Association of eosinophilic esophagitis with autoimmune and connective tissue disorders, and the impact on treatment response

Eosinophilic esophagitis (EoE) has been associated with autoimmune (AI) and connective tissue disorders (CTDs), but clinical correlates and treatment response to topical corticosteroids (tCS) for patients with both conditions are not well known. We aimed to determine the prevalence and clinical features of AI/CTDs in EoE patients, and assess the response to tCS. In this retrospective cohort study of adults and children newly diagnosed with EoE in the University of North Carolina EoE Clinicopathologic database, we extracted clinical characteristics and treatment response data. We compared EoE patients with and without AI/CTDs, identified independently associated factors, and explored treatment responses. Of 1029 EoE patients, 61 (5.9%) had an AI/CTDs. The most common AI/CTDs were psoriasis/psoriatic arthritis (P/PA) (1.7%), Hashimoto’s (1.2%), and rheumatoid arthritis (RA) (1%). Compared to those without AI/CTDs, AI/CTDs patients were older (35 vs. 28 years, P = 0.004), more likely to be female (51% vs. 30%, P = 0.001), have insurance (93% vs. 78%, P = 0.004) and a longer symptom duration prior to EoE diagnosis (10 vs. 7 years, P = 0.02). Older age, female sex, having insurance, and having allergic rhinitis were independently associated with AI/CTDs. AI/CTD patients with EoE were less likely to have a symptom response (47% vs. 79%, P = 0.003). Overlap between EoE and AI/CTDs was uncommon, seen in approximately 6%, with P/PA, Hashimoto’s, and RA being most frequent. In conclusion, older age, female sex, having insurance, and allergic rhinitis were independently associated with AI/CTDs. EoE patients with AI/CTDs had less symptom response, with trendtowards lower endoscopic and histologic responses, to tCS therapy.

autoimmune, connective tissue, eosinophilic esophagitis, outcomes, treatment

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease, characterized by marked eosinophilic inflammation of the esophagus (≥15 eosinophils per high-power field [eos/hpf]) and symptoms of esophageal dysfunction.1–4 These symptoms can vary with age and prolonged inflammation can progress to fibrostenotic complications.5–7 Although EoE is considered a rare condition, its incidence and prevalence has been increasing with robust efforts put forth to study the disease and assess for associated conditions. The most commonly studied conditions related to EoE are atopic diseases, but these are not universally present. In addition, there are some EoE patients who have more of an autoimmune rather than atopic profile, which has prompted some investigation into this alternate disease association. Limited population-based data exist regarding an association between EoE and autoimmune disease (AI) or connective tissue disease (CTD).8–10 The most well-reported association has been with celiac disease, where multiple studies have shown an increased prevalence of celiac disease among patients with EoE.11–16 In addition to celiac disease, type 1 diabetes17 and inflammatory bowel disease (IBD)8,18,19 have been associated with EoE, and genome-wise association studies have pointed to possible associations between EoE and genes associated with autoimmunity,20 while others report conflicting data.21 Even with these reports, there is a need to further investigate the relationship between EoE, AI, and CTD, and whether treatment outcomes may differ between these groups. Therefore, the aim of this study was to evaluate this association using a cohort comprising adults and children managed at our center. We also aimed to assess for differences in treatment response to topical corticosteroid (tCS) treatment among EoE patients with AI/CTD diagnoses compared to patients with EoE alone.

