1. INTRODUCTION

Inflammatory Bowel Diseases (IBDs) are multifactorial diseases that cause continuous inflammation of the gastrointestinal tract [1]. Although the prevalence and incidence of IBD are highest in Western populations, Asia and the Middle East have witnessed a large increase in prevalence, with estimates of 4.9–168.3 per 100,000 persons with Ulcerative Colitis (UC) cases as compared with an increase of 37.5–248.6 per 100,000 persons in North America. Crohn’s Disease (CD) has showed a variation in incidence globally, with reports of an increase of 0.88–67.9 per 100,000 persons in Asia and the Middle East compared with a much higher prevalence in North America, from 16.7 to 318.5 per 100,000 persons [2]. IBD has become an increasing concern due to its relapsing gastrointestinal manifestations and its association with other systems. Disease-related morbidity can significantly affect quality of life and work productivity, and may lead to increased health expenditure [3].

Extraintestinal Manifestations (EIMs) of IBD, which involve the joints, eyes, skin, and biliary tract, have a marked impact on the morbidity and mortality of IBD, with overall occurrence frequencies of 6–47% [4–11]. However, several studies conducted in Asia have found that EIMs are less prevalent among IBD patients when compared with those in Western countries [12,13]. A systematic review found that the most common of these manifestations are inflammatory arthropathies, with a prevalence of 10–35% [14]. Other common EIMs include oral and ocular lesions, which reportedly occur in 4–20% and 2–29% of IBD patients, respectively. The skin may also be involved in the form of Erythema Nodosum (EN) in 2–20% of cases and Pyoderma Gangrenosum (PG) in 0.5–2% of cases [14,15]. A group of manifestations may occur secondary to metabolic and anatomical features of the disease itself, such as osteopenia and osteoporosis, anemia, cholelithiasis, and nephrolithiasis [11]. One-fifth of IBD patients are affected with more than one EIM at a time, as shown by a study conducted in 2015 [16]. Researchers in Hungary have found that EIMs are more common in CD than in UC patients, excluding ocular manifestations and Primary Sclerosing Cholangitis (PSC). Gender differences and EIMs that vary according to the phenotype of the disease have also been found [17]. Most of these manifestations appear after IBD has been diagnosed; however, they have been shown in one study to appear before IBD diagnosis in 25.8% of cases [18].

Studies conducted in Saudi Arabia have found that the most common EIMs found in UC patients are osteopenia, followed by EN, and then arthritis, with a prevalence of 30.5%, 23.8%, and 17.5%, respectively [19]. However, only 5% of CD patients have dermatological manifestations, 15.5% have arthritis or arthralgia, and 2.3% have deep vein thrombosis (DVT) [20]. A study in Riyadh showed that 32% of pediatric IBD patients have EIMs, most of them have indeterminate colitis [21].

Despite many studies that have investigated the prevalence of EIMs in IBD populations across the world, both cohort and cross-sectional, few have been conducted in the Middle East. Therefore, we aim to investigate the incidence of EIMs and examine possible relationships between EIMs and key demographic and clinical factors in IBD patients living in the Middle East.

2. PATIENTS AND METHODS

We conducted a retrospective study involving all patients diagnosed with IBD between 2013 and 2018 using the International Classification of Diseases coding 10th Revision (ICD-10). We used the IBD Information System (IBDIS) database at King Abdulaziz University to identify patients with IBD. Patients with confirmed IBD according to conventional clinical, radiographic, endoscopic, and histological criteria were included, irrespective of age. Demographic, clinical, and endoscopic findings were ascertained directly from the IBDIS. Clinical, radiological, and laboratory findings were reviewed to confirm the presence or absence of EIMs.

