Clinical Phenotype and Disease Course of Inflammatory Bowel Disease: A Comparison Between Sporadic and Familial Cases

Abstract

Background

The role of genetic and environmental factors in inflammatory bowel disease’s (IBD) clinical course is not fully clear. We aimed to assess the clinical phenotype, disease course, and prognosis of familial IBD in comparison with sporadic cases.

Methods

We conducted a prospective national matched case-control study of registered IBD patients in the Iranian Registry of Crohn’s and Colitis (IRCC) recruited from 2017 until 2020. Sporadic and familial IBD patients were matched based on age, sex, and disease duration. Data on demographics, past medical disease, family history of IBD, disease type, clinical phenotype, extraintestinal manifestations, IBD medications, IBD activity using the IBD-control-8 questionnaire and the Manitoba IBD index, emergency visits in the past 12 months, admissions in the past 3 months, history of colon cancer, IBD-related surgeries, and aggressive phenotype were gathered. Variable distributions were compared between sporadic and familial cases.

Results

Overall, 5231 patients with ulcerative colitis (UC, 18.3% familial) and 1438 patients with Crohn’s disease (CD, 16.7% familial) were registered in the IRCC. Age at diagnosis was similar between familial and sporadic cases. After matching, 3523 UC patients and 908 CD patients were enrolled in the study. Extraintestinal manifestations, UC extent, CD location and behavior, anti-TNF use, disease activity, colon cancer, IBD-related surgeries and the aggressive phenotype were similar between these sporadic and familial cases.

Conclusions

The prevalence of familial UC and CD cases in Iran was more similar to western countries, and family history did not show a predictive value for disease phenotype, course, and outcomes in our study.

Introduction

Inflammatory bowel disease (IBD) is a general term used to describe the chronic inflammation in the gastrointestinal tract and comprises 2 distinct entities, Crohn’s disease (CD) and ulcerative colitis (UC).¹ Inflammatory bowel disease prevalence has increased gradually from 1990 until 2017 in the world.^1-6 Furthermore, IBD has a significant impact on the patients’ lives; the age-standardized rate of disability-adjusted life-years is estimated at 23.2 per 100 000 population.¹

Some studies have shown positive family history to increase the incidence of IBD in first-degree relatives by 10 to 15 times.^7,8 A positive family history in patients with IBD ranges between 1.8% in North Korea and 5% to 39% in western countries.^9-11 Although previous research has suggested a possible role of genetic and environmental factors in IBD’s pathogenesis and clinical course, mechanisms of effect of such factors in familial cases are not fully clear.^12,13 A recent study has found several hereditary IBD-associated deleterious gene variants and identified IBD-specific gut microbiota in familial IBD cases.¹⁴ On the other hand, positive family history of IBD cannot only be attributed to genetics, as the family members usually experience the same environmental factors which could play their part by altering gene expression.^12,15

There is controversial evidence regarding IBD characteristics among familial and sporadic cases. Although some studies have reported differences in clinical phenotype and disease course,^16,17 others have shown similar disease characteristics between these groups.^18-20 Current literature on the difference between these subtypes is limited due to lack of multicenter studies, small sample size, and incomplete data availability. Better understanding of the effect of familial IBD on the clinical phenotype and disease course might be helpful for prognostic purposes and could facilitate clinical decision-making. To address this issue, we designed a national prospective study aiming to compare (1) the clinical phenotype, (2) disease course, and (3) prognosis of familial IBD in comparison with sporadic cases.