Study design and patients We conducted a retrospective cohort study of the University of North Carolina (UNC) EoE Clinicopathologic database, details of which have previously been published.22–26 Subjects were adults and children with a new diagnosis of EoE per consensus guidelines that were in effect at the time of diagnosis.27–30 Specifically, patients were required to have ≥15 eosinophils in at least 1 high-power field (eos/hpf) on esophageal biopsy, symptoms related to esophageal dysfunction, and no secondary causes related to esophageal eosinophilia. Non-response to proton pump inhibitors (PPI) was required for diagnosis in patients prior to 2018. In addition to assessing this overall cohort, we also identified a sub-cohort of patients who had documented treatment with a tCS and a follow-up endoscopy with biopsy, in order to assess treatment responses by AI/CTD status. Treatment was prescribed as clinically indicated, and at our center this typically involves an initial course of swallowed budesonide or fluticasone (adapted from asthma preparations, and with dose dependent on patient age and size) for 2–3 months, followed by repeat endoscopy to assess response. Data collection Patient demographics, clinical characteristics, comorbidities, and procedural data were extracted from the UNC electronic medical record. AI/CTDs diagnoses of interest included type I diabetes mellitus (DM), Hashimoto’s thyroiditis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome, scleroderma, psoriasis/psoriatic arthritis (P/PA), multiple sclerosis, celiac disease, Marfan syndrome, Ehler Danlos syndrome, and Loeys-Dietz syndrome. Covariates of interest included demographics (age at diagnosis and gender), insurance status, coexisting allergic conditions (allergic rhinitis, asthma and food allergy), duration of symptoms prior to EoE diagnosis, EoE symptoms (dysphagia, food impaction, heartburn, chest pain, and abdominal pain), endoscopic findings (exudates, rings, edema, linear furrows, structuring, narrowing, crepe-paper mucosa, and dilation), and peak histologic eosinophil count. For endoscopic findings, we also extracted the EoE Endoscopic Reference Score (EREFS) when it was available,31–33 but because this was not used prior to 2013, we also calculated an Endoscopic Severity Score (ESS) which was the sum of the presence (1 point) or absence (0 points) of edema, rings, exudates, furrows, or stricture (range: 0–5, with higher scores indicating worsening severity), as this information was available for all patients, and such a scoring option has recently been assessed.34 Data related to treatment and response, including steroid type and dose, were also extracted for the subset who had documented tCS treatment and received a follow-up endoscopy with biopsy. At our center, budesonide is used as a viscous swallowed slurry, typically at a 2 mg total daily dose for adolescents and adults, while fluticasone is swallowed from a metered inhaler, typically at a 1760 mcg total daily dose; doses can be lower in children. The primary post-treatment outcome was histologic response, defined as <15 eos/hpf,35,36 with additional assessments of ≤6 and <1 eos/hpf. As this was a retrospective study, we could not use validated patient-reported outcomes, and instead assessed the global symptom response, as documented in the chart. We similarly recorded a global endoscopic response (documented by the endoscopist), as well as recorded post-treatment EREFS and ESS. Statistical analysis Descriptive statistics were used to summarize study population characteristics. Bivariate analysis was used to compare demographic, clinic, endoscopic, and histologic characteristics between EoE patients with and without AI/CTDs in the overall study population. Similar comparisons were then made in the tCS treatment subgroup, for features before and after treatment. Tests of association included chi-square testing for categorical variables and two sample t-tests for continuous variables for the between-group comparisons, and McNemar’s test for categorical variables and paired t-tests for the pre/post-treatment within group analyses. Given the small sample size in some of the sub-analyses, we also performed non-parametric testing. However, as the results of non-parametric testing were the same as for the parametric tests, we opted to present the parametric results for ease of interpretation. Multivariate logistic regression was used to test for independent associations between EoE patients with and without AI/CTDs. The model initially included covariates of interest and those with P < 0.10 on the bivariate analysis, and was then reduced using backwards elimination with a change in effect threshold of 10%. Statistical analysis was performed in Stata version 12 (College Station, TX, USA), and this study was approved by the UNC IRB.

