort of patients with probable or definite PM or DM according to Bohan and Peter criteria1 were recruited for this study. Patients with IIM who fulfilled criteria for another defined connective tissue disease were included as myositis overlap syndrome cases, and those with a diagnosis of cancer within 3 years of the diagnosis of myositis were considered cancer-associated myositis (CAM) cases. No patients with sporadic IBM were included in the study. Serologic groups were defined according to the positivity of the different autoantibodies (antisynthetase syndrome, anti–TIF1-γ, anti-PM/Scl, and anti-Ro52).
All patients who participated received an esophageal symptom survey and subsequently underwent HRM (both during the same day). Independent operators who were not aware of the results of the other tests or the patients’ clinical characteristics performed and interpreted all examinations. Creatine kinase (CK) and forced vital capacity (FVC) values obtained closest to the time of manometry were collected retrospectively through chart review. FVC values were expressed as percentages that were adjusted according to reference values proposed by Roca15 for the Mediterranean population. The hospital ethics committee approved the study protocol and patients gave informed consent for all the procedures.
Interstitial lung disease (ILD) was established based on American Thoracic Society criteria using a multidisciplinary approach that combined clinical, radiologic, and pathologic information, as appropriate.16
Autoantibody Detection.
Myositis-specific and associated autoantibodies were identified by enzyme-linked immunoassay (ELISA) or line immunoassay (Myositis Profile Euroline; Euroimmun, Lübeck, Germany),17 and were confirmed by RNA or protein immunoprecipitation assay with radiolabeled HeLa cells.18 Autoantibodies present in > 10% of the patients were considered as a grouping variable for statistical analysis.
Esophageal Symptom Survey.
The dysphagia survey included 5 esophageal symptoms: dysphagia for liquids; dysphagia for solids; heartburn; regurgitation; and chest pain. Individual scores for each symptom were obtained according to the following scoring system: 0 = never; 1 = less than once a month; 2 = monthly; 3 = weekly; 4 = daily; and 5 = with every meal or >3 times daily. Individual symptoms were considered clinically significant when the score was ≥3, as previously reported.19
High-Resolution Manometry.
HRM was performed in all patients using a solid-state catheter with 36 circumferential sensors. The sensors were spaced 1 cm apart along the intra-corporal part of the catheter assembly (Sierra Scientific Instruments, Inc., Los Angeles, California) (Fig. 1).
FIGURE 1.
Representation of the esophagus with the high-resolution manometry catheter inside. The central scale shows the 36 circumferential sensors placed along the esophagus, spaced by 1 cm.
Fasting for a minimum of 8 hours was required before the procedure. All drugs that could interfere with esophageal motility were discontinued. The catheter was introduced transnasally with the patient seated, until the most distal recording sensors were correctly placed in the stomach. Once positioned, the catheter was fixed in place by taping it to the nose. Subsequently, the patient adopted the supine position.
The protocol started with the measurements of the basal sphincter pressures after a 30-second period baseline recording. During this time, the patient was requested to breathe normally and not swallow. A minimum of 10 swallows of water (5 ml each) were then indicated, spaced by 30 seconds. The morphology of the peristaltic waves (hypertonic, failed, hypotonic, fragmented, and normal waves), upper (UES) and lower (LES) esophageal sphincter pressures (normal UES pressure: 34–104 mm Hg; normal LES pressure: 15–47 mm Hg), and specific HRM measurements [distal contractile integral (DCI), integrated relaxation pressure (IRP), intrabolus pressure (IBP), and distance contractile latency (DL)] were calculated for each examination using dedicated software (ManoView; Given Imaging, Yoqneam, Israel). To adapt the HRM reports to actual definitions, all examinations were reviewed retrospectively at the end of the study according to the Chicago Classification v3.0. Thus, each HRM was categorized into 1 of the following groups: normal esophageal motility; ineffective esophageal motility; absent contractility; jackhammer esophagus (a disorder characterized by high-amplitude peristaltic contractions in the distal esophagus); esophagogastric junction (EGJ) outflow obstruction; achalasia type I, II, or III; distal esophageal spasm; or fragmented peristalsis.8
Statistical Analysis.
Dichotomous variables are expressed as percentages and absolute frequencies. Continuous variables are expressed as mean [standard deviation (SD)] or as medians and first and third quartiles (Q1–Q3), as appropriate.