Materials and Method

Study Design and Participants

In this matched case-control study, all IBD patients registered in the Iranian Registry of Crohn’s and Colitis (IRCC), a nationwide registry with the collaboration of more than 400 gastroenterologists from 31 provinces of Iran,²¹ were included from December 2017 until December 2020. The diagnosis of IBD (UC and CD) was made using clinical, imaging, colonoscopic, and pathologic features according to the 2015 World Gastroenterology guidelines.²² Gastroenterologists completed a questionnaire based on clinical records about IBD disease type, age at diagnosis, months of follow-up, extraintestinal manifestations (including sclerosing cholangitis [PSC], ankylosing spondylitis [AS], autoimmune hepatitis [AIH], erythema nodosum, uveitis, pyoderma gangrenosum [PG], and peripheral arthritis), UC extent based on the Montreal classification (classified as proctitis, left-sided colitis, and pancolitis),²³ CD location (classified as ileal, colonic, ileocolonic, and upper GI), CD behavior (classified as fistulizing vs stricture forming), history of colon cancer, and IBD-related surgeries.²¹

Thereafter, a research assistant conducted a telephone interview gathering additional information about demographics, comorbidities, family history of IBD including the number of affected relatives and degree of kinship, the disease activity during the past 2 weeks using the IBD-control-8 questionnaire (a score of more than 13 indicating inactive disease),²⁴ the disease activity during the past 6 months using the Manitoba IBD Index (a score of more than 4 indicating inactive disease),²⁵ health care use (admissions in the past 3 months, emergency room [ER] visits in the past 12 months), IBD medications (eg, 5-aminosalicylic acid [5-ASA], antitumor necrosis factor (anti-TNF), immunomodulators, including azathioprine/methotrexate/mercaptopurine, and prednisolone).^21,26

Positive family history of IBD was defined as having at least 1 first-degree (parents, siblings, or children) or second-degree (grandparents, aunts, or uncles) relative with proven IBD. The prevalence of positive family history was determined, and comparison of age at diagnosis was performed in the IRCC database. Then, all the patients with familial IBD were enrolled in the study, and sporadic cases were matched to the familial cases based on age, sex, and disease duration at the ratio of 3:1.

The following outcomes were compared between the familial and sporadic cases after the matching process: Ulcerative colitis extent, CD location, and CD behavior were used to categorize clinical phenotype. Disease course and outcomes were delineated by extraintestinal manifestations, IBD medications, active disease during the past 2 weeks, active disease during the past 6 months, ER visits in the past 12 months, number of admissions in the past 3 months, history of colon cancer, and IBD-related surgeries. Aggressive phenotype was defined as either active disease in the past 6 months, any admissions in the past 3 months, any ER visits in the past 12 months, anti-TNF usage, or any history of IBD-related surgeries.

Statistical Analysis

We performed all statistical analyses using the Stata 11.2 edition (Stata Corp. 2011, Stata Statistical Software, Release 12, College Station, TX, StataCorp LP) for Windows. Continuous variables are described as mean (SD) and categorical variables are expressed as percentage. Kolmogorov-Smirnov test was used to assess the normalcy of variable distributions. Independent sample t test was used for comparing means. Pearson χ ² and Fisher exact test (if needed) were used for comparing categorical variables. A P value <.05 was considered significant in all instances.

Ethical Considerations

The ethics committee of Tehran University of Medical Sciences approved this study (IR.TUMS.MEDICINE.REC.1399.452), and informed consent was obtained from the study participants.

Results

At the time of this study, 6669 IBD patients were registered in the IRCC, with 5231 UC and 1438 CD patients. Positive family history was observed in 18.3% (955 of 5231) of UC patients, 617 of whom had a first-degree relative with IBD. Patients with CD had 16.7% (240 of 1438) positive family history, 154 being first-degree relatives. Table 1 shows the gender and age-based prevalence of positive family history of IBD in the IRCC database.

The mean age at diagnosis was 40.1 (SD, 13.4) and 40.7 (SD, 13.1) years old for sporadic (N = 4272) and familial (N = 959) UC patients, respectively (P = .195). Sporadic CD patients’ (N = 1998) mean age at diagnosis was 39.1 (SD, 13.7) years old, and the mean age at diagnosis was 38.8 (SD, 13.2) in familial cases (N = 240; P = .808).

After the matching process, 3523 (out of 5231) patients with UC and 908 (out of 1438) patients with CD were enrolled. The results of the investigation on this population is provided herein.

