Association between allergic diseases and mucosal healing in ulcerative colitis

Yamamoto Y., Furukawa S., Miyake T., Watanabe J., Nakamura Y., Taguchi Y., Yamamoto T., Kato A., Kusumoto K., Yoshida O., Takeshita E., Ikeda Y., Yamamoto N., Saeki Y., Yamaguchi O., et. al.

Gong T., Brew B.K., Lundholm C., Smew A.I., Harder A., Kuja-Halkola R., Ludvigsson J.F., Lu Y., Almqvist C.

Abstract Background Little is known about shared origins between inflammatory bowel disease (IBD) and allergic diseases (asthma, allergic rhinitis, and eczema). We aimed to expand current knowledge on the etiological sources of comorbidities between these disorders using a range of genetically informed methods. Methods Within-individual and familial co-aggregation analysis was applied to 2 873 445 individuals born in Sweden from 1987 to 2014 and their first- and second-degree relatives. Quantitative genetic modeling was applied to 38 723 twin pairs to decompose the genetic and environmental sources for comorbidity. Polygenic risk score analysis between IBD and allergic diseases was conducted in 48 186 genotyped twins, and linkage disequilibrium score regression was applied using publicly available data to explore the genetic overlap. Results IBD was associated with asthma (adjusted odds ratio [aOR], 1.35; 95% confidence interval [CI], 1.30 to 1.40), allergic rhinitis (aOR, 1.27; 95% CI, 1.20 to 1.34), and eczema (aOR, 1.47; 95% CI, 1.38 to 1.56), with similar estimates for ulcerative colitis or Crohn’s disease. The ORs for familial co-aggregation decreased with decreasing genetic relatedness. Quantitative genetic modeling revealed little evidence of common genetic factors between IBD and allergic diseases (eg, IBD and allergic rhinitis; genetic correlation ra = 0.06; 95% CI, −0.03 to 0.15) but did reveal some evidence of unique environmental factors between IBD and eczema (re = 0.16; 95% CI, 0.00 to 0.32). Molecular genetic analyses were similarly null for IBD and allergic diseases, except for a slight association between Crohn’s disease polygenic risk score and eczema (OR, 1.09; 95% CI, 1.06 to 1.12). Conclusions We found little evidence to support a shared origin between IBD and any allergic disease but weak evidence for shared genetic and unique environmental components for IBD and eczema.

Joel M.Z., Damsky W., Cohen J.M.

Our study investigated the association between atopic dermatitis and inflammatory bowel disease using the All of Us Research Program, a National Institutes of Health database providing health information on over 300,000 Americans.This cross-sectional study demonstrated that individuals with atopic dermatitis have an approximately 2-fold increase in odds of having inflammatory bowel disease, Crohn's disease and ulcerative colitis, compared to individuals without atopic dermatitis.

Kisiel M.A., Sedvall M., Malinovschi A., Franklin K.A., Gislason T., Shlunssen V., Johansson A., Modig L., Jogi R., Holm M., Svanes C., Lindholdt L., Carlson M., Janson C.

Asthma and inflammatory bowel disease (IBD) are common inflammatory diseases. The aim of this study was to investigate the associations of IBD with asthma and respiratory symptoms.This study is based on 13,499 participants from seven northern European countries that filled in a postal questionnaire on asthma, respiratory symptoms, IBD including ulcerative colitis and Crohn's disease and various lifestyle variables.There were 195 participants with IBD. The prevalence of asthma (14.5 vs 8.1%, p = 0.001), different respiratory symptoms (range 11.9-36.8% vs range 6.0-18.6%, p < 0.005), non-infectious rhinitis (52.1 vs. 41.6%, p = 0.004) and chronic rhinosinusitis (11.6 vs 6.0%, p = 0.001) were higher in subjects with IBD than in those without IBD. In multivariable regression analysis, the association between IBD and asthma was statistically significant (OR 1.95 (95% CI 1.28-2.96)) after adjusting for confounders such as sex, BMI, smoking history, educational level and physical activity. There was a significant association between asthma and ulcerative colitis (adjusted OR 2.02 (95% CI 1.27-2.19)), and asthma but not Crohn's disease (adjusted OR 1.66 (95% CI 0.69-3.95)). A significant gender interaction was found with a significant association between IBD and asthma in women but not in men ((OR 2.72 (95% CI 1.67-4.46) vs OR 0.87 (95% CI 0.35-2.19), p = 0.038).Patients with IBD, particularly those with ulcerative colitis and female, have a higher prevalence of asthma and respiratory symptoms. Our findings indicate that it is important to consider respiratory symptoms and disorders when examining patients with manifest or suspected IBD.

Aniwan S., Santiago P., Loftus E.V., Park S.H.