Univariate comparisons between groups were made using the Wilcoxon rank sum test or Student t-test for continuous variables, and the Fisher exact test or chi-square test for categorical variables. The Pearson coefficient was used to measure correlations between continuous variables. Multiple linear regression was used to explore the association between the FVC and manometric parameters, adjusting for possible confounding variables (age, gender, and autoantibody status).
Statistical analyses were performed using Stata version 13 (StataCorp, Inc., College Station, Texas), following the recommendations of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement for reporting results of observational studies.20 Because this was an exploratory study, a 2-sided P < 0.05 without multiple comparison adjustment was considered statistically significant.21
RESULTS
Patients.
Fifty-three consecutive adult patients were included in the study (79% women; median age at manometry: 60 years): 21 had PM; 24 had DM; 5 had CAM; and 3 had an overlap syndrome. Of these 53 patients, 16 presented with antisynthetase syndrome (AS), 10 were positive for anti–TIF1-γ, 8 for anti-PM/Scl, and 16 for anti-Ro52. Among the 5 patients who had CAM, 3 were positive for anti–TIF1-γ. Among the 3 patients with overlap syndrome, 2 met criteria for systemic sclerosis according to the American College of Rheumatology/European League against Rheumatism collaborative initiative criteria22 (both positive for anti-PM/Scl), and 1 fulfilled lupus criteria23 (positive for anti-Ku). No patient had a history of surgery or radiotherapy involving the upper airways or known neurologic, psychiatric, or otorhinolaryngological diseases that may have caused secondary esophageal motility disorders.
Clinical and serologic groups were homogeneous with regard to gender distribution, age at manometry, and time from the onset to manometry. Maximum CK was lower in the DM patients (600 IU/L) than in the remaining patients, and ILD was highly prevalent in the AS (93%) and anti-PM/Scl (88%) groups, yet not detected in any anti–TIF1-γ patient. The median time from manometry to CK assessment was 91 days, and from the manometry to FVC assessment it was 251 days (Tables 1 and 2).
Table 1.
Clinical features and esophageal symptoms by clinical group
| Clinical groups | ||||
|---|---|---|---|---|
| DM (n = 24) | PM (n = 21) | CAM (n = 5) | Total (n = 53) | |
| Gender (women) | 79% (n = 19) | 76% (n = 16) | 80% (n = 4) | 79% (n = 42) |
| Age at manometry (years) | 62.7 (14.3) | 53 (16.1) | 66.7 (20) | 58.3 (16.4) |
| Time from onset (years) | 5.2 (6.4) | 5 (4.8) | 2.9 (2.7) | 5 (5.4) |
| Maximum CK (IU/L) | 600 (300–2,000)* | 1,678 (900–3,900) | 1,149 (375–2,254) | 1,000 (445–3,300) |
| ILD | 46% (n = 11) | 0% (n = 0) | 100% (n = 5) | 47% (n = 25) |
| Autoantibodies | ||||
| Anti-Jo1 | 17% (n = 4) | 38% (n = 8)* | 0% (n = 0) | 23% (n = 12) |
| Anti-PL7 | 8% (n = 2) | 0% (n = 0) | 0% (n = 0) | 4% (n = 2) |
| Anti-PL12 | 4% (n = 1) | 5% (n = 1) | 0% (n = 0) | 4% (n = 2) |
| Anti-Mi2 | 17% (n = 4)* | 0% (n = 0) | 0% (n = 0) | 8% (n = 4) |
| Anti-TIF1-γ | 21% (n = 5) | 10% (n = 2) | 60% (n = 3)* | 19% (n = 10) |
| Anti-PM/Scl | 13% (n = 3) | 14% (n = 3) | 0% (n = 0) | 15% (n = 8) |
| Anti-Ro52 | 21% (n = 5) | 43% (n = 9) | 40% (n = 2) | 30% (n = 16) |
| Esophageal symptoms | 46% (n = 11) | 43% (n = 11) | 80% (n = 0) | 45% (n = 24) |
| Dysphagia to solids | 25% (n = 6) | 29% (n = 9) | 40% (n = 0) | 26% (n = 14) |
| Dysphagia to liquids | 8% (n = 2) | 24% (n = 6) | 40% (n = 0) | 17% (n = 9) |
| Pyrosis | 8% (n = 2) | 10% (n = 6) | 40% (n = 0) | 11% (n = 6) |
| Regurgitation | 17% (n = 4) | 10% (n = 8) | 0% (n = 0) | 11% (n = 6) |
| Painful swallowing | 8% (n = 2) | 0% (n = 6) | 20% (n = 0) | 6% (n = 3) |
Comparisons made between each group (column) and the rest of the sample. Continuous variables are expressed as mean (SD) or as median (Q1–Q3), as appropriate. Qualitative variables are expressed as percent (n). DM, dermatomyositis; PM, polymyositis; CAM, cancer-associated myositis; ILD, interstitial lung disease.