Sporadic and Familial UC

Table 2 summarizes demographic features and disease characteristics of the 3523 UC patients enrolled in the study after the matching process of 5231 UC patients. These patients had a mean age of 41.4 years (SD, 13.1), and 1850 (52.4%) were male. Of the 883 patients with a family history of IBD, 102 (11.5%) had more than 1 affected family member.

The association between clinical phenotype, disease course, and outcome in patients with UC and positive family history is presented in Table 3. Extraintestinal manifestations and extent of UC were not different between sporadic and familial cases (P = .688 and .427, respectively), with pancolitis as the most common type of disease. There was no significant difference between sporadic and familial cases with respect to disease activity in the past 2 weeks or past 6 months, admissions in the past 3 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype. Emergency room visits in the past 12 months were needed by 19.5% (172 out of 883) of the familial UC patients in comparison with 15.8% (418 out of 2649) of sporadic cases (P = .011). Among medications, prednisolone use was more prevalent in familial cases (P < .001), whereas anti-TNF usage was not different between the sporadic and familial cases. The consideration of only first-degree relatives as positive family history and grouping patients based on the number of affected family members did not affect these results.

Sporadic and Familial CD

Table 4 demonstrates demographic features and disease characteristics of the 908 CD patients enrolled in the study after the matching process of 1438 CD patients. The mean age of these patients was 40.3 years (SD, 13.1), and 528 (58.2%) were male. Eighteen out of 227 (7.9%) CD patients with a family history of IBD had more than 1 affected family member.

The association between clinical phenotype, disease course, and outcomes in patients with CD and positive family history is shown in Table 5. Extraintestinal manifestations, disease location, and behavior of CD were not significantly different between sporadic and familial cases. Admissions in the past 3 months were significantly different among familial and sporadic CD cases, with 14.1% (32 out of 227) and 9.4% (64 out of 681), respectively (P = .046). Disease activity in either the past 2 weeks or 6 months, ER visit in the past 12 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype were not significantly different between sporadic and familial cases. Medication consumption including prednisolone, 5-ASA, immunomodulator, and anti-TNF use were similar between the 2 groups. Grouping patients based on the number of affected family members and defining positive family history as only first-degree relatives did not affect these results.

Disease Type Concordance Among Familial CD and UC

Among the familial IBD patients who knew their family member’s disease type, 88.4 % (214 out of 242) of UC patients had a family member with UC, and 11.6% (28 out of 242) had a family member with CD. On the other hand, 44.2% (23 out of 52) of CD patients had a family member with CD, and 55.8% (29 out of 52) had a family member with UC.

Discussion

This matched case-control study describes the clinical phenotype, course, and outcome in patients with UC and CD based on positive IBD family. Age at diagnosis, extraintestinal manifestations, UC extent, CD location and behavior, anti-TNF use, disease activity in either past 2 weeks or 6 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype were similar between sporadic and familial cases.

Sporadic and Familial UC

The prevalence of familial UC varied in different regions. Chung et al reported a prevalence of 2.4% in North Korea,²⁷ whereas only 4.3% of UC patients were reported familial in India.¹⁶ Reports from Europe showed a prevalence ranging from 6.6% to 13.8%, ^20,28 and this same prevalence was 32% in the United States.¹⁷ Moreover, A meta-analysis consisting of 86 824 UC patients reported a 12% prevalence of positive family history (range, 0% to 39%).²⁹ In our study, 18.3% of UC patients had a positive family history, including a 11.8% first-degree involvement; this result is closer to western countries. This variation could be attributed to the difference in the definition of positive family history and the genetic and environmental variations among geographic areas. Our study showed that there are more men than women with IBD in the IRCC; this finding is similar to other reports of higher IBD prevalence among men in eastern counteries.

