Esophageal achalasia is an idiopathic disorder characterized by degeneration of neurons in the myenteric plexus of the esophagus.1 Enteric neuropathies, primary and secondary, have been proposed as causes of enteric motility disorders, including achalasia. Secondary causes of enteric neuropathies have been attributed to diabetes mellitus, autoimmune diseases, paraneoplastic syndromes, infectious disease, and states of systemic inflammation.1,2 Case reports of pediatric patients with Triple-A syndrome (adrenocorticotropic hormone insensitivity, achalasia, and alacrima) and concomitant autonomic neuropathy, as well as a case of a patient with Sjogren’s syndrome, achalasia, and sensory neuropathy suggest that systemic disease leading to metabolic or inflammatory derangements may play a role in the pathogenesis of achalasia.3,4 The All of Us Research Program by the National Institutes of Health (NIH) collects data from a diverse set of participants across the country and provides a unique opportunity to study associations between different medical conditions,5 including rare diseases like achalasia. In this study, we sought to describe the characteristics of participants with a diagnosis of achalasia in the All of Us Research Program and explore whether a diagnosis of achalasia was associated with autoimmune, neoplastic, infectious, and common medical conditions that are known causes of neuropathy.
This was a case-control study using data from the All of Us Research Program, a precision medicine initiative from the NIH.5 Our study used the data set known as the “All of Us Registered Tier Dataset v5”, which contained electronic health record data from 214,206 volunteer participants, all ≥ 18 years of age. The data were collected from the inception of the program in 2018 until April 2021. Information on the data curation is available at https://allofus.nih.gov/. For this study, all diagnoses and comorbidities were defined by the presence of corresponding International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes in the database. Participants with a diagnosis of achalasia were identified with code K22.0, representing achalasia of cardia, and controls with code Z00.0, representing an encounter for a general adult medical examination. Participants were excluded if they lacked information on sex, race, or were deceased. They were also excluded if they had ICD-10 codes for Barrett’s esophagus, esophageal or gastric neoplasms, or Chagas disease.
All analyses were conducted with Python (Version 3.7.12; Python Software Foundation, Wilmington, DE). Univariable analyses were performed to compare participant characteristics. Continuous variables were presented as mean ± standard deviation (SD), and categorical variables as proportions. Means were compared using the Student’s t-test, and proportions using the Chi-squared or Fisher’s exact test. Multivariable logistic regressions were performed to control for potential confounding variables including age, race, sex, and overweight or obesity diagnoses. Results from logistic regressions were expressed using odds ratios with 95% confidence intervals. A p-value < 0.05 (two-tailed) was considered significant.
The search identified 173 participants with a diagnosis of achalasia and 43,144 controls. Both cohorts were predominately White (78% vs. 72%; p=0.40), non-Hispanic (99% vs. 98%; p=0.27), and female (60% vs. 65%; p=0.17). The achalasia cohort was older than the control cohort (59 vs. 53 years; p<0.01) (Table 1). Multivariable analyses controlling for age, race, sex, and overweight or obesity diagnoses showed that the achalasia cohort had significantly higher rates of systemic scleroderma (p<0.01), rheumatoid arthritis (p=0.04), Sjogren’s syndrome (p<0.01), systemic lupus erythematosus (p<0.01), and Guillain-Barré Syndrome (p<0.01) (Table 2).
Table 1.
Demographic and Clinical Characteristics of Participants with a Diagnosis of Achalasia
| Achalasia (n=173) | Control (n=43144) | p-value | |
|---|---|---|---|
| Age (years), mean ± SD | 59 ± 14 | 53 ± 16 | <0.01 |
| Sex, n (%) | |||
| Male | 69 (40) | 14916 (35) | 0.17 |
| Female | 104 (60) | 28228 (65) | |
| Race, n (%) | |||
| Non-Hispanic White | 135 (78) | 31250 (72) | |
| Black | 29 (17) | 8697 (20) | 0.40 |
| Asian | * | 1561 (4) | |
| Other | * | 1636 (4) | |
| Ethnicity, n (%) | |||
| Hispanic | * | 832 (2) | 0.27 |
| Not Hispanic | 172 (99) | 42312 (98) | |
| Comorbidities, n (%) | |||
| Amyloidosis | * | 28 (0) | 1.00 |
| Atherosclerosis | * | 485 (1) | 0.01 |
| Chronic Kidney Disease | * | 1855 (4) | <0.01 |
| Guillain-Barré Syndrome | * | * | 0.06 |
| Chronic Hepatitis C | * | 466 (1) | 0.12 |
| Herpes Zoster | * | 485 (1) | 0.13 |
| HIV | * | 425 (1) | 0.24 |
| Hypothyroidism | 21 (12) | 3620 (8) | 0.10 |
| Localized Scleroderma | * | 23 (0) | 1.00 |
| Systemic Scleroderma | * | 44 (0) | <0.01 |
| Monoclonal Gammopathy | * | 168 (0) | 1.00 |
| Paraneoplastic Neuropathy | * | * | 1.00 |
| Rheumatoid Arthritis | * | 188 (0) | 0.05 |
| Sarcoidosis | * | 190 (0) | 0.54 |
| Sjogren’s Syndrome | * | 247 (1) | <0.01 |
| Systemic Lupus Erythematosus | * | 311 (1) | <0.01 |
| Small B-Cell Lymphoma | * | * | 1.00 |
| Type 1 Diabetes Mellitus | * | 486 (1) | 0.07 |
| Type 2 Diabetes Mellitus | 29 (17) | 4722 (11) | 0.02 |
| Overweight and Obesity | 40 (23) | 7166 (17) | 0.03 |
Counts suppressed per the All of Us Data and Statistics Dissemination Policy. Due to the All of Us Research Program Data and Statistics Dissemination Policy, participant counts of 1 to 20 may not be published. Data or statistics can also not be reported to allow a participant count of less than 20 participants to be derived.