P < 0.05.
Table 2.
Clinical features and esophageal symptoms by serologic group
| Serologic groups | |||||
|---|---|---|---|---|---|
| AS (n = 16) | Anti-TIF1-γ (n = 10) | Anti-PM/Scl (n = 8) | Anti-Ro52 (n = 16) | Total (n = 53) | |
| Gender (women) | 69% (n = 11) | 100% (n = 10) | 75% (n = 6) | 63% (n = 10) | 79% (n = 42) |
| Age at manometry (years) | 51.9 (13.5) | 58.7 (22.4) | 50.1 (17.3) | 57.8 (15) | 58.3 (16.4) |
| Time from onset (years) | 4 (7.9) | 3.2 (2.6) | 4.9 (4.3) | 4 (4) | 5 (5.4) |
| Maximum CK (IU/L) | 1,489 (636–4,185) | 1,000 (479–2,174) | 1,346 (729–2,048) | 1,346 (729–2,048) | 1,000 (445–3,300) |
| ILD | 94% (n = 15)*** | 0% (n = 0)** | 88% (n = 7)* | 56% (n = 9) | 47% (n = 25) |
| Autoantibodies | |||||
| Anti-Jo1 | 75% (n = 12)*** | 0% (n = 0) | 0% (n = 0) | 38% (n = 6) | 23% (n = 12) |
| Anti-PL7 | 13% (n = 2) | 0% (n = 0) | 0% (n = 0) | 6% (n = 1) | 4% (n = 2) |
| Anti-PL12 | 13% (n = 2) | 0% (n = 0) | 0% (n = 0) | 6% (n = 1) | 4% (n = 2) |
| Anti-Mi2 | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 8% (n = 4) |
| Anti-TIF1-γ | 0% (n = 0)* | — | 13% (n = 1) | 13% (n = 2) | 19% (n = 10) |
| Anti-PM/Scl | 0% (n = 0) | 10% (n = 1) | — | 13% (n = 2) | 15% (n = 8) |
| Anti-Ro52 | 50% (n = 8) | 20% (n = 2) | 25% (n = 2) | — | 30% (n = 16) |
| Esophageal symptoms | 38% (n = 6) | 70% (n = 7) | 38% (n = 3) | 56% (n = 9) | 45% (n = 24) |
| Dysphagia to solids | 25% (n = 4) | 50% (n = 5) | 25% (n = 2) | 38% (n = 6) | 26% (n = 14) |
| Dysphagia to liquids | 19% (n = 3) | 20% (n = 2) | 25% (n = 2) | 25% (n = 4) | 17% (n = 9) |
| Pyrosis | 6% (n = 1) | 20% (n = 2) | 0% (n = 0) | 6% (n = 1) | 11% (n = 6) |
| Regurgitation | 19% (n = 3) | 0% (n = 0) | 13% (n = 1) | 25% (n = 4) | 11% (n = 6) |
| Painful swallowing | 0% (n = 0) | 20% (n = 2) | 13% (n = 1) | 0% (n = 0) | 6% (n = 3) |
Comparisons made between each group (column) and the rest of the sample. Continuous variables are expressed as mean (SD) or as median (Q1–Q3), as appropriate. Qualitative variables are expressed as percent (n). AS, antisynthetase syndrome; ILD, interstitial lung disease.
P < 0.05.
P < 0.01.
P < 0.001.
Esophageal Symptoms.
Twenty-four (45%) patients had significant esophageal symptoms at the time of the HRM. Dysphagia to solids was the most common symptom (26%, n = 14), followed by dysphagia to liquids (17%, n = 9) and then pyrosis (11%, n = 6). No significant differences were found between the clinical and serologic groups (Tables 1 and 2).
High-Resolution Manometry.
