The prevalence of allergic diseases is associated with clinical outcomes in ulcerative colitis

doi:10.21203/rs.3.rs-3960197/v1

Background: No evidence regarding the association between the prevalence of allergic diseases and the clinical activity of ulcerative colitis (UC) exists, although several studies have shown the positive association between allergic diseases and onset of UC. Aim: This study aimed to investigate this issue in patients with UC.

Methods: We studied 289 Japanese patients with UC. Information regarding allergic diseases (asthma, atopic dermatitis, pollen allergy, food allergy, and drug allergy) diagnosed by a medical doctor, lifestyle, and medical history were collected using a self-administered questionnaire. The definition of mucosal healing (MH) was Mayo Endoscopic Score 0. The association between each allergic disease and its multimorbidity with MH was evaluated using multivariate logistic regression analyses.

Results: Pollen allergy was the most common allergic disease (36.3%). Pollen allergy and food allergy were independently positively associated with MH (pollen allergy adjusted odds ratio (OR): 1.82 [95% confidence interval (CI): 1.01–3.26]; food allergy adjusted OR: 3.47 [95% CI: 1.26–9.68]). The rate of MH for 0, 1, 2, and 3 or more allergic diseases was 22.6%, 21.3%, 29.7%, and 59.3%, respectively. After adjustment, 3 or more allergic diseases was independently and positively associated with MH (adjusted OR for 3 or more diseases: 8.13 [95% CI: 2.17–34.04], p for trend = 0.020).

Conclusions.: In patients with UC, pollen allergy and food allergy were independently positively associated with MH, respectively. Additionally, allergic multimorbidity was independently positively associated with MH.

allergic diseases

ulcerative colitis

inflammatory bowel disease

atopic dermatitis

food allergy

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation in the colonic mucosa. The prevalence of UC has traditionally been higher in Western countries [1], but recent studies indicate a rapid increase in Asia, including Japan [2–4]. In the clinical setting, achieving mucosal healing (MH) is a standard treatment target in patients with UC [5]. MH is associated with fewer early relapses [6, 7], lowered rates of bowel resection [8] and colorectal cancer [9], and an improved quality of life [10, 11]. Several factors, including unhealthy dietary habits [12], the severity of mucosal inflammation [13], duration of clinical remission [14], disease extent [14], and medication [13–15], affect the achievement of MH. However, the associated factors for MH remain unclear in UC patients.

Several studies have shown the association between allergic diseases, mainly asthma and atopic dermatitis (AD), and IBD including UC. Systematic reviews and meta-analyses have demonstrated the association between asthma, AD, and IBD including UC [16, 17]. Additionally, an association between other allergic diseases and IBD has been found [18–21]. The number of allergic diseases was associated with the incidence of UC in a Korean study [22]. In a Polish study of pediatric IBD patients, the prevalence of several allergic diseases in IBD patients was higher compared to controls, although the findings were not statistically significant [23].

We hypothesized that allergic diseases would be associated with poor clinical outcomes in UC. To the best of our knowledge, no study regarding the relationship between specific allergic diseases and MH as a clinical outcome in UC patients has been conducted. In addition, the relationship between allergic multimorbidity and MH has remained unclear.

The primary objective of this research is to investigate the association between the each allergic disease and clinical outcomes of UC. The secondary objective is to elucidate the relationship between allergic multimorbidity and clinical outcomes of UC.

Study population

Between 2015 and 2019, a total of 387 patients with UC were enrolled in this study from Ehime University Hospital and several other affiliated institutions in Ehime Prefecture, either as inpatients or outpatients. All included individuals had previously been diagnosed with UC, as confirmed by colonoscopy and further validated by clinical, radiological, and histological evidence. A subset of 98 participants was excluded due to incomplete data, resulting in 74.7% (289/387) of the original cohort being enrolled and evaluated in this study.

Ethical statement

The research protocol was carefully designed in accordance with the ethical requirements of the 1964 Declaration of Helsinki and its subsequent revisions. Ethical approval for this study was granted by the Ethics Committee of Ehime University School of Medicine (approval number 1505011). Each participant provided written informed consent and completed a self-administered survey. This study is also registered UMIN (000051334).