Table 2.
Logistic Regressions for Participants with a Diagnosis of Achalasia and Comorbidities Controlling for Age, Race, Sex, and Overweight and Obesity
| Comorbidities (Yes/No) | Odds Ratio | 95% Confidence Intervals | p-value |
|---|---|---|---|
| Atherosclerosis | 2.24 | 0.98–5.14 | 0.06 |
| Chronic Kidney Disease | 1.59 | 0.92–2.76 | 0.10 |
| Guillain-Barré Syndrome | 17.42 | 2.25–134.81 | <0.01 |
| Systemic Scleroderma | 16.88 | 5.15–55.31 | <0.01 |
| Rheumatoid Arthritis | 3.46 | 1.09–11.00 | 0.04 |
| Sjogren’s Syndrome | 5.79 | 2.52–13.31 | <0.01 |
| Systemic Lupus Erythematosus | 5.62 | 2.44–12.92 | <0.01 |
| Type 1 Diabetes Mellitus | 2.43 | 0.99–5.99 | 0.05 |
| Type 2 Diabetes Mellitus | 1.31 | 0.85–2.02 | 0.22 |
Our study is the first case-control study to demonstrate an association between a diagnosis of achalasia and systemic scleroderma and rheumatoid arthritis. Our findings support previous studies reporting increased odds of Sjogren’s syndrome and systemic lupus erythematosus in individuals with achalasia and encourage further inquiry into the link between autoimmune connective tissue disorders and achalasia.6 Variations in the human leukocyte antigen (HLA) complex that are present in achalasia and autoimmune connective tissue disorders make the relationship plausible. Multiple studies have shown that some, but not all, individuals with achalasia have higher frequencies of specific HLA-DQA1 alleles, such as DQA10103 and DQB10603.7 Similarly, allele variants in the HLA-DQA1 gene have been found more commonly in individuals with systemic scleroderma.8 These findings exist in the context of a well-studied susceptibility to systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis according to HLA class II alleles and haplotypes.7–9
Our study also shows an association between a diagnosis of achalasia and Guillain-Barré Syndrome, previously documented in case reports, and hypothesized to occur as a non-specific autoimmune response to infection.10 However, we did not find an increased odds of a diagnosis of achalasia in participants with human immunodeficiency virus (HIV) or chronic hepatitis C, other viruses hypothesized to play a role in autoimmune disease.9 Further research is necessary to better understand the relationship between Guillain-Barré Syndrome and achalasia, or esophageal motility disorders with similar presentations.
There are several limitations to this study, many of which are inherent from the use of administrative data. Notably, one major limitation was this study’s reliance on ICD-10 codes for the identification of diseases, including achalasia and overweight or obesity. ICD-10 codes were used due to the lack of available procedural and physical measurement data for many participants in our cohorts. As esophageal manometric data are necessary to confirm achalasia, using only ICD-10 codes may have led to an overestimation of the diagnosis of achalasia since unspecified esophageal dysfunction is known to occur in individuals with autoimmune connective tissue disorders. Similarly, we may have underestimated the number of participants with overweight or obesity as weight status is not reliably documented in the medical record. In addition to limitations from using ICD-10 codes for disease classification, our study may have been affected by the data collection process. First, the All of Us Research Program relies on data shared by active, volunteer subjects and encourages the participation of groups historically underrepresented in medical research. These factors may have affected the participant characteristics and the generalizability of our results. Second, the All of Us Research Program relies on electronic health record data shared by each participant’s health care provider. Variability in provider documentation practices may have led to missing, or incorrect, diagnostic data. Finally, another limitation to our study was the possibility of selection bias if the control cohort had significantly better overall health than the achalasia cohort. We, however, took steps to prevent this by selecting for controls that presented for general medical encounters, irrespective of the findings from their visit, and by controlling for demographic differences in our analyses.
This study is intended to describe the clinical characteristics of participants with a diagnosis of achalasia in the All of Us Research Program. While the lack of manometric data limits us from determining whether achalasia is associated with systemic scleroderma, Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, and Guillain-Barré Syndrome, the results from our study suggest that many individuals with these medical conditions may present with achalasia-like symptoms and be diagnosed with achalasia. These results encourage future studies on the associations of achalasia and autoimmune diseases that are supported with manometric data.
Highlights.
Achalasia is an idiopathic disorder characterized by degeneration of esophageal myenteric neurons
Enteric neuropathies secondary to systemic diseases have been implicated in the pathogenesis of achalasia
The All of Us Research Program database from the National Institutes of Health (NIH) allows for the examination of achalasia and systemic disease associations
A diagnosis of achalasia is associated with several autoimmune conditions including systemic scleroderma, rheumatoid arthritis, and Guillain-Barré Syndrome
Acknowledgements:
This research was made possible by the participants who partner with the All of Us Research Program, as well as the All of Us Research Program team. *
Financial Support:*
This study was supported by the National Institutes of Health, Office of the Director (Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276).
This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR003098 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH.
Footnotes
Conflict of interests: The authors have no relevant financial or non-financial interests to disclose.
* These sections are requested to be included in the final publication by the All of Us Research Program.
Disclaimer:* The All of Us Research Program includes a demographically, geographically, and medically diverse group of participants, however, it is not a representative sample of the population of the United States. Enrollment in the All of Us Research program is open to all who choose to participate, and the program is committed to engaging with and encouraging participation of minority groups that are historically underrepresented in biomedical research.
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