The prevalence and association between immune-mediated inflammatory disorders and inflammatory bowel disease

Introduction

Inflammatory bowel disease (IBDs) refers to a set of chronic gastrointestinal inflammatory illnesses. The two most common types of IBD are ulcerative colitis ([UC]) and Crohn's disease ([CD]). CD can affect any part of the gastrointestinal system, but UC is limited to the large intestine (Centers for Disease Control and Prevention, 2023).

Immune-mediated inflammatory disorders ([IMIDs]) occur when the immune system fails to distinguish between normal and foreign cells, resulting in an attack on healthy cells and chronic inflammation, which is a common feature of IMIDs. There are about 80 different IMIDs that affect various body organs (David et al., 2018). Notable IMIDs include rheumatoid arthritis (RA), systemic lupus erythematous (SLE), thyroid disorders, diabetes mellitus (DM), and coeliac disease. IBDs Bar Yehuda et al. (2019) are thought to be caused by an abnormal immune response to gut microbiota in those with genetic predispositions. There is a large overlap between the genetic changes found in several IMIDs (Farh et al., 2015) and those with inflammatory bowel disease (Criswell et al., 2005). That may explain why patients with IBDs are more likely to acquire other IMIDs (Cotsapas et al., 2011; Vyse and Todd, 1996; Chun et al., 2017; Wilson et al., 2016; Halling et al., 2017). Disease classification at the time of diagnosis is critical since it offers important information about the disease's progression. These statistics are critical for providing best medical treatment to patients. The Montreal classification system is used to categories individuals with IBDs based on the severity of the ailment and if it is associated with the development of IMIDs. This classification assesses the extent of disease and severity of symptoms with predictive value (Monstad et al., 2014).

A 2015 study of 17428 patients with IBDs and 17428 non-IBDs cases found that patients with IBDs had a higher prevalence of IMIDs than non-IBDs patients (Wilson et al., 2016). Furthermore, a 2017 study of individuals with 20 distinct IMIDs discovered that they occurred more commonly in those with IBDs.10 Nonetheless, there have been few research examining the relationship between IBD and IMIDs among Middle Eastern and Persian Gulf populations.

Thus, this study aimed to estimate the prevalence of IMIDs in patients with IBDs in Saudi Arabia.

Methods

A single-center retrospective analysis was carried out on adult patients with confirmed IBD, regardless of age, country, or gender, who were followed up at King Abdulaziz University Hospital in Jeddah, Saudi Arabia, from 2017 to 2022. The King Abdulaziz University ([KAU]) Inflammatory Bowel Disease Information System ([IBDIS]) registry was used to determine eligible patients. All patients over the age of 18 with a confirmed diagnosis of IBD using standard clinical, endoscopic, and histologic criteria were considered eligible.

Results

Study outcomes

Of the total study cohort ([N = 172]), 87 ([50.6%]) patients had IMIDs other than IBD ([ Figure 1]). Among the patients with IMIDs, the most common disorders were DM type 1 ([31%]) and primary sclerosing cholangitis ([PSC]) ([24.1%]) ([ Figure 2]). The prevalence of IMID was significantly higher among male patients compared to female patients ([54% vs. 46%, respectively]); ([P < .05]) ([ Table 3]). The mean duration of disease was significantly shorter among patients with IMIDs ([10.06 (6.60) vs. 12.23 (5.23) years]) compared to those without IMIDs (P < .05). At the same time, IMID prevalence was significantly higher among patients with higher mean values of WBCs ([8.29 (4.03) vs. 7.11 (3.77)]) and serum albumin ([39.04 (8.91) vs. 34.83 (11.79)]) ([P < .05]). The IMID prevalence was significantly lower among patients with CD with EIMs ([episcleritis, EN, or pyoderma gangrenosum [PG]]) (24.1% vs. 49.4%) ([P < .05]). Among patients with UC, the IMID prevalence was significantly lower among those with EN or aphthous stomatitis (1.1% vs. 18.8%) ([P < .05]). As for IBD complications, the IMID prevalence was substantially lower among patients with CD having fistulas (5.7% 15.3%) ([P < .05]), while the IMID prevalence was significantly higher among patients with UC who developed colon cancer as a complication (8% vs. 1.2%) ([P < .05]) [ Table 3].

Figure 1. Percentage distribution of immune-mediated inflammatory disorders among studied patients (N = 172).

Figure 2. Percentage distribution of type of immune-mediated inflammatory disorders among patients with IBD (N = 87).

N.B.: Thyroid diseases = (Hashimoto’s thyroiditis /chronic lymphocytic thyroiditis/autoimmune thyroiditis).