Alenezy N., Nugent Z., Herman S., Zaborniak K., Ramsey C.D., Bernstein C.N.

Abstract Objective This study aimed to determine whether having a diagnosis of asthma or allergic rhinitis (AR) increased the risk of being diagnosed with inflammatory bowel disease (IBD) and whether there was increased incidence of these diseases after a diagnosis of IBD. Design This is a retrospective, historical cohort–based study. We used the administrative data of Manitoba Health and the population-based University of Manitoba IBD Epidemiology Database. We used numbers of prescriptions for drugs used to treat asthma and to treat AR to identify diagnoses of asthma and AR, respectively. We calculated relative risks (RRs) to assess incidence of IBD compared with matched controls after diagnoses of asthma and AR and hazard ratios to determine the incidence of asthma and AR after IBD diagnosis. Results Compared with controls, a diagnosis of asthma or AR preceding a diagnosis of IBD was increased in cases (RR, 1.62; 95% confidence interval [CI], 1.50-1.75; and RR, 2.10; 95% CI, 1.97-2.24) with a similar outcome by subtype of IBD (Crohn’s disease vs ulcerative colitis) and by sex. On sensitivity analysis, diagnoses of asthma or AR were comparable when considering at least 5, 10, 15 or 20 drug prescriptions. Persons with IBD were more likely to develop asthma or AR than controls after being diagnosed with IBD (hazard ratio for asthma, 1.31, 95% CI, 1.18-1.45; and hazard ratio for AR, 2.62, 95% CI, 2.45-2.80). Conclusions The association between asthma, AR, and IBD suggest the possibility that whatever triggers the onset of these atopic diseases may trigger the onset of IBD as well, and aeroallergens are plausible culprits.

Villablanca E.J., Selin K., Hedin C.R.

Almost all currently available treatments for inflammatory bowel disease (IBD) act by inhibiting inflammation, often blocking specific inflammatory molecules. However, given the infectious and neoplastic disease burden associated with chronic immunosuppressive therapy, the goal of attaining mucosal healing without immunosuppression is attractive. The absence of treatments that directly promote mucosal healing and regeneration in IBD could be linked to the lack of understanding of the underlying pathways. The range of potential strategies to achieve mucosal healing is diverse. However, the targeting of regenerative mechanisms has not yet been achieved for IBD. Stem cells provide hope as a regenerative treatment and are used in limited clinical situations. Growth factors are available for the treatment of short bowel syndrome but have not yet been applied in IBD. The therapeutic application of organoid culture and stem cell therapy to generate new intestinal tissue could provide a novel mechanism to restore barrier function in IBD. Furthermore, blocking key effectors of barrier dysfunction (such as MLCK or damage-associated molecular pattern molecules) has shown promise in experimental IBD. Here, we review the diversity of molecular targets available to directly promote mucosal healing, experimental models to identify new potential pathways and some of the anticipated potential therapies for IBD. Attaining mucosal healing without immunosuppression is an attractive option for the treatment of inflammatory bowel disease (IBD). This Review describes the mechanisms of mucosal healing and how they might be altered in IBD and discusses potential therapeutic approaches to promote mucosal healing and regeneration.

Meisinger C., Freuer D.

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

Soh H., Lee H.J., Han K., Park S., Hong S.W., Moon J.M., Kang E.A., Lee J., Chun J., Im J.P., Kim J.S.

Background & Aims The association between atopic diseases and inflammatory bowel diseases (IBD) is unclear. We conducted a nationwide population-based study in Korea to investigate the effect of atopic diseases on the development of IBD. Methods A total of 9,923,521 participants, who received a medical check-up in 2009, were included and followed through 2017. The presence of any atopic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma, was evaluated. Patients who developed IBD, including Crohn's disease (CD) and ulcerative colitis (UC), were identified using claims data from National Health Insurance; the association between atopic diseases and the risk of IBD was evaluated using Cox proportional hazard models, and presented as adjusted hazard ratios (aHRs) with 95% CIs. Results During a mean follow-up period of 7.3 years, 1419 patients (0.014%) developed CD and 5897 patients (0.059%) developed UC. The incidences of CD (per 100,000 person-years) were 3.756, 2.248, and 2.346 in patients with AD, AR, or asthma, respectively. The incidences of UC were 11.952, 9.818, and 9.358 in patients with AD, AR, or asthma, respectively. Multivariable analysis revealed that the aHRs for incident CD in patients with AD, AR, or asthma were 2.02, 1.33, and 1.60 (95% CIs, 1.118–3.663, 1.149–1.529, and 1.193–2.136, respectively) compared with controls. The risks of incident UC in patients with AD, AR, or asthma were 1.51, 1.32, and 1.29 (95% CIs, 1.082–2.104, 1.229–1.410, and 1.115–1.491, respectively) compared with controls. Moreover, an increase in the number of atopic diseases gradually increased the risk for CD and UC; for 1 or 2 or more atopic diseases, the aHRs for CD were 1.35 and 1.65 (95% CIs, 1.171–1.560 and 1.146–2.376), and the aHRs for UC were 1.30 and 1.49 (95% CIs, 1.211–1.392 and 1.249–1.774), respectively. Conclusions Based on a nationwide population-based study in Korea, patients with any atopic disease, including AD, AR, or asthma, have an increased risk for CD and UC. The risk for IBD increases with the increase in the number of atopic diseases.