Other studies show that in western countries, IBD is either more common among women or is similar between men and women.³⁰

Understanding the association between family history of IBD and age at diagnosis is important for managing patients properly—in case positive family history is associated with younger onset of disease, informing potential patients could lead to better disease management.³¹ We found no significant difference between the mean age at diagnosis among sporadic and familial UC cases. This was similar to previous findings.^20,27,32 However, a number of studies have found that familial UC cases were diagnosed earlier.^16,17,33 The clinical value of the reported difference in diagnosis age of familial and sporadic cases is not clear. These studies report diagnosis in familial UC cases 2 to 5 years earlier, and the findings were statistically significant—but this could be attributed to increased medical vigilance by patients with a family history of IBD.^17,33

Prognostic factors for disease course are critical for appropriate patient management. In our study, extraintestinal manifestations, UC extent, anti-TNF use, disease activity in either the past 2 weeks or 6 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype were similar between sporadic and familial UC cases. This is similar to the results of the meta-analysis by Childers et al, which showed no differences in need for surgeries, disease behavior, disease activity, disease extent, or extraintestinal manifestations.²⁹ Other studies have also supported the similarity between colectomy rate, immune-suppressors usage, oral medical treatment, hospitalization, and clinical phenotypes between sporadic and familial UC cases.^{27,28,32,34-37} This finding is reassuring for patients with family history of IBD. However, Banerjee et al reported 1.9 times higher pancolitis rate and a higher biological drug usage rate among familial UC.¹⁶ This variation could be attributed to the genetic and environmental diversity among different geographic areas.

In this study, patients with familial UC had a higher risk of emergency room visits in the past 12 months; because there were no differences between the disease-related outcomes, we hypothesized that this difference could be due to the difference in patients’ sensitivity and concerns regarding their symptoms. Also, we hypothesized that the significantly more prevalent use of prednisolone in the familial UC cases could be a random finding in as much as the disease-related outcomes were similar between sporadic and familial cases. Further studies are needed for clarification.

Sporadic and Familial CD

The prevalence of familial CD ranges from a low rate of 1.5% to 2.5% in Korea ^9,27 to a high of 39.3% in the United States,¹¹ and Europe stands somewhere in between.^20,28 Our data were closer to western countries, with a prevalence of 16.7% for familial CD, including a 10.7% first-degree involvement.

We did not find an association between family history and age at diagnosis among patients with CD. Previous studies support the notion of similar age at diagnosis among familial and sporadic cases.^10,20,27 However, Henriksen et al reported a significantly younger age at diagnosis among CD patients with positive family history of IBD only in patients with colonic involvement.³² Other studies that have reported a younger age at diagnosis in familial cases also had lower percentage of only small bowel involvement in comparison with our study.^16,32,38-40 This finding suggests a possible genetic difference between these groups, which needs further elaboration in future studies.

In our study, there was no difference between sporadic and familial CD cases in regards to extraintestinal manifestations, CD location and behavior, anti-TNF use, disease activity in either the past 2 weeks or 6 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype. Similarity of extraintestinal manifestations between the groups in our study is similar to the findings of Chung et al.²⁷ However, in some studies, positive IBD family history was associated with 1.8–5.6 times higher extraintestinal manifestations among patients with CD.^37,41 The literature about the relationship between family history and involved organs in CD is controversial. Although some studies reported higher ileal involvement compared with colonic involvement in familial CD cases, others found no difference regarding disease localization.^20,32,38 Some studies reported fistulizing, stricturing, penetrating disease, perianal complications, and disease-related surgeries to be more prevalent in familial CD cases^16,17,33,39; however, others found no difference between these groups.^{20,28,32,36,42} Moreover, there is evidence of higher anti-TNF and biologic use among familial CD patients.^16,27,33 Studies have shown that CD localization is an intrinsic aspect, in part genetically determined (eg, ileal localization is more frequent among NOD2 allele carriers).^39,43 These genes also have numerous variations.^44,45 These findings highlight the important role of genotype in disease course of CD patients, and there is a need to compare the population of CD patients with the use of genetic data.

We found a significant difference between admissions in the past 3 months in sporadic and familial CD cases. However, we hypothesized that this difference could be due to the difference in familial patients’ attitude toward their symptoms. Future studies are needed to explore this hypothesis.