Study design

Cross-sectional study

Definition of mucosal healing and clinical remission

An expert in endoscopy performed a total colonoscopy to evaluate the endoscopic activity of UC. In this study, the Mayo Endoscopic Score (MES) 0 was interpreted as MH [24]. Both MES and MH were assessed by an endoscopy specialist who was unaware of the presence of allergic diseases. Clinical remission (CR) was defined as the absence of rectal bleeding combined with stool frequency not exceeding the norm (less than 3 times/day). A board-certified gastroenterologist was responsible for assessing clinical symptoms.

Assessment of allergic diseases

Information on the diagnosis of asthma, AD, pollen allergy, food allergy, and drug allergy was obtained using a self-administered questionnaire. Participants were asked to answer either “YES” or “NO” to indicate whether they had been diagnosed with each allergic disease.

Other measurements

Data on smoking, alcohol consumption, and medical history were collected using a self-administered questionnaire. Current smoking status was assigned if a participant confirmed active smoking. Current alcohol consumption was classified if the participant reported regular consumption of alcoholic beverages, regardless of frequency and volume.

Statistical Analysis

The number of allergic diseases was divided into the following four categories: 0 (reference), 1, 2, and 3 or more. Estimates of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for clinical outcomes associated with allergic diseases were performed using logistic regression analysis. Multiple logistic regression analyses were used to adjust for potential confounders. Age, sex, body mass index, current alcohol use, current smoking, steroid use, and tumor necrosis factor (TNF)-α monoclonal antibody use were selected as potential confounders. Statistical analyses were performed with the SAS software package, version 9.4 (SAS Institute Inc., Cary, NC, USA). All probability values for statistical tests were two-tailed, and p < 0.05 was considered statistically significant.

Subject Characteristics

The characteristics of the 289 UC patients are shown in Table 1. The mean age, duration of UC, and body mass index were 50.1 ± 16.0 years, 8.3 ± 8.4 years, and 22.63 ± 4.60 kg/m², respectively. Males accounted for 57.8% of participants. Administration of 5-aminosalicylates, prednisolone, thiopurines, and TNF-α monoclonal antibody therapies occurred in 91.4%, 20.1%, 14.5%, and 5.5% of cases, respectively. The mean MES was 1.22 ± 0.91. MH and clinical remission were observed in 24.6% and 59.4% of patients, respectively. Pollen allergy was the most common allergic disease (36.3%), followed by asthma (11.8%). The incidence of AD, drug allergy, and food allergy were 9.0%, 8.3%, and 6.2%, respectively. Almost half (49.5%) of the subjects had one or more allergic diseases, while 4.2% had three or more such diseases.

Association Between Each Allergic Disease and Clinical Outcomes in UC Patients

Table 2 shows the crude and adjusted ORs and 95% CIs for the association between allergic disease and clinical outcomes in UC patients. After adjustment for age, sex, body mass index, current smoking, current drinking, use of steroids, and TNF-α monoclonal antibody, pollen allergy and food allergy were independently positively associated with MH (adjusted OR for pollen allergy: 1.82 [95% CI: 1.01–3.26] and food allergy: 3.47 [95% CI: 1.26–9.68]). There was no significant difference in the association between each allergic disease and clinical remission (CR) in this cohort study.

Association Between Number of Allergic Diseases and Clinical Outcomes in UC Patients

Table 3 shows the crude and adjusted ORs and 95% CIs for the number of allergic diseases associated with MH or CR in UC patients. The rates of MH with 0, 1, 2, and 3 or more allergic diseases were 22.6%, 21.3%, 29.7%, and 59.3%, respectively. After adjusting for confounders, 3 or more allergic diseases was independently positively associated with MH, and multimorbidity of allergic diseases tended to correlate with the rate of MH in UC patients (adjusted OR for 3 or more diseases: 8.13 [95% CI: 2.17-34.04], p for trend = 0.020). The prevalence of CR with 0, 1, 2, and 3 or more allergic diseases was 62.3%, 54.3%, 56.8%, and 75.0%, respectively. There was no association between allergic multimorbidity and CR in this cohort study.

In the present study, pollen allergy and food allergy, and number of allergic diseases, were independently positively associated with MH. This is the first study to demonstrate the association between allergic diseases, including allergic multimorbidity and clinical outcomes, in UC patients.