Patient characteristics and AI and CTD features Of 1029 EoE patients included in this study, 61 (6%) had at least one diagnosis of AI/CTD. The most common AI/CTDs were P/PA (n = 17; 2%), Hashimoto’s thyroiditis (n = 12; 1%), and RA (n = 10; 1%). Other conditions included SLE (n = 1), celiac (n = 10), type 1 DM (n = 5), Sjogren’s syndrome (n = 1), multiple sclerosis (n = 2), Ehlers-Danlos (n = 3), and Loeys-Dietz (n = 1); none had concomitant scleroderma. AI was more frequently seen (6%) than CTD (0.4%) and only five patients (0.5%) had more than one AI/CTD. Compared to those without AI/CTDs, AI/CTDs patients were older (35.2 vs. 28.2 years; P = 0.004), more likely to be female (51% vs. 30%; P = 0.001), have insurance (93% vs. 78%; P = 0.004), and have a longer symptom length prior to EoE diagnosis (10 years vs. 7 years; P = 0.02) (Table 1). There were no differences for race, comorbid allergic conditions, PPI non-response (for those diagnosed prior to 2018), symptoms, or endoscopic findings between the two groups. More than half (54%) of the patients with EoE and AI/CTD diagnoses developed their AI/CTD prior to their EoE diagnosis. Table 1. | No autoimmune or CTD (n = 968) | Autoimmune or CTD present (n = 61) | P | | |---|---|---|---| | Age at diagnosis (mean years ± SD) | 28.2 ± 18.4 | 35.2 ± 19.3 | 0.004 | | Age < 18 years (n, %) | 360 (37) | 17 (29) | 0.14 | | Female (n, %) | 292 (30) | 31 (51) | 0.001 | | White (n, %) | 773 (80) | 51 (84) | 0.54 | | Insurance (n, %) | 750 (78) | 57 (93) | 0.004 | | Allergic conditions (n, %) | ||| | Allergic rhinitis | 394 (42) | 29 (48) | 0.09 | | Asthma | 244 (26) | 14 (23) | 0.13 | | Food allergy | 252 (28) | 18 (30) | 0.13 | | Symptom length prior to diagnosis (mean years ± SD) | 7.4 ± 8.1 | 10.3 ± 11.4 | 0.02 | | On PPI at diagnosis (n, % PPI non-responsive) | 624 (66) | 36 (59) | 0.53 | | Symptoms (n, %) | ||| | Dysphagia | 717 (75) | 46 (75) | 0.89 | | Food impaction | 331 (35) | 15 (25) | 0.10 | | Heartburn | 354 (37) | 17 (28) | 0.32 | | Chest pain | 95 (10) | 8 (13) | 0.72 | | Abdominal pain | 166 (17) | 18 (30) | 0.06 | | Endoscopic findings (n, %) | ||| | Exudates | 382 (40) | 32 (52) | 0.05 | | Rings | 483 (50) | 33 (54) | 0.56 | | Edema | 369 (38) | 23 (38) | 0.92 | | Furrows | 625 (65) | 45 (74) | 0.16 | | Stricture | 265 (28) | 19 (31) | 0.54 | | Narrowing | 156 (16) | 7 (11) | 0.33 | | Crepe-paper mucosa | 40 (4) | 1 (2) | 0.60 | | Dilation | 281 (29) | 21 (34) | 0.39 | | Total EREFS (mean ± SD)* | 3.8 ± 2.0 | 3.3 ± 1.4 | 0.17 | | Total ESS (mean ± SD)* | 2.2 ± 1.6 | 2.5 ± 1.5 | 0.17 | | Peak eosinophil count (mean eos/hpf ± SD) | 65.1 ± 44.3 | 66.3 ± 43.6 | 0.84 | *EREFS data available for n = 405 and 35; ESS = endoscopic severity score, for which all data are available. After multivariate logistic regression, older age (adjusted odds ratio [aOR] 1.02 per increasing year, 95% confidence interval [CI]: 1.00–1.03), female sex (aOR 2.08, 95% CI: 1.23–3.57), having insurance (aOR 3.43, 95% CI: 1.21–9.73), and having allergic rhinitis (aOR 1.29, 95% CI: 1.00–1.67, P < 0.05) were independently associated with having AI/CTD (Table 2). Table 2. | Characteristic | Unadjusted odds ratio (OR) and 95% CIs | Adjusted odds ratio (aOR) and 95% CIs | |---|---|---| | Age at diagnosis* | 1.02 (1.01–1.03) | 1.02 (1.00–1.03) | | Female sex | 2.39 (1.42–4.03) | 2.08 (1.23–3.57) | | Insurance | 4.05 (1.45–11.3) | 3.43 (1.21–9.73) | | Allergic