Wave Morphology and High-Resolution Manometry Parameters.
Compared with the rest of the patients, PM patients had an increased percentage of failed waves (46% vs. 16%, P = 0.006) and significantly decreased UES pressure (47 vs. 70 mm Hg, P = 0.04).
Regarding the different autoantibody groups, anti–TIF1-γ patients had a higher DCI (2,848 vs. 1,144 mm Hg/cm·s, P = 0.05) and IBP (23 vs. 18 mm Hg, P = 0.05) and more fragmented waves (2.2%, P = 0.002) than the rest of the sample. Moreover, AS patients had decreased LES pressure (17 vs. 23 mm Hg, P = 0.04) and an increased percentage of low LES pressure values (44% vs. 16%, P = 0.04) (Tables 3 and 4).
Table 3.
Manometric features, wave morphology, and Chicago Classification v3.0 by clinical group
| Clinical groups | ||||
|---|---|---|---|---|
| DM (n = 24) | PM (n = 21) | CAM (n = 5) | Total (n = 53) | |
| DCI (mm Hg/cm·s) | 1,428 (959–2,660) | 775 (0–1,798) | 3,874 (892–4,767) | 1,311 (370–2,900) |
| IRP (mm Hg) | 10 (6.5–12) | 8 (5–12) | 6 (5–12) | 10 (5–12) |
| DL (s) | 6 (5–7) | 5 (0–6) | 7 (5–7) | 6 (5–7) |
| IBP (mm Hg) | 19 (15–25) | 19 (15–22) | 19 (15–27) | 19 (15–22.5) |
| Wave morphology [mean %] | ||||
| Hypertonic | 2.5 (7.2) | 4.8 (12.9) | 13.4 (30) | 4.9 (13.6) |
| Failed | 16.2 (28.7) | 45.9 (42)** | 22 (43.8) | 27.8 (37.7) |
| Hypotonic | 14.5 (22.2) | 3.8 (11.5)* | 4 (8.9) | 9.4 (18) |
| Fragmented | 0.4 (2) | 0.5 (2.2) | 0 (0) | 0.4 (1.9) |
| Normal | 66.4 (35) | 45.1 (38.4) | 60.6 (43.7) | 57.5 (37.3) |
| Pharyngeal pressure (mm Hg) | 11.5 (9–17.5) | 14 (9–17) | 14 (9–15) | 12 (9–17) |
| UES pressure (mm Hg) | 71 (39–93.5) | 47 (26–65)* | 70 (32–72) | 62 (36–82) |
| LES pressure (mm Hg) | 23 (15.5–35) | 20 (13–29) | 20 (18–22) | 22 (16–35) |
| High UES pressure (%) | 12.5% (n = 3) | 0% (n = 0) | 44.7% (n = 2.2) | 7.5% (n = 4) |
| Low UES pressure (%) | 12.5% (n = 3) | 33.3% (n = 7) | 54.8% (n = 2.7) | 22.6% (n = 12) |
| High LES pressure (%) | 4.2% (n = 1) | 9.5% (n = 2) | 44.7% (n = 2.2) | 9.4% (n = 5) |
| Low LES pressure (%) | 25% (n = 6) | 33.3% (n = 7) | 0% (n = 0) | 24.5% (n = 13) |
| Chicago Classification v3.0 | ||||
| Normal esophageal motility | 70.8% (n = 17)* | 38.1% (n = 8)* | 54.8% (n = 2.7) | 54.7% (n = 29) |
| Ineffective esophageal motility | 12.5% (n = 3) | 23.8% (n = 5) | 0% (n = 0) | 17% (n = 9) |
| Absent contractility | 8.3% (n = 2) | 28.6% (n = 6) | 44.7% (n = 2.2) | 17% (n = 9) |
| Jackhammer esophagus | 8.3% (n = 2) | 4.8% (n = 1) | 44.7% (n = 2.2) | 9.4% (n = 5) |
| EGJ outflow obstruction | 0% (n = 0) | 4.8% (n = 1) | 0% (n = 0) | 1.9% (n = 1) |
| Achalasia type I, II, or III | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
| Distal esophageal spasm | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
| Fragmented peristalsis | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
Comparisons made between each group (column) and the rest of the sample. Continuous variables are expressed as mean (SD) or as median (Q1–Q3), as appropriate. Qualitative variables are expressed as percent (n). DM, dermatomyositis; PM, polymyositis; CAM, cancer-associated myositis; DCI, distal contractile integral; IRP, integrated relaxation pressure; IBP, intrabolus pressure; DL, distance contractile latency; UES, upper esophageal sphincter; LES, lower esophageal sphincter; EGJ, esophagogastric junction.