Olfatifar M., Zali M.R., Pourhoseingholi M.A., Balaii H., Ghavami S.B., Ivanchuk M., Ivanchuk P., Nazari S.H., shahrokh S., Sabour S., Khodakarim S., Aghdaei H.A., Rohani P., Mehralian G.

The projection studies are imperative to satisfy demands for health care systems and proper response to the public health problems such as inflammatory bowel disease (IBD). To accomplish this, we established an illness-death model based on available data to project the future prevalence of IBD in Asia, Iran in particular, separately from 2017 to 2035. We applied two deterministic and stochastic approaches. In 2035, as compared to 2020, we expected a 2.5-fold rise in prevalence for Iran with 69 thousand cases, a 2.3-fold increment for North Africa and the Middle East with 220 thousand cases, quadrupling of the prevalence for India with 2.2 million cases, a 1.5-fold increase for East Asia region with 4.5 million cases, and a 1.6-fold elevation in prevalence for high‐income Asia‐Pacific and Southeast Asia regions with 183 and 199 thousand cases respectively. Our results showed an emerging epidemic for the prevalence of IBD in Asia regions and/or countries. Hence, we suggest the need for immediate action to control this increasing trend in Asia and Iran. However, we were virtually unable to use information about age groups, gender, and other factors influencing the evolution of IBD in our model due to lack of access to reliable data.

Furukawa S., Yagi S., Shiraishi K., Hashimoto Y., Kitahata S., Hanayama M., Tange K., Mori K., Ninomiya T., Suzuki S., Shibata N., Murakami H., Ohashi K., Hasebe A., Tomida H., et. al.

Although the association between eating habits which can be modified and digestive diseases has been reported, to date, no research has evaluated the association between eating habits and ulcerative colitis (UC). Thus, we investigate the association between eating behavior and clinical outcome in Japanese patients with UC. Eating quickly, eating until full, and skipping breakfast data was obtained from a self-administered questionnaire. Information on clinical outcome was collected from medical records. Mucosal healing (MH) and partial MH was defined as a Mayo endoscopic subscore of 0 or 0–1, respectively. Age, sex, BMI, current smoking, current drinking, prednisolone use, and anti-TNFα monoclonal antibody use were selected a priori as potential confounding factors. Study subjects consisted of 294 Japanese patients with UC. Eating at speed moderate and eating quickly were independently inversely associated with MH: the adjusted odds ratios (ORs) were 0.38 (95% confidence interval [CI] 0.16–0.85) and 0.38 (95% CI 0.17–0.81) (p for trend = 0.033). Eating until full was independently inversely associated with MH: the adjusted OR was 0.38 (95% CI 0.27–0.86). MH in patients who skipped breakfast was marginally lower than that in patients who did not skip breakfast. No association between eating habits and clinical remission or partial MH was found. Among patients with UC, eating rate and eating until full may be independently inversely associated with MH but not clinical remission.

Turner D., Ricciuto A., Lewis A., D’Amico F., Dhaliwal J., Griffiths A.M., Bettenworth D., Sandborn W.J., Sands B.E., Reinisch W., Schölmerich J., Bemelman W., Danese S., Mary J.Y., Rubin D., et. al.

BACKGROUND The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment-targets in 2015 for adult IBD patients. We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD. METHODS Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in two surveys and two voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale. RESULTS In the systematic-review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey (n=39 on Crohn's Disease (CD) and n=36 on ulcerative colitis (UC)) identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed (n=70). STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in CD and histological healing in UC are not formal targets but should be assessed as measures of the remission depth. CONCLUSIONS STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This framework should be adapted to individual patients and local resources to improve outcomes.

Lee H., Lee J.H., Koh S., Park H.