rhinitis | 1.28 (1.00–1.64) | 1.29 (1.00–1.67) | *OR and aOR are for a one year increase in age. Response to treatment with tCS We identified 467 patients in our cohort treated with tCS, 28 of whom had an AI/CTD diagnosis. AI/CTD patients with EoE were less likely to have a global symptom response (47% vs. 79%; P = 0.003), and had a numerically but not significantly lower probability of histologic response (43% vs. 59%, P = 0.10) (Table 3). Histologic responses were similar between the groups whether budesonide or fluticasone were used. The global symptom response finding persisted after multivariate analysis after adjusting for the above differences between EoE patients with and without AI/CTDs (aOR 0.17; 95% CI: 0.05–0.59). There was no difference between mean steroid dose and post-treatment peak eosinophil count among EoE patients with and without AI/CTDs, though fluticasone was interestingly more commonly used in the AI/CTD group. Of note, the peak eosinophil count significantly improved in both AI/CTD and non-AI/CTD EoE patients following treatment with tCS, though endoscopic findings improved more substantially in EoE patients without AI/CTDs (Table 3). Table 3. | No autoimmune or CTD (n = 439) | Autoimmune or CTD present (n = 28) | P | | |---|---|---|---| | Type of steroid used (n, %) | 0.01 | || | Fluticasone | 132 (30) | 16 (57) | | | Budesonide | 306 (70) | 12 (43) | | | Mean steroid dose (mcg ± SD) | 1722 ± 719 | 1582 ± 484 | 0.31 | | Symptom response (n, %)* | 135 (79) | 8 (47) | 0.003 | | Post-treatment peak eosinophil count (mean eos/hpf ± SD) | 24.3 ± 37.6 | 28.8 ± 30.8 | 0.53 | | P value vs. baseline | <0.001 | <0.001 | | | Histologic response and thresholds (n, %) | ||| | < 15 eos/hpf | 257 (59) | 12 (43) | 0.10 | | ≤ 6 eos/hpf | 226 (51) | 11 (39) | 0.21 | | < 1 eos/hpf | 132 (30) | 7 (25) | 0.57 | | Post-treatment endoscopic findings (n, %) | ||| | Normal | 95 (22) | 7 (25) | 0.68 | | Exudates | 103 (24) | 8 (30) | 0.51 | | Rings | 193 (45) | 14 (52) | 0.46 | | Edema | 116 (27) | 12 (44) | 0.05 | | Stricture | 134 (31) | 12 (44) | 0.15 | | Narrowing | 77 (18) | 5 (19) | 0.94 | | Crepe-paper mucosa | 4 (1) | 0 (0) | 0.62 | | Dilation | 130 (30) | 12 (44) | 0.12 | | Candida | 31 (7) | 3 (11) | 0.46 | | Endoscopic response (n, %) | 318 (73) | 15 (54) | 0.03 | | Post-treatment endoscopic severity (mean scores ± SD) | ||| | ERFES** | 2.3 ± 2.0 | 2.6 ± 1.9 | 0.43 | | P value vs. baseline | <0.001 | 0.08 | | | ESS | 1.7 ± 1.5 | 2.3 ± 1.7 | 0.06 | | P value vs. baseline | <0.001 | 0.10 | *Available for n = 187 (170 and 17, respectively) **Available for n = 246 (239 and 7, respectively) When examining histologic response across selected AI/CTDs, 57% of EoE patients with Hashimoto’s disease and 33% of RA patients showed histologic response to tCS, while 44% of EoE patients with P/PA showed histologic response. When examining EoE treatment response in the context of therapies prescribed for AI/CTDs, we found that 31 patients were taking concomitant medications for AI/CTDs during their tCS treatment for EoE. Of 61 AI/CTDs patients who had received AI/CTD medications sometime in their life, 13 patients received biologics (21%), 5 received immunomodulators (8%), and 12 received NSAIDs (20%). At the time of their post-tCS endoscopy, only six patients were taking medications for the AI/CTD (26%), thus limiting our ability to analyze any additive effect of these treatments on EoE.