Disease Type Concordance Among Familial CD and UC

The UC patients had an 88.4% rate of disease type concordance in comparison with 44.2% in CD patients. This finding is similar to previous studies that have reported a disease type concordance from 37% to 82%.^16,35,38 However, this finding should be interpreted cautiously due to the limited access to the family members’ disease type in this study.

This study has several major strengths. This prospective study was the largest in the middle east to address family history’s role in IBD phenotype. Also, we matched some of the main confounders, including the participant’s age, sex, and disease follow-up duration. This was a national study with participants from all of the provinces of Iran. Additionally, we used valid questionnaires, and variables were defined based on the international standardized guidelines.

Our study faced several limitations. Although we covered all the provinces, the centers that participated in the study were mostly referral centers of each province, leading to selection bias. Also, different provinces did not participate equally in the IRCC. Moreover, we did not access all the family members’ clinical records and relied on patients’ declarations. Additionally, the research assistant asked retrospective questions, which could lead to recall bias. Moreover, medication use was determined by the history of medication use, and length and dose of medications were not investigated in this study.

Conclusions

The prevalence of familial UC and CD cases in Iran were closer to western countries, and no difference was observed between age at diagnosis, extraintestinal manifestations, UC extent, CD location and behavior, anti-TNF use, disease activity in either the past 2 weeks or 6 months, history of colon cancer, IBD-related surgeries, and the aggressive phenotype in sporadic and familial patients with IBD. Although family history did not show a predictive value for disease phenotype and course in our study, there is a need for more extensive studies with longer follow-up durations. In addition, genetic investigation in different geographical areas and ethnicities is needed due to the inconsistent and inconclusive results in the literature.

Acknowledgments

All authors contributed solely as volunteers. Authors are grateful for the employees of the IRCC cohort for their contribution to data gathering. IRCC members that contributed to this study: Dr. Mohamadreza Seyedmajidi, Dr. Mohamadreza Ghadir, Dr. Ahmad Hormati, Dr. Manouchehr Khosbaten, Dr. Mehdi Pezeshki Modares, Dr. Mohamad Javad Zahedi, Dr. Mohammad Valizade Toosi, Dr. Amir Abbas Hassan Zadeh, Dr. Seyed Vahid Hoseini, Dr. Abdolsamad Gharavi, Dr. Nadie Baniasadi, Dr. Abdolrasoul Hayatbakhsh, Dr. Khalil Ahmadi, Dr. Arash Kazemi Visari, Dr. Javad Pournaghi, Dr. Reza Rezazadeh, Dr. Jalal Naghshbandi, Dr. Mohsen Bahrami, Dr. Ladan Goshayeshi, Dr. Abazar Parsi, Dr. Pejman Khosravi, Dr. Mitra Ahadi, Dr. Masoud Dooghaee Moghadam, Dr. Tarang Taghavi, Dr. Asghar Khoshnood, Dr. Roya Hosseini Hemat Abadi, Dr. Frough Alborzi, Dr. Katrin Behzad, Dr. Hosein Alimadadi, Dr. Bijan Ahmadi, Dr. Elham Mokhtari Amirmajdi, Dr. Sadif Darvishmoghadam, Dr. Afshin Shafaghi, Dr. Hayedeh Adilipoor, Dr. Ali Beheshti Namdar, Dr. Ali Ghavidel, Dr. Seyed Mohamadhasan Mortazavi Shahroudi, Dr. Mehdi Saberfirouzi, Dr. Maryam Hojati, and Dr. Sahar Rismantab.

Author Contribution

B.S., A.R.S. contributed to the conceptualization, data acquisition, analysis of data, writing, review and editing. A.K. contributed to conceptualization, analysis of data, review and editing. A.A., F.M., H.F., H.V., F.S., A.Y., S.H.M., H.V., I.M., S.N., B.K., M.M., S.A., A.S., S.K., M.R., R.M. contributed to conceptualization, data acquisition, review and editing.

Funding

This work was supported by Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Conflicts of Interest

Authors declare no conflict of interest.

References