Table 3. Relationship between immune-mediated inflammatory disorders, extraintestinal manifestations, and disease complications for CD and UC (N = 172).

Variable	Total No. (%)	Immune-mediated inflammatory disorders		χ2	p-value
		No N (%)	Yes N (%)
Crohn’s disease (N = 98)
Total extraintestinal manifestations (more than one answer was allowed)	63 (64.2)	42 (49.4)	21 (24.1)	11.83	0.001
Arthralgia (n = 1)	26 (26.5)	13 (15.3)	13 (14.9)	0.004	0.949
Aphthous stomatitis (n = 3)	17 (17.3)	12 (14.1)	5 (5.7)	3.38	0.066
Episcleritis (n = 4)	12 (12.2)	10 (11.8)	2 (2.3)	5.93	0.015
Erythema nodosum (n = 10)	25 (25.5)	21 (24.7)	4 (4.6)	13.99	<0.001
Pyoderma gangrenosum (n = 11)	19 (19.3)	15 (17.6)	4 (4.6)	7.45	0.006
Pancreatitis (n = 5)	1 (1)	1 (1.2)	0 (0.0)	1.03	0.31
Peritonitis (n = 6)	1 (1)	0 (0.0)	1 (1.1)	0.98	0.322
Demyelinating disease (n = 8)	1 (1)	0 (0.0)	1 (1.1)	0.98	0.322
Hepatic steatosis (n = 9)	1 (1)	1 (1.2)	0 (0.0)	1.03	0.31
Ulcerative colitis (N = 74)
Total extraintestinal manifestations (More than one answer was allowed)	47 (63.5)	26 (30.6)	21 (24.1)	0.9	0.343
Arthralgia (n = 1)	29 (61.7)	11 (12.9)	18 (20.7)	1.84	0.175
Erythema nodosum (n = 10)	17 (36.1)	16 (18.8)	1 (1.1)	15.07	<0.001
Aphthous stomatitis (n = 3)	/*6 (12.7)	6 (7.1)	0 (0.0)	6.36	0.012
Episcleritis (n = 4)	8 (17)	6 (7.1)	2 (2.3)	2.19	0.138
Pyoderma gangrenosum (n = 11)	11 (23.4)	8 (9.4)	3 (3.4)	2.55	0.11
Arthritis (n = 2)	2 (4.2)	0 (0.0)	2 (2.3)	1.97	0.17
Pancreatitis (n = 5)	2 (4.2)	2 (2.4)	0 (0.0)	2.07	0.15
Hepatic steatosis (n = 9)	1 (2.1)	0 (0.0)	1 (1.1)	0.98	0.322
Complications of Crohn’s disease (No.:98)	49 (50)	29 (34.1)	20 (23)	2.61	0.106
Type of complications of Crohn’s disease (N = 49) (More than one answer was allowed)
Colon cancer (n = 1)	1 (2)	0 (0.0)	1 (1.1)	0.98	0.322
Venous Thrombo Embolism (n = 2)	6 (12.2)	3 (3.5)	3 (3.4)	0.001	0.977
Intestinal obstruction (n = 3)	6 (12.2)	1 (1.2)	5 (5.7)	2.66	0.102
Fistulas (n = 4)	18 (36.7)	13 (15.3)	5 (5.7)	4.18	0.041
Malnutrition (n = 8)	2 (4)	0 (0.0)	2 (2.3)	1.97	0.16
Osteoporosis (n = 11)	21 (42.8)	12 (14.1)	9 (10.3)	0.57	0.45
Perineal disease (n = 5)	10 (20.4)	7 (8.2)	3 (3.4)	1.79	0.18
Perforated bowel (n = 7)	3 (6.1)	2 (2.4)	1 (1.1)	0.36	0.547
Hernia (n = 12)	1 (2)	0 (0.0)	1 (1.1)	0.98	0.322
Complications of UC (n = 74)	23 (31)	8 (9.4)	15 (17.2)	2.27	0.131
Type of Complications of UC disease (n = 23) (More than one answer was allowed)
Colon cancer (n = 1)	8 (34.7)	1 (1.2)	7 (8)	4.57	0.032
Venous Thrombo Embolism (n = 2)	4 (17.3)	2 (2.4)	2 (2.3)	0.001	0.981
Perforated bowel (n = 7)	1 (4.3)	0 (0.0)	1 (1.1)	0.98	0.322
Osteoporosis (n = 11)	8 (34.7)	3 (3.5)	5 (5.7)	0.47	0.49
Perineal disease (n = 5)	2 (8.6)	1 (1.2)	1 (1.1)	0.001	0.989
Malnutrition (n = 8)	1 (4.3)	0 (0.0)	1 (1.1)	0.98	0.322

The prevalence of IMID was significantly lower among patients treated with mesalazine (34.5% vs. 57.6%) ([P < .05]). In contrast, the IMID prevalence was substantially higher among patients who underwent surgery (34.5% vs. 25.9%)([P < .05]) ([ Table 4]).