While EoE is considered to be an allergic condition, some studies show an association between EoE and AI,11–17,20 but limited clinical data exist. We aimed to identify the prevalence of AI and CTDs among EoE patients and evaluate demographic characteristics and variations in symptomatic and histologic response between patients with AI/CTD and EoE and EoE patients without AI/CTDs. We found that among our cohort of 1029 patients, a concomitant AI/CTD diagnosis was relatively uncommon, found in just 6%. However, this prevalence appears to be higher than what has been reported for the general US population (2–3%),37 though with the current study design we are unable to make direct comparisons. EoE patients with AI/CTD were also more likely to be older at the time of diagnosis, female, have insurance, and have a longer symptom length prior to EoE diagnosis, and these were all independently associated with AI/CTD. Additionally, our data suggest that AI/CTD patients with EoE might be somewhat resistant to tCS treatment with a significantly lower global symptom response and a numerically (but not statistically significant) lower rate of histologic response, though the sample size and lack of validated symptom metrics tempers this conclusion. When reviewing the literature on EoE and AI/CTD, the most common associations reported are between celiac disease and EoE,14,38,39 and IBD and EoE,9,10,18,19,40,41 though the strength of association varies and there is some conflicting evidence specifically for celiac disease.21,42 However, fewer studies have assessed other AI and CTDs. Peterson and colleagues found patients with EoE have an increased risk of multiple AIs, including celiac disease and IBD; however, their study did not test for an association between EoE and CTDs other than systemic sclerosis.8 Ayaki and colleagues evaluated EoE patients in three Japanese clinical centers and saw higher rates of ulcerative colitis in their cohort of EoE patients,9 though they only evaluated the association between EoE and ulcerative colitis, autoimmune polyendoscrine syndrome type 2, and endometriosis. These studies did not extensively examine response rates to tCS. Our study is the first study to report an association between sex, insurance status, and allergic disease for patients with EoE and AI/CTD. However, we note that these are associations and the data cannot be used to draw conclusions about causality; for example, it is not necessarily clear why insurance status is associated with AI/CTD unless having insurance allows a greater diagnostic opportunity for these conditions. The present study is also the first to describe response rates to topical steroids in this sub-population. We found post-treatment differences in symptom response among EoE patients with and without AI/CTD, with AI/CTD patients having less symptom response trend towards less histologic response and less endoscopic improvement (particularly compared with the more robust endoscopic improvements seen in EoE patients without AI/CTDs). Differences in global symptom response scores may reflect underlying variation in fibrostenotic disease, other secondary effects of long-term eosinophilic inflammation among patients with AI/CTD, or perhaps other superimposed symptoms from the AI/CTDs themselves. However, the small number of patients with AI/CTD with post-treatment follow-up data necessitates interpretation of these findings and the non-significant trends with caution. It is interesting to hypothesize why there may be less histologic and endoscopic improvement in the AI/CTD subgroup, but additional studies would be needed to determine if there are different pathogenic mechanisms underlying this phenotype.

of our study include the retrospective single center design and data abstraction from the electronic medical record. This may result in misclassification bias and may potentially underestimate the number of participants diagnosed with AI/CTD, if their diagnosis took place after data abstraction or if they sought care for AI/CTD in a separate hospital system. Global symptom response needs to be interpreted with caution, given that this is not a validated patient-reported outcome measure. The number of patients with AI/CTD was small, limiting the power to detect significant differences in outcomes, and if AI/CTD patients are more likely to be insured, this can lead to an exclusion selection bias. However, strengths include the large overall sample of newly diagnosed EoE patients, stringent inclusion criteria that were aimed at limiting selection bias by assessing all EoE patients at our institution, and rigorous and standardized data extraction methodology. In conclusion, EoE patients with AI/CTD were more likely to be older at the time of diagnosis, female, have insurance, and have allergic rhinitis after accounting for potential confounding factors on multivariate analysis. After topical steroid treatment, the AI/CTD subgroup appeared to be more resistant to therapy, with a lower global symptom response and less endoscopic response, as well as a trend towards less histologic response. These data support a role for ongoing evaluation of patients with EoE and AI/CTD in order to further characterize differences in disease progression and therapeutic response when compared to EoE patients without AI/CTD. Clinicians should consider AI/CTD in EoE patients as a risk factor for worse endoscopic and symptom response when treating EoE with tCS, and may need to evaluate the impact of these concomitant conditions on the disease course of EoE. Author contributions All authors approved the final manuscript. Xue and Miller: Study design, data collection and interpretation, manuscript drafting, and critical revision. Abramson, Thakkar, Ketchem, Reddy, Greenberg, Abichandani, Chang, Eluri, Reed: Data collection and interpretation, critical revision. Dellon: Project conception, study design, data collection, data analysis/interpretation, manuscript drafting, and critical revision. Financial support This study was supported by NIH T35 DK007386 and T32 DK007634. Disclosures None of the authors report any potential conflicts of interest related to this manuscript. Supplementary Material Contributor Information Zeyun Xue, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Talya L Miller, Swedish Digestive Health Institute, Swedish Health, Seattle, WA, USA. Lior Abramson, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Kisan P Thakkar, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Corey J Ketchem, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Sumana Reddy, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Sydney B Greenberg, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Sonia Abichandani, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Nicole C Chang, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Swathi Eluri, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Craig C Reed, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Evan S Dellon, Department of Medicine, Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

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