AIM: To demographically and clinically characterize inflammatory bowel disease (IBD) from the local registry and update data previously published by our group.

METHODS: A descriptive study of a cohort based on a registry of patients aged 15 years or older who were diagnosed with IBD and attended the IBD program at Clínica Las Condes in Santiago, Chile. The registry was created in April 2012 and includes patients registered up to October 2015. The information was anonymously downloaded in a monthly report, and the information on patients with more than one visit was updated. The registry includes demographic, clinical and disease characteristics, including the Montreal Classification, medical treatment, surgeries and hospitalizations for crisis. Data regarding infection with Clostridium difficile (C. difficile) were incorporated in the registry in 2014. Data for patients who received consultations as second opinions and continued treatment at this institution were also analyzed.

RESULTS: The study included 716 patients with IBD: 508 patients (71%) were diagnosed with ulcerative colitis (UC), 196 patients (27%) were diagnosed with Crohn’s disease (CD) and 12 patients (2%) were diagnosed with unclassifiable IBD. The UC/CD ratio was 2.6/1. The median age was 36 years (range 16-88), and 58% of the patients were female, with a median age at diagnosis of 29 years (range 5-76). In the past 15 years, a sustained increase in the number of patients diagnosed with IBD was observed, where 87% of the patients were diagnosed between the years 2001 and 2015. In the cohort examined in the present study, extensive colitis (50%) and colonic involvement (44%) predominated in the patients with UC and CD, respectively. In CD patients, non-stricturing/non-penetrating behavior was more frequent (80%), and perianal disease was observed in 28% of the patients. There were significant differences in treatment between UC and CD, with a higher use of corticosteroids, and immunosuppressive and biological therapies was observed in the patients with CD (P < 0.05 and P < 0.01). Significant surgical differences were also observed: 5% of the UC patients underwent surgery, whereas 38% of the CD patients required at least one surgery (P < 0.01). The patients with CD were hospitalized more often during their disease course than the patients with UC (55% and 35% of the patients, respectively; P < 0.01). C. difficile infection was acquired by 5% of the patients in each group at some point during the disease course. Nearly half of the patients consulted at the institution for a second opinion, and 32% of these individuals continued treatment at the institution.

CONCLUSION: IBD has continued to increase in the study cohort, slowly approaching the level reported in developed countries.

Inflammatory bowel disease (IBD) includes a spectrum of typically progressive chronic diseases, including Crohn’s disease (CD), ulcerative colitis (UC) and unclassified colitis. Unclassified colitis occurs in patients who have clinical and endoscopic evidence of chronic IBD affecting the colon without small bowel involvement and no definitive histological or other evidence suggesting either CD or UC[1]. Although IBD mortality is low, the onset of this disease during early adulthood and its chronicity as a lifelong disease result in a significant decline in the quality of life of the patients and a heavy burden on the healthcare system due to high treatment costs[2]. Natural history studies have helped identify subsets of patients whose disease prognosis can be stratified according to clinical features. These data might improve the management of patients with IBD by defining changes in disease phenotype and risks of relapse, hospitalization and surgery[3].

Several studies have reported that the incidence of IBD has markedly increased over the latter part of the 20th century, whereas other studies have suggested a plateau or even a decline in IBD incidence in certain geographical areas[4,5]. However, an increase in these diseases has been described in countries where their frequency was very low[6-9]. IBD has been associated with the industrialization of nations[10,11], and thus, the increasing incidence of these diseases in developing countries might reflect this phenomenon. However, other factors, such as increased physician awareness, advancements in diagnostic methods and better access to medical services, such as colonoscopies, should be considered[12]. Although few epidemiological studies have been conducted in developing Latin American countries, these analyses have also described an increased incidence of IBD[13-19]. As we previously published, the incidence and prevalence of IBD in Chile are unknown; however, consistently with two other studies, our data suggest increases in the numbers of local cases of CD and UC[16,18,20]. The objective of this study was to demographically and clinically characterize IBD from a local registry and thereby update previously published data.