Allergic diseases and UC have clinical and pathophysiological similarities. The prevalence of asthma and AD are associated with UC [16, 17]. The prevalence of asthma is higher in female patients with UC [25]. The prevalence of asthma is a risk factor for UC [26]. In a Canadian study, the prevalence of asthma is associated with the onset of IBD [18]. Similarly, the prevalence of AD in UC patients is higher compared to that of the general population [19, 27]. The development of UC in patients with AD is high in Korean [23], Japanese [28], and large European database studies [27]. On the other hand, evidence regarding the association between other allergy diseases and IBD including UC is limited. The prevalence of pollen allergy is twice as high in UC compared to controls in the US study [19]. A high incidence of food allergy has been reported in Iranian pediatric IBD patients [29]. Food allergy has been suggested to be associated with the pathogenesis of IBD [21, 21]. In the present study, neither asthma nor AD were associated with clinical outcomes including MH. On the other hand, a positive association between pollen allergy, food allergy, and MH was found.

Allergic multimorbidity is positively associated with respiratory and allergic symptoms, anxiety, depression, functional gastrointestinal diseases, and UC [23, 30, 31]. In the present study, an independent positive association between allergic multimorbidity and MH was observed.

The discrepancy between the association of allergic disease with the onset of UC in previous studies and the favorable clinical outcomes of UC in the present study may be explained by the definition of each allergic disease, the number of years of treatment for allergic disease and UC, and the fact that this study examined the association with disease activity and not the incidence or prevalence of UC. As the present cohort consists of patients who make regular hospital visits, long-term treatment for both diseases might mask the true association between allergy diseases and MH. A combination of specific food allergy immunotherapy and probiotics are effective for UC-related symptoms in patients with both UC and food allergy [32, 33]. Antihistamine medication improved intestinal inflammation and clinical outcomes in UC patients [34, 35]. In addition, upadacitinib, a JAK (Janus kinase) inhibitor, is used for both atopic dermatitis and UC [36, 37].

The underlying mechanism that links allergic diseases, allergic multimorbidity, and clinical outcomes in patients with UC remains unclear. The pathogenesis of UC includes immune abnormalities of the Th2 pathway (typical of allergic diseases), abnormalities of the Th1 and Th17 pathways, and mast cell dysfunction [30, 38]. Allergic diseases themselves and/or medication for allergic diseases may have a potentially favorable effect for controlling UC activity via controlling mast cell function, histamine secretion, and a JAK signal transductor and activator of transcription. Future examination of the intricate interactions between allergic diseases and UC has the potential to optimize treatment and improve clinical outcomes for UC patients.

Our study has several limitations. First, the reliance on self-reported diagnosis of allergic diseases may have introduced reporting bias. Second, the cross-sectional design of our study precludes us from establishing a temporal relationship between allergic diseases and MH in UC. Third, the study was conducted in a single geographic region, which limits the generalizability of our findings. Despite these limitations, our study is one of the few to address the impact of allergic multimorbidity on MH in UC. Furthermore, the robust statistical adjustment for potential confounders lends credibility to our findings.

In conclusion, pollen allergy and food allergy were independently positively associated with MH, respectively, in patients with UC. Additionally, allergic multimorbidity was independently positively associated with MH.

Acknowledgements

The authors would like to thank Keitarou Kawasaki, Yuji Mizukami, Satoshi Imamine, Masamoto Torisu, Kenichiro Mori, Aki Hasebe, Harumi Yano, Makoto Yano, Masato Murakami, Masumi Hino, and Tomo Kogama.

Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contribution

Conception and design: YY, SF, and YH; Material preparation and data collection: KS, YH, KT, SY, MH, TN, SS, NS, HM, KO, HT, YY. ET, and YI; Data analysis: SF; Interpretation of data: SK, SF, TM, and YH; the first draft of the manuscript was written by YY and SF; the first draft of the manuscript was edited by SF, TM, and OY. Supervision: YH. All authors read and approved the final manuscript.

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Table 1. Clinical characteristics of 289 study participants

Variables		Mean ± SD or n (%)
Age (years)		50.1 ± 16.0
Male (%)		167 (57.8)
Disease extent (n; pancolitis/left-sided/proctitis/other)		120/78/84/7
Duration of UC (years)		8.3 ± 8.4
BMI		22.63 ± 4.60
Current smoking		21 (7.3)
Current drinking		118 (40.8)
Medication for UC
5-Aminosalicylates		264 (91.4)
Prednisolone		58 (20.1)
Thiopurines		42 (14.5)
TNF-α monoclonal antibody		16 (5.5)
Mayo Endoscopic Subscore (MES)		1.22 ± 0.91
Complete mucosal healing (MES 0)		71 (24.6)
Clinical remission		172 (59.5)
Allergy disease
Asthma (n, %)		34 (11.8)
Atopic dermatitis (n, %)		26 (9.0)
Pollen allergy (n, %)		105 (36.3)
Food allergy (n, %)		18 (6.2)
Drug allergy (n, %)		24 (8.3)
Number of allergy diseases		0.72 ± 0.88
0 (n, %)		146 (50.5)
1 (n, %)		94 (32.5)
2 (n, %)		37 (12.8)
3 or more (n, %)		12 (4.2)