Table 4. Relationship between immune-mediated inflammatory disorders and medications, nutritional support, surgery type, and outcome (N = 172).

Variable	Total N (%)	Immune-mediated inflammatory disorders		χ2	p-value
		No N (%)	Yes N (%)
Medications
No	22 (12.8)	9 (10.6)	13 (14.9)	0.73	0.393
Yes	150 (87.2)	76 (89.4)	74 (85.1)
Medications used
Mesalazine	79 (45.9)	49 (57.6)	30 (34.5)	9.29	0.002
Azathioprine	62 (36)	34 (40)	28 (32.2)	1.13	0.286
Vedolizumab	11 (6.4)	5 (5.9)	6 (6.9)	0.07	0.786
Infliximab	28 (16.3)	12 (14.1)	16 (18.4)	0.57	0.448
Ustekinumab	3 (1.7)	1 (1.2)	2 (2.3)	0.31	0.574
Adalimumab	45 (26.2)	23 (27.1)	22 (25.3)	0.07	0.792
Corticosteroids	95 (55.6)	51 (60)	44 (51.2)	1.35	0.245
ASA	88 (51.5)	51 (60)	37 (42.5)	5.25	0.022
NSAIDS	50 (29.1)	22 (25.9)	28 (32.2)	0.82	0.363
Nutritional support	14 (8.1)	4 (4.7)	10 (11.5)	7.51	0.23
Normal diet	68 (39.5)	28 (32.9)	40 (46)
Not applicable	90 (52.3)	53 (62.4)	37 (42.5)
Nutritional support type (n = 14)
Diabetic diet	3 (21.6)	1 (1.2)	2 (2.3)	4.27	0.113
Full liquid diet	1 (7.1)	1 (1.2)	0 (0.0)
High potassium diet	1 (7.1)	0 (0.0)	1 (1.1)
High potassium, Low fiber diet	1 (7.1)	1 (1.2)	1 (1.1)
Low fat diet	2 (14.2)	1 (1.2)	1 (1.1)
Low salt	2 (14.2)	0 (0.0)	2 (2.3)
	3 (21.6)	0 (0.0)	3 (3.4)
	1 (7.1)	1 (1.2)	0 (0.0)
Surgery
No	116 (67.4)	63 (74.1)	53 (60.9)	6.07	0.048
Yes	52 (30.2)	22 (25.9)	30 (34.5)
Not applicable	4 (2.3)	0 (0.0)	4 (4.6)
Dead	5 (2.9)	3 (3.5)	2 (2.3)	0.23	0.631
Alive	167 (97.1)	82 (96.5)	85 (97.7)

Discussion

IBD, including UC and CD, are chronic IMIDs that cause recurring inflammation of the gastrointestinal tract because of the immune system attacking healthy cells. Shared genetic changes may aid in the coexistence of numerous IMIDs. This study sought to investigate the relationship between IMIDs and IBD. Our findings revealed a substantial relationship between IBD and IMIDs. Specifically, we discovered that roughly half of the patients with IBD ([50.6%]) had multiple IMIDs in addition to IBD ( Figure 1). Concerning specific IMIDs, our retrospective investigation found that T1DM was the most common in our sample, accounting for 31% of cases ([ Figure 2]). This finding is consistent with a prior study that included 47,325 IBD patients and proposed the existence of two possible pathways linking IBD and T1DM. These pathways include potential shared susceptibility genes like PTPN2 and changes in gut microbiota composition (Halling et al., 2017; Bar Yehuda et al., 2019). Additionally, PSC was the second most common IMID found in our retrospective study, accounting for 24.1% ([ Figure 2]). The association between IBD and PSC is well established, with a previous systematic review and meta-analysis conducted in 2021 revealing that patients with UC are 1.7 times more likely to develop PSC than those with CD (Barberio et al., 2021).

