This study was designed to determine the role of a positive family history in pediatric IBD in the era of biologic therapy. Taken as a whole, 25.2% of the children in our cohort had a positive family history of IBD, with a higher prevalence of a positive family history among the patients that were diagnosed during 2016–2020 compared to the prevalence between 2010–2015 (p = 0.024). While a positive family history of IBD had a mild impact on IBD phenotype, there was no significant impact on IBD outcome in the first years after diagnosis.
The frequency of a positive family history of IBD that was observed in our cohort, irrespective of IBD type was higher compared to the values published in older studies. This rate, however, was equivalent to other contemporary studies in western countries  that observed a high rate of familial clustering. The rate may be even higher in the Jewish population, that comprises the vast majority of our cohort . In 2018, Schiff et al.  reported a 40% rate of familial cases of IBD in the Ashkenazi Jewish population in the UK. That high rate may reflect a greater genetic burden for IBD among that population compared to others. Furthermore, 28% of the patients with a positive family history in our cohort had more than one family member with IBD, and 8.5% had three family members or more. The high incidence of a family history of IBD in western countries compared to Asian countries [11, 14] might imply an environmental component in the pathogenesis of IBD.
The type of IBD was concordant with the family member’s type in 70.7% of our population, and the concordance was significantly increased in CD compared to UC. Borren et al.  have also reported a similar rate of concordance for type of IBD. In their meta-analysis , Childers et al. reported a 9% prevalence of a family history of UC among UC patients, while the prevalence of a family history of CD among their UC patients was only 2%. Roma et al.  reported a concordance between the family member and the pediatric patient of 100% for UC and 58.3% for CD .
Several studies have suggested that a family history of IBD may be related to an IBD phenotype. In our cohort, children with CD who had a family history of IBD had a higher probability for a stricturing compared to an inflammatory phenotype (p = 0.052). In addition, there was a trend towards more frequent ileo-cecal involvement compared to colonic disease in children who had a positive family history of IBD (p = 0.085). Similarly to our results, Borren et al.  also observed an increased risk for complicated (stricturing or penetrating) CD in the presence of an affected first-degree family member, as did Andreu et al.  who reported a higher percentage of ileocolic location, penetrating behavior, and perianal disease in familial CD. Interestingly, another Israeli study by Ben-Horin et al.  observed no difference between sporadic and familial CD patients in terms of disease location, phenotype, complications, and medications. Other studies have also showed contrasting results [13, 14, 17, 25].
The children with a positive family history of IBD in our cohort, and specifically those with UC, were treated more frequently with nutritional therapy and less with corticosteroids. Nutritional therapy is a cornerstone of induction therapy for pediatric CD but not for UC. Nevertheless, the knowledge and experience of the families with its use may explain the more frequent utilization of nutritional therapy in familial cases. Roma et al. reported no difference in familial IBD with regard to other therapies, such as 5-ASA, immunomodulators, and biologic agents, as had been shown in other studies . Contrary to our study, Hwang et al.  reported that anti-tumor necrosis factor alpha agents were more frequently used in familial cases of CD. Although familial cases have been associated with a younger age at diagnosis in many studies [11–13], no difference between age or duration to diagnosis was found in our current study or in others .
While the effect of family history on the IBD phenotype has been investigated in depth with conflicting results, that effect on IBD outcome is even more controversial. We found no correlation between the presence of family history of IBD and the major IBD outcomes, such as risk to biologic therapy, IBD exacerbation, IBD-related hospitalization, or surgery, in the first years after diagnosis of IBD. Nevertheless, we observed that intensification of biologic therapy was significantly less frequent in patients with a family history of IBD. This is opposed by several studies that reported an adverse effect of family history on IBD. Kuwahara et al.  reported a greater disease severity in familial cases. A high relapse rate in familial UC cases was also observed by Henriksen et al. , and a number of studies reported a higher risk for surgery in familial cases [14, 16, 26, 27]. However, our current results are in line with other studies that reported no relation between a family history of IBD and the risk of surgery [13, 17] or a more severe disease course (28). Importantly, the more severe phenotype that was observed in some of these studies does not necessarily imply a true more aggressive disease course, but may rather reflect a greater concern among patients, families, and physicians, that may be more likely to lead to the adoption of a more aggressive approach earlier in the disease course .
Our study is based upon a large database that contained extensive data on clinical disease characteristics, including phenotype, severity, therapy, and course. All of the patients in the study cohort had complete data at diagnosis and follow-up. To the best of our knowledge, this is the first study to describe the relation between a family history of IBD to disease outcome in the era of biologic therapy in a pediatric population. Furthermore, while most of the earlier studies had focused on first-degree relatives, we included patients with second- and third-degree relatives as well.
The study has several limitations that bear mention. Its retrospective design precludes any assessment of causality in the observed interaction between family history and IBD phenotype and outcomes. The chosen outcomes were clinical and did not include endoscopic assessment of mucosal healing due to a large diversity in the endoscopic follow-up descriptions. Finally, this is a single-center study. Importantly, while the presence of a family history of IBD supports but does not necessitate a certain genetic etiology, family members are likely to share environmental factors as well. The familial effect may also be mediated through differences in the microbiome . Nevertheless, the recognition of a positive family history as a risk factor and as potential predictor of IBD phenotype and disease course is an important component of the care of the patients and their families, including improving risk stratification and prediction of disease-related complications.
To conclude, the prevalence of a positive family history of IBD is increasing. While familial cases have a more frequent stricturing phenotype, a positive family history has no significant impact on pediatric IBD outcome. Further studies that focus on the role of family history in the interrelationship between genetic and environmental factors in the pathogenesis of IBD and as a potential predictor of IBD prognosis are warranted.