3. RESULTS

4. DISCUSSION

The primary objective of this study was to estimate the incidence of EIMs in a Middle Eastern cohort of patients with IBD. Two hundred and eighty-four IBD patients’ records were identified and reviewed using a database designed to follow up their clinical progress over 5 years. The EIMs investigated in our study included: EN; PG; aphthous ulcers; arthritis; PSC; scleritis and episcleritis; and VTEs. EIMs were encountered in almost half of the patients included in this population (48.6%). This is considered a high percentage of EIMs compared with results from three large prospective cohort studies conducted in the USA, Switzerland, and India [10,22,23], which reported incidence rates ranging between 36% and 38%. The variation between incidence rates could be attributed to multiple factors such as differences in study design, inclusion and exclusion criteria, and geographical diversity. Other factors that may contribute to this variation include the differences between the diagnostic methods and definitions of EIMs between studies, and the completeness of patients’ data during their follow up. According to hypothesis testing, no difference in the overall EIM incidence was observed between UC and CD patients (48.5 vs. 49.2, p = 0.70), concordant with results of another cohort study in India [23]. However, multiple regression analysis showed a higher likelihood of developing EIMs in UC patients (OR = 0.50, p = 0.03).

The secondary objective of this study was to examine possible correlations between EIMs, and identify possible relationships between EIMs and other factors. There were indeed significant associations between IBD subtype and the occurrence of some EIMs. For example, arthritis and PSC were more common in UC patients, whereas PG was more common in CD patients. Nevertheless, arthritis was the most common EIM in this cohort, with a frequency of 33.3%, consistent with a number of other studies [17,22,24–26]. As it is a diagnosis based primarily on clinical assessment, we considered any reported form of arthritis in this population as an EIM and did not classify it into type 1 and type 2 since we considered this classification to show no clinical value [27]. The high incidence of arthritis can be explained by the difficulty in differentiating between arthropathy and arthralgia. In addition, it could be a consequence of selected IBD medications, relapses, or extent of disease activity [22], as well as the malabsorptive nature of the disease [28]. According to the literature, certain genetic mutations are shared between IBD and rheumatic diseases, which might also explain the overlap in symptoms [29,30]. However, unlike previous studies, our study reveals that arthritis is significantly more common in UC (p = 0.02) [25,31,32].

The second most common EIM found in our study population was aphthous ulcers, which are considered part of the mucocutaneous manifestations of IBD that also include PG and EN. Aphthous ulcers, which frequently occur during IBD relapses [2,4,14], are painful, round, pale-looking ulcers with a surrounding red halo [14,33]. Aphthous ulcers are diagnosed clinically and commonly occur with other diseases; they are sometimes labeled idiopathic [33], which might explain why it is the second most common EIM in our cohort with a frequency of 15.9%. PG, which is considered the most severe skin manifestation of IBD, is an immune-mediated skin manifestation that arises more often in the lower extremities [14]. Similar to other studies, the overall incidence of PG in our center was not high (7.95%) [34,35]. However, our report showed a significant association between PG and CD (p = 0.002), unlike previous studies that conversely linked PG with UC.

Finally, PSC, a chronic and progressive immuno-inflammatory disorder of the bile ducts [14], accounted for 6.8% of EIMs in our study and was significantly associated with UC (p = 0.001). PSC is generally difficult to diagnose owing to its vague clinical picture: patients are either asymptomatic or complain of nonspecific symptoms, and lab findings are inconclusive. Moreover, a definitive diagnosis can only be made by endoscopic retrograde cholangio pancreatography (ERCP) or magnetic resonance cholangio pancreatography (MRCP), which might explain its low incidence. PSC has been associated with a significant increase in the cumulative risk of colorectal cancer among UC patients [36]; thus, underscoring the importance of drawing attention to its diagnosis during the follow up of UC patients.