P < 0.05.
P < 0.01.
Table 4.
Manometric features, wave morphology, and Chicago Classification v3.0 by serologic group
| Serologic groups | |||||
|---|---|---|---|---|---|
| AS (n = 16) | Anti-TIF1-γ (n = 10) | Anti-PM/Scl (n = 8) | Anti-Ro52 (n = 16) | Total (n = 53) | |
| DCI (mm Hg/cm/s) | 1,052 (311–1,517.5) | 2,847.5 (892–6,197)* | 1,206.5 (536–2,804) | 1,206.5 (536–2,804) | 1,311 (370–2,900) |
| IRP (mm Hg) | 7 (3–11) | 11 (6–12) | 10 (7.5–12.5) | 10 (7.5–12.5) | 10 (5–12) |
| DL (s) | 6 (5–6.5) | 6.5 (6–7) | 5.5 (2.5–6) | 5.5 (2.5–6) | 6 (5–7) |
| IBP (mm Hg) | 16 (13–22) | 22.5 (19–27)* | 19.5 (14.5–21.5) | 19.5 (14.5–21.5) | 19 (15–22.5) |
| Wave morphology [mean %] | |||||
| Hypertonic | 1.3 (5) | 13.7 (24.7) | 12.7 (0) | 0.6 (2.5) | 4.9 (13.6) |
| Failed | 31.9 (37.2) | 13 (31.3) | 41.6 (0) | 37.9 (38.2) | 27.8 (37.7) |
| Hypotonic | 12.9 (22.3) | 2 (6.3) | 3.2 (0) | 6.1 (13.6) | 9.4 (18) |
| Fragmented | 0 (0) | 2.2 (4.4)** | 3.5 (0) | 0.6 (2.5) | 0.4 (1.9) |
| Normal | 53.9 (38) | 69.3 (33.1) | 39.7 (33) | 54.8 (35.6) | 57.5 (37.3) |
| Pharyngeal pressure (mm Hg) | 12 (8.5–20) | 13.5 (11–14) | 11.5 (8.5–16) | 11.5 (8.5–16) | 12 (9–17) |
| UES pressure (mm Hg) | 68 (50–87.5) | 38.5 (32–94) | 45 (20.5–83) | 45 (20.5–83) | 62 (36–82) |
| LES pressure (mm Hg) | 17 (11.5–30.5)* | 22.5 (18–41) | 28.5 (16–39) | 28.5 (16–39) | 22 (16–35) |
| High UES pressure (%) | 6.3% (n = 1) | 10% (n = 1) | 0% (n = 0) | 6.3% (n = 1) | 7.5% (n = 4) |
| Low UES pressure (%) | 18.8% (n = 3) | 30% (n = 3) | 37.5% (n = 3) | 37.5% (n = 6) | 22.6% (n = 12) |
| High LES pressure (%) | 0% (n = 0) | 20% (n = 2) | 12.5% (n = 1) | 0% (n = 0) | 9.4% (n = 5) |
| Low LES pressure (%) | 43.8% (n = 7)* | 20% (n = 2) | 25% (n = 2) | 25% (n = 4) | 24.5% (n = 13) |
| Chicago Classification v3.0 | |||||
| Normal esophageal motility | 62.5% (n = 10) | 60% (n = 6) | 62.5% (n = 5) | 62.5% (n = 10) | 54.7% (n = 29) |
| Ineffective esophageal motility | 18.8% (n = 3) | 0% (n = 0) | 12.5% (n = 1) | 18.8% (n = 3) | 17% (n = 9) |
| Absent contractility | 18.8% (n = 3) | 10% (n = 1) | 12.5% (n = 1) | 18.8% (n = 3) | 17% (n = 9) |
| Jackhammer esophagus | 0% (n = 0) | 30% (n = 3)* | 12.5% (n = 1) | 0% (n = 0) | 9.4% (n = 5) |
| EGJ outflow obstruction | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 1.9% (n = 1) |
| Achalasia type I, II, or III | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
| Distal esophageal spasm | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
| Fragmented peristalsis | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) | 0% (n = 0) |
Comparisons made between each group (column) and the rest of the sample. Continuous variables expressed as mean (SD) or as median (Q1–Q3), as appropriate. Qualitative variables are expressed as percent (n). AS, antisynthetase syndrome; DCI, distal contractile integral; IRP, integrated relaxation pressure; IBP, intrabolus pressure; DL, distance contractile latency; UES, upper esophageal sphincter; LES, lower esophageal sphincter; EGJ, esophagogastric junction.