Background Recently, atopic dermatitis has been suggested as a systemic inflammatory disorder that can accompany other inflammatory diseases, including inflammatory bowel disease. However, comprehensive reviews that specifically focus on the association between inflammatory bowel disease and atopic dermatitis are lacking. Objective To determine the association between inflammatory bowel disease and atopic dermatitis. Methods We searched for relevant studies from MEDLINE, EMBASE, and the Cochrane Library from inception to November 22, 2019. Considering a potential bidirectional relationship, studies reporting inflammatory bowel disease in patients with atopic dermatitis and atopic dermatitis in patients with inflammatory bowel disease were evaluated separately. Results We included 10 studies with 95,291,110 patients (4 studies on the prevalence of atopic dermatitis in inflammatory bowel disease, 2 on the prevalence and incidence of inflammatory bowel disease in atopic dermatitis, and 4 on either the prevalence or incidence of inflammatory bowel disease in atopic dermatitis). Meta-analyses revealed a statistically significant association between inflammatory bowel disease and atopic dermatitis in both directions (4 studies on atopic dermatitis prevalence in inflammatory bowel disease, odds ratio 1.39, 95% confidence interval 1.28-1.50; 5 on inflammatory bowel disease prevalence in atopic dermatitis, odds ratio 1.35, 95% confidence interval 1.05-1.73; and 3 studies on inflammatory bowel disease incidence in atopic dermatitis, relative risk 1.46, 95% confidence interval 0.98-2.17). Limitations A small number of observational studies were reviewed. Conclusion Published literature suggests a bidirectional relationship between inflammatory bowel disease and atopic dermatitis.

Blöndal V., Malinovschi A., Sundbom F., James A., Middelveld R., Franklin K.A., Lundbäck B., Janson C.

Asthma is common worldwide and a large part of subjects with asthma have concomitant allergic multimorbidity in the form of rhinitis and/or eczema.The aim of this study is to investigate whether the presence of allergic multimorbidity in asthma relates to allergic sensitization, allergic and respiratory symptoms, quality of life, inflammatory markers, lung function, use of medication and background factors.A total of 437 asthmatics from the (GA2 LEN) cross-sectional survey in Sweden were grouped depending on the presence of rhinitis and/or eczema. The impact of allergic multimorbidity was assessed in terms of allergic sensitization, allergic and respiratory symptoms, quality of life, type-2 inflammatory markers (exhaled nitric oxide, eosinophil activation markers, periostin), lung function, use of medication and background factors.Subjects with asthma, rhinitis and eczema were more likely to be sensitized to seasonal allergens (67% vs 32%, P < .001), food allergens (54% vs 18%, P < .001) and to have a higher degree of sensitization than subjects with only asthma (23% vs 10%, P < .001). Subjects with allergic multimorbidity more often had allergic reactions to food (28% vs 10%, P = .002), more respiratory symptoms and anxiety/depression (40% vs, 14%, P < .001) than subjects with only asthma, despite having similar levels of type 2 inflammatory markers. Individuals with allergic multimorbidity were more likely to be diagnosed with asthma before the age of 12 (48% vs 27%, P = .016) and to have maternal heredity for allergy (53% vs 33%, P = .011) than subjects with only asthma.Asthmatics with allergic multimorbidity are more likely to be sensitized to seasonal aeroallergens, food allergens and they have a higher degree of sensitization compared with those with only asthma. Allergic multimorbidity is associated with respiratory and allergy symptoms, anxiety and/or depression.

Matsuoka K., Igarashi A., Sato N., Isono Y., Gouda M., Iwasaki K., Shoji A., Hisamatsu T.

Abstract Background and Aims Recent treatment guidelines for ulcerative colitis [UC] do not recommend long-term corticosteroid [CS] use. The present study aimed to capture the changes in CS use from 2006 to 2016 and to identify factors associated with long-term CS use after 2014, when the first two anti-tumour necrosis factor antibodies [infliximab and adalimumab] became available. Methods A retrospective study using the JMDC Claims Database included UC patients who initiated UC medications in any year from January 2006 to December 2016, or after January 2014, who were under continuous observation from 6 months before to 12 months after initiation. Patients with Crohn’s disease before initiation and those prescribed &lt;8 days of CSs were excluded. Results Among 7907 UC patients who initiated UC medications within the study period, 1555 were prescribed CSs. The proportion of patients using CSs in each year decreased from 2011 as use of thiopurines and biologics increased. The proportion of patients with a starting dose ≥30 mg/day of CSs and patients continuing CSs for &lt;90 days increased from 2011, reaching 49.1% and 41.0%, respectively, in 2016. However, even in 2016, 34.3% continued to use CSs for ≥180 days. Among 1230 patients with CS use after January 2014, low initial CS dose [&lt;10 mg/day] was most strongly associated with long-term CS use [≥180 days]. Conclusions CS use became more appropriate as use of thiopurine and biologics increased, although there were still many cases of inappropriate use. Long-term CS use was most strongly associated with low initial doses of CSs.