These findings should encourage clinicians who manage IBD patients to maintain a high level of clinical awareness and alertness in the face of the possibility of PSC co-occurrence. Careful and regular screening for PSC in this patient population is essential, since early and precise diagnosis is vital for avoiding significant consequences. Interestingly, our current findings indicate a higher likelihood of IMIDs in CD patients. This data is consistent with a recent study conducted in Switzerland, which found a preponderance of IMIDs among CD patients (Wilson et al., 2019). These findings have significant implications for comprehensive management approaches, particularly for educating patients about the increased risk of developing additional IMIDs. Our study investigated the correlation between IMIDs and IBD severity using the Montreal classification. Contrary to previous research indicating heightened autoimmune disease severity in patients with multiple immune-mediated conditions (Wilson et al., 2019), we found no statistically significant association between severe forms of IBD and the development of IMIDs ( Table 2). However, it is crucial to acknowledge that our methodology for assessing IBD severity is relatively rudimentary, and further investigation is needed to validate these preliminary findings.

In our attempt to find predictors of IMID incidence among IBD patients, multiple logistic regression analysis found that male patients were more likely to have other IMIDs, as opposed to earlier research where female patients were more impacted by IMIDs (Gjymishka et al., 2013). However, this disparity may be due to the small sample size from a single center. We also looked at the relationship between IMIDs and laboratory indicators such CRP, ESR, and total leukocyte count ([ Table 2]). The findings indicated no significant associations between CRP levels ([P = .199]), ESR ([P = .321]), total leukocyte count ([P = .234]), and the presence of IMIDs in the study population.

However, it is essential to note that these markers represent only a subset of potential predictors, and further investigation is warranted to explore additional markers or combinations for a more comprehensive assessment of immune-mediated inflammation. While prior research has mostly focused on the increased likelihood of developing IMIDs because of an increasing number of IBD-related symptoms (Wilson et al., 2016), our study reveals a novel discovery on EIMs. We found that combining EN with UC and CD greatly reduced the formation of IMIDs ([P <.001]) ([ Table 3]). This study has significant clinical implications, implying that the existence of EIMs may indicate a more favorable disease course or a lower risk of extra immune-mediated problems in patients with UC and CD.

Further research is needed to clarify the underlying mechanisms and explore potential therapeutic implications. Patients with concomitant IMIDs may have a more aggressive form of IBD that may account for the shorter mean duration of IBD than those without IMIDs. Individuals diagnosed with IMID before IBD exhibit a more aggressive pattern of IBD, according to another study (Akiyama et al., 2022). According to García et al. (2020), the existence of an IMID before IBD is not a reliable predictor of surgery. As a result, the IMID diagnostic date may predict IBD. Before being identified with IBD, people with IMID may require more rigorous treatment and closer monitoring to prevent surgery and improve their quality of life (The 46th Annual Meeting of the European Society, 2020).

Our findings demonstrated substantial relationships between treatment methods and the occurrence of IMIDs in IBD patients. We found a substantial decrease in IMID prevalence among patients treated with mesalazine ([P < .005]), indicating a potential preventive effect against IMID formation. However, additional prospective studies with bigger sample sizes and a controlled study design are required to validate and expand on these findings.

The study's shortcomings include a small and potentially non-representative sample size and the retrospective nature of data collecting from electronic medical records. These issues may limit the findings' generalizability and induce bias due to poor recording, compromising their accuracy. Future research should use larger sample numbers and better data collection methods to improve dependability and develop more strong findings about the relationship between IBD and IMIDs. More research is needed to look into additional indicators or combinations for a more comprehensive assessment of immune-mediated inflammation, as well as to confirm the potential therapeutic applications of EIMs in patients with UC and CD.

Conclusions

This retrospective analysis demonstrates the increased risk of IBD patients having concomitant IMIDs. In our group, 50% of persons with IBD had concomitant IMIDs, with type 1 diabetes and PSC being the most frequent. Several variables have been associated to the onset of IMIDs, including male sex, shorter disease duration, specific laboratory results, and the occurrence of comorbidities. Patients treated with mesalazine, CD patients with EIMs, and UC patients with EN or aphthous stomatitis had considerably lower prevalences. These findings indicate protective factors and areas for further research into managing IMIDs in the setting of IBD.

Ethics and consent

This work received ethical permission from the Research Ethics Committee of King Abdulaziz University Hospital in Jeddah, Saudi Arabia [Ethical permission Number: 441-23].

Date of approval: Monday, October 2, 2023.

This retrospective study utilized data from patient records for individuals who had previously provided informed consent for the use of their health information in research. Consent was obtained in accordance with ethical guidelines, and the study was conducted in compliance with applicable regulations to ensure the confidentiality and privacy of the participants.

This is a retrospective study and consent was waived by ethical committee for this study.