P < 0.05.
P < 0.01.
Chicago v3.0 Classification.
HRM showed an esophageal disorder in half of the patients in our sample, the most common being ineffective esophageal motility (17%, n = 9), absent contractility (17%, n = 9), and jackhammer esophagus (9%, n = 5). Significantly fewer patients with PM had a normal HRM compared to those with DM (38% vs. 71%, P = 0.05), and jackhammer esophagus was significantly more frequent in the anti–TIF1-γ patients than in the rest of the sample (30% vs. 5%, P = 0.04) (Tables 3 and 4).
Association between Manometric Findings and Esophageal Symptoms.
Esophageal symptoms were not significantly associated with manometric pattern. Indeed, 48% of the patients with normal manometry had symptoms, but just 42% of those with a pathologic HRM had significant esophageal manifestations (P = 0.8).
Association between Esophageal Involvement and Creatine Kinase.
Median CK was not correlated with any manometric parameter and was not increased significantly in patients with esophageal symptoms or with any Chicago v3.0 diagnosis.
Association between Esophageal Involvement and Interstitial Lung Disease.
Independent of their age, gender, or autoantibody status, patients with regurgitation had lower FVC than patients without regurgitation (58% vs. 79%, P = 0.04), and upper esophageal pressure was weakly to moderately associated with FVC (R = 0.4, P = 0.04).
DISCUSSION
In this study, using HRM we have demonstrated that patients with IIM have a high prevalence of esophageal involvement, which is more common in PM than in DM. We also found that manometric involvement is poorly correlated with the esophageal symptoms and that specific autoantibody groups have characteristic manometric features with a higher prevalence of jackhammer esophagus in anti–TIF1-γ patients and LES involvement in the AS patients. Finally, we found an association between esophageal involvement and ILD severity.
Esophageal smooth muscle involvement in IIM was proposed long ago. In fact, in the 1960s, Donoghue et al. reported that 45% of DM patients had generalized esophageal muscular defects that resembled esophageal involvement in systemic sclerosis. Moreover, they noted that the upper esophageal skeletal muscle weakness, which is usually obvious clinically, may obscure symptoms of dysphagia arising from the rest of the esophagus.3 Since that original study, among the main advances in myositis has been the discovery of autoantibodies associated with characteristic clinical24 and histopathologic features.25 In the present study, in addition to reproducing most of the results of earlier studies,3,4 we could define specific manometric features for some serologic subgroups in myositis.
Antisynthetase syndrome is a clinic–serologic disease characterized by the presence of autoantibodies against 1 of the aminoacyl-tRNA syntethases.26 We found decreased LES pressure and a higher proportion of hypotonic LES in the AS cohort, suggesting that, in this syndrome, the autoimmune reaction may affect smooth muscle of the esophageal body and LES, as it occurs in other autoimmune diseases, such as systemic sclerosis.27
Interestingly, we could not detect manometric LES involvement in patients positive for anti-PM/Scl, which is an autoantibody also associated with scleroderma-like features. As pointed out in what follows, the analysis of this specific group of patients was probably underpowered, considering that we studied 16 patients with the AS and just 8 positive for anti-PM/Scl.