BMI, body mass index; UC, ulcerative colitis; SD, standard deviation; TNF, tumor necrosis factor; Other: right-sided, segmental colitis, and postoperative patients (lack of any preoperative medical records for postoperative patients)

Table 2. Crude and adjusted odds ratios and 95% confidence intervals for allergy diseases related to clinical outcomes

Variable	Prevalence (%)	Crude OR (95% CI)	Adjusted OR (95% CI)
MH
Asthma, n (%)
No	62/255 (24.3)	1.00	1.00
Yes	9/34 (26.5)	1.12(0.47–2.45)	1.18 (0.49–2.68)
Atopic dermatitis, n (%)
No	65/263 (24.7)	1.00	1,00
Yes	6/26 (23.1)	0.91 (0.32–2.25)	1.11 (0.38–2.89)
Pollen allergy, n (%)
No	39/184 (21.2)	1.00	1.00
Yes	32/105 (30.5)	1.63 (0.94–2.81)	1.82 (1.01–3.26)
Food allergy, n (%)
No	62/271 (22.9)	1.00	1.00
Yes	9/18 (50.0)	3.37 (1.27–9.00)	3.47 (1.26–9.68)
Drug allergy, n (%)
No	62/265 (23.4)	1.00	1.00
Yes	9/24 (37.5)	1.97 (0.79–4.64)	1.81 (0.70–4.49)

Clinical remission
Asthma, n (%)
No	151/255 (59.2)	1.00	1.00
Yes	21/34 (61.8)	1.11 (0.54–2.37)	1.19 (0.54–2.71)
Atopic dermatitis, n (%)
No	159/263 (60.5)	1.00	1.00
Yes	13/26 (50.0)	0.65 (0.29–1.48)	0.75 (0.31–1.83)
Pollen allergy, n (%)
No	113/184 (61.4)	1.00	1.00
Yes	59/105 (56.2)	0.81 (0.50–1.31)	0.78 (0.46–1.33)
Food allergy, n (%)
No	161/271 (59.4)	1.00	1.00
Yes	11/18 (61.1)	1.07 (0.41–3.00)	0.96 (0.34–2.89)
Drug allergy, n (%)
No	153/265 (57.7)	1.00	1.00
Yes	19/24 (79.2)	2.78 (1.08– 8.59)	2.75 (0.98–9.31)

Adjusted for age, sex, body mass index, current drinking, current smoking, use of steroid, and TNF-α monoclonal antibody.

OR, odds ratio; CI, confidence interval; NA, not applicable; FD, functional dyspepsia; IBS, irritable bowel syndrome

Table 3. Crude and adjusted odds ratios and 95% confidence intervals for number of allergy diseases related to clinical outcome

Variable	Prevalence (%)	Crude OR (95% CI)	Adjusted OR (95% CI)
Number of allergy diseases
MH
0	33/146 (22.6)	1.00	1.00
1	20/94 (21.3)	0.93 (0.49–1.72)	0.93 (0.48–1.79)
2	11/37 (29.7)	1.45 (0.63–3.19)	1.48 (0.61–3.44)
3 or more	7/12 (58.3)	4.79 (1.44–17.15)	8.13 (2.17–34.04)
p for trend			0.020

Clinical remission
0	91/146 (62.3)	1.00	1.00
1	51/94 (54.3)	0.72 (0.42–1.21)	0.66 (0.37–1.17)
2	21/37 (56.8)	0.79 (0.38–1.67)	0.66 (0.30–1.48)
3 or more	9/12 (75.0)	1.81 (0.52–8.43)	2.99 (0.72–16.71)
p for trend			0.85

Adjusted for age, sex, body mass index, current drinking, current smoking, use of steroid, and TNF-α monoclonal antibody.

OR, odds ratio; CI, confidence interval; FD, functional dyspepsia; IBS, irritable bowel syndrome

No competing interests reported.

The prevalence of allergic diseases is associated with clinical outcomes in ulcerative colitis

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Abstract

Introduction

Methods

Results

Discussion

Declarations

References

Tables

Additional Declarations

Status:

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