When evaluating the correlation of EIMs with each other, there was a significant association between arthritis and skin manifestations, namely EN (p = 0.008) and aphthous ulcers (p = 0.03), arthritis and PSC (p = 0.001), and arthritis and VTE (p = 0.01). EN was also significantly associated with VTE (p = 0.04) and aphthous ulcers (p = 0.03). Furthermore, ocular manifestations were significantly associated with EN (p = 0.001) and PG (p = 0.001). Multiple studies have presented similar data to ours, finding a significant association between arthritis and skin manifestations, and the recurrence of aphthous ulcers in patients with other EIMs [31]. A 25-year follow-up study showed that ocular manifestations are more likely to be encountered with other EIMs [17], as did a Swiss cohort study, which reported associations between EIMs [22]. The most reasonable conclusion of the synchronicity of multiple EIMs is that all EIMs in this analysis are part of the overall inflammatory and immune-mediated process of IBD; some mimic each other in terms of pathogenesis and others have a similar inherited genetic component [30]. Thus, they tend to occur more during the active phase of IBD [17] and in conjunction with other EIMs. However, the multiplicity of factors in this investigation suggests that a clear cause may not be determined. The relevance of this reasoning is that although IBD is a disease of the gastrointestinal tract, other systems could be involved, and as multiple EIMs tend to coexist, the existence of one EIM can legitimately raise the suspicion of the presence of another. Thus, gastroenterologists should pay more attention to this by regularly assessing IBD patients with the engagement of other specialties to mitigate the overall risk of morbidity and mortality.

An important finding is that the only significant predictors of overall EIM incidence are IBD subtype and age at diagnosis. Multiple regression analysis demonstrated a higher probability of developing EIMs in UC patients (OR = 0.50, p = 0.03) and an increased EIM incidence with increased age at diagnosis of IBD (OR = 1.04, p = 0.001). However, this is discordant with some other studies, such as one conducted in Hungary that showed higher frequencies of EIMS in UC patients and a gender predisposition favoring females [17]. Disease subtype was also a significant predictor in the occurrence of two EIMs considered individually: PSC is more common in UC patients and PG more common in CD patients. Broadly, the existing literature reports similar data for the association between UC and PSC, but not for PG and CD.

In the present study, arthritis, EN, ocular manifestations, and VTE were all affected by age at diagnosis. Gender and disease duration were associated with the incidence of ocular manifestations and VTE, respectively. When following up IBD patients, predictors can be used as clinical tools that help to judge the likelihood of EIMs in different individuals with respect to the variation of disease characteristics between them. However, it remains a vague area in the literature and requires further research.

The limitations of this study supervene on the retrospective nature of data collection, which resulted in our data suffering from missing clinical information. Not all EIMs were accurately diagnosed as we relied on the clinical diagnosis mentioned in patients’ files rather than diagnostic tests, which are needed to confirm certain EIMs, such as radiological investigations for PSC. The incidences of other EIMs, for example, osteopenia, nephrolithiasis, and uveitis, were not included. This also raises the concern of other confounding factors, which may have been not accounted for in analysis but which may have affected EIM occurrence, including comorbid diseases. Although the IBDIS registry includes only data from one center, it is continuously updated. This enabled us to have a thorough long-term follow up of patients. Another strength of the study is that we performed a multiple regression analysis to estimate EIM predictors, which enabled drawing more reliable associations.

5. CONCLUSION

Our results demonstrate that more than half of IBD patients have at least one EIM. Contrary to what has been reported generally, EIMs occur more commonly in UC compared with CD. IBD is an emerging health burden in our geographical area, thus an increased awareness of the possible implications of IBD in the form of EIMs has become a necessity in the Middle East to guide patients in seeking appropriate medical care. Also, this study has shown that the management of EIMs by other specialties should be done in close collaboration with gastroenterologists to effectively adjust the therapeutic regimens and to improve the morbidity and mortality of IBD patients.

CONFLICTS OF INTEREST

The authors declare they have no conflicts of interest.

AUTHORS’ CONTRIBUTION

MM contributed in guarantor of the article. MM, MA, HA, and OS contributed in development of study concept and design. MM, MA, HA and OS contributed in acquisition, analysis, and interpretation of the data. MM contributed in statistical analysis. MM, MA, HA and OS contributed in drafting of the manuscript. MM, MA, HA and OS contributed in critical revision of the manuscript for important intellectual content.

FUNDING

This research project is eligible for the Saudi IBD master class grant once published.

ACKNOWLEDGMENTS

We would like to thank Dr. Trevor Rawbone, Cardiff, UK, for kindly reviewing and editing the manuscript.

ABBREVIATIONS

ETHICAL APPROVAL AND CONSENT TO PARTICIPATE

Ethical approval was obtained from King Abdulaziz University research ethics board.