Another relevant autoantibody important in inflammatory myopathy is anti–TIF1-γ, which is strongly correlated with cancer.28 In our study, it was found to be associated with a higher DCI (a parameter used to measure the distal esophageal contraction), a higher IBP (used to measure the pressure of the liquid bolus into the esophagus), and jackhammer esophagus. Even if the etiology of jackhammer esophagus is still largely unknown, the association with anti–TIF1-γ is intriguing and, if confirmed, would suggest either a common pathophysiology or that the inflammatory phenomenon is triggering the esophageal disease. This last theory would be supported by reports suggesting that the trigger of jackhammer esophagus may be local irritation caused by gastroesophageal reflux.29
High-resolution manometry is the “gold standard” for evaluation of motility disorders of the body and LES of the esophagus, but its usefulness for evaluating the pharynx and UES is more limited due to the complex anatomy and movement of this part of the esophagus. Although the Chicago Classification v3.0 does not consider this region, there is evidence suggesting that HRM may be more trustworthy than videofluoroscopic swallow study or X-ray–based analysis of swallowing.30,31 Our results identified significant involvement of the pharynx and UES region, as expected, because this part of the esophagus with skeletal muscle is known to be susceptible to involvement in the myositis inflammatory process. Moreover, in our experience, life-threatening dysphagia due to pharyngeal or UES weakness is a rare phenomenon in myositis (around 1.5% of the patients of our cohort) and, in the only patient included in the study with this extremely severe form of dysphagia, the HRM showed severely decreased pharyngeal and UES pressure.
Interestingly, we identified an association between esophageal involvement and ILD. Specifically, patients with regurgitation showed lower FVC than patients without it, and UES pressure was directly associated with FVC, independent of the autoantibody group. The cross-sectional design of our study could not demonstrate causality, and thus it is equally plausible that regurgitation may induce ILD or, on the contrary, that ILD increases the likelihood of regurgitation.
If regurgitation was a contributing factor to ILD, anti-reflux medication may be considered as an adjuvant therapy for ILD. In support of this finding, chronic microaspiration has been recently associated with the genesis of ILD in systemic sclerosis,32 and, as discussed earlier, some myositis groups (such as the AS group) showed evidence of systemic sclerosis-like lower esophageal involvement.
Alternatively, the severity of ILD may lead to an increase in intrathoracic pressure and exacerbate gastroesophageal reflux. In any case, given the high prevalence of functional esophageal disorders associated with IIM and the poor correlation between the symptoms and manometric involvement, it is reasonable to suggest a need for screening DM and PM patients for functional esophageal disorders. This screening could lead to early treatment, thus avoiding harmful secondary effects such as Barret esophagus or esophageal neoplasms. This would be especially true for patients with polymyositis due to the higher risk of esophageal involvement we found in our study, and those with the AS, because of the higher rate of LES dysfunction.
Our study must be regarded as exploratory and with a number of limitations. First, even if the number of patients included was rather high considering the rarity of the disease, some analyses may still have been underpowered. Second, as mentioned previously, the cross-sectional nature of the study cannot demonstrate causality, and the heterogeneity of the patients may have induced bias even after statistical adjustment. Third, we could review the HRM retrospectively to adapt it to actual definitions9 but the esophageal symptom survey could not be adapted to the modern instrumentation that was unavailable at the start of the study.33 Finally, in some cases, there was a significant amount of time between laboratory data collection and pulmonary function tests and the date of manometry, which may explain why there was no significant association between the manometric parameters and CK. However, there was no potential bias regarding the time between the HRM and the esophageal symptoms survey, because both were performed at the same time.
In conclusion, inflammatory myopathies have significant esophageal involvement that correlates poorly with esophageal symptoms. In addition, we found an association between esophageal involvement and ILD severity and characteristic manometric features in specific autoantibody groups.
Acknowledgments
This work was funded by Instituto de Salud Carlos III, grant PI12-01320 and PI15-02100 cofinanced by the European Regional Development Fund (ERDF) and also by the Spanish Ministry of Economy and Competitiveness (Dirección General de Investigación Científica y Técnica, SAF 2016-76648-R). Ciberehd is funded by the Instituto de Salud Carlos III. Dr. Pinal-Fernandez research is supported by a Fellowship from the Myositis Association.
Abbreviations:
- AS
antisynthetase syndrome
- CAM
cancer-associated myositis
- CK
creatine kinase
- DCI
distal contractile integral
- DL
distance contractile latency
- DM
dermatomyositis
- EGJ
esophagogastric junction
- FVC
forced vital capacity
- HRM
high-resolution manometry
- IBM
inclusion-body myositis
- IBP
intrabolus pressure
- IIM
idiopathic inflammatory myopathies
- ILD
interstitial lung disease
- IRP
integrated relaxation pressure
- LES
lower esophageal sphincter
- PM
polymyositis
- Q1
first quartile
- Q3
third quartile
- UES
upper esophageal sphincter
Footnotes
The authors thank Cassie Parks for critical reading and suggestions.
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