This was a descriptive study of a cohort based on a registry of patients aged 15 years and older, diagnosed with IBD according to clinical, endoscopic, histological and radiologic findings and attending the IBD program at Clínica Las Condes in Santiago, Chile. The registry was created in April 2012 and includes patients who attended the program until October 2015. Retrospective data were obtained from those patients diagnosed prior to the indicated date. The registry is composed of online forms available in the electronic medical record of each patient that were completed by gastroenterologists and colorectal surgeons during clinic visits. On each subsequent visit, the information was prospectively updated as deemed necessary. The information was anonymously downloaded in a monthly report, and the information for patients with more than one total visit was updated. The registry includes demographic, clinical and disease characteristics, such as extension, location and behavior, changes in diagnosis from UC to CD, phenotype changes in CD, medical treatment, surgeries and hospitalizations for crisis. Data concerning Clostridium difficile (C. difficile) infection were incorporated into the registry in 2014. A polymerase-chain reaction assay for C. difficile detection was requested for patients presenting with moderate-to-severe activity. In CD, the Montreal Classification was used to define the phenotype as follows: B1, non-stricturing/non-penetrating; B2, stricturing; and B3, penetrating. A “p” was added to any of these classifications in case of perianal disease. The same classification was used to define the location of the disease: L1, ileum; L2, colon; L3, ileocolonic; and L4, concomitant upper gastrointestinal involvement. The extension of UC was defined according to the Montreal Classification: E1, ulcerative proctitis; E2, left-sided UC (distal UC); and E3, extensive UC (pancolitis)[1]. However, because Clínica Las Condes is a tertiary center that receives patients from locations throughout the country, the data for patients who received consultations as a second opinion and continued treatment at this institution were also analyzed. Patients with two or more visits over the next year were considered patients who were continuing treatment with the IBD program at this institution. This study was approved through the Institutional Ethics Committee.

The study included 716 patients with IBD: 508 patients (71%) were diagnosed with UC, 196 patients (27%) were diagnosed with CD, and 12 patients (2%) were diagnosed with unclassifiable IBD. The UC/CD ratio was 2.6/1. The median age was 36 years (range 16-88), and 58% of the patients were female, with a median age at diagnosis of 29 years (range 5-76). Most patients with UC and CD were diagnosed between the ages of 20 and 29 years (Figure 1), without differences in gender. However, 22 patients (3%) were diagnosed when over 60 years of age. In the past 15 years, a sustained increase in the number of patients diagnosed with IBD has been observed, and significant increases were obtained from the comparison of the periods 1971-1985, 1986-2000 and 2001-2015, with 87% of patients diagnosed in the last period. The frequency of patients with IBD distributed according to the year of diagnosis is shown in Figure 2, illustrating an increase in the diagnosis of new cases of UC and CD over time. The demographic and disease characteristics of patients are shown in Table 1. In both UC and CD patients, articular symptoms were the most frequent extraintestinal manifestations. Primary sclerosing cholangitis (PSC) was diagnosed in eight patients (2%) with UC and two patients (1%) with CD.

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Figure 1 Frequency of patients with ulcerative colitis and Crohn´s disease at age of diagnosis. UC: Ulcerative colitis; CD: Crohn´s disease.

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Figure 2 Frequency of patients with inflammatory bowel disease distributed by year of diagnosis. IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn´s disease.

The number of patients in the registry more than doubled compared with the number detailed in our previous publication[20]. This increase not only allowed us to better characterize these patients but also facilitated a comparison with studies conducted worldwide. This population increase reflects not only the recognition of this institute as a referral center but also the increased rate of IBD diagnoses in recent years.

The cohort UC/CD ratio in 2014 was 2.9/1, and the current ratio has increased 2.6/1, showing a slow approaching to the ratio reported in developed countries (1/1)[6,13,21,22]. However, genetic, environmental and geographic factors may influence this difference. A gender-based analysis showed that the percentages of UC and CD were slightly higher in women, which is consistent with the results obtained by other series[13,14,17]. The median age at diagnosis was 29 years, and 64% of patients were diagnosed between 20 and 39 years of age. No second peak was observed at an older age, which is consistent with the results from recent studies[6,7,23-25].

An active smoking habit was almost twice as frequent in patients with CD (16%) compared with patients with UC (9%), regardless of whether the patients with CD received counseling and were told of the particular deleterious effect of smoking. This finding demonstrates that smoking education is important and that smoking cessation should be emphasized on every visit. Nonetheless, the frequencies of patients with active smoking habits observed in the present study were low compared with the frequency of active smokers in the general population. The last National Health Survey has demonstrated that 40.6% of the adult population smokes regularly, indicating that cigarette smoking is an important health problem in Chile and that other factors, such as environmental factors, may be influencing the increase in the diagnosis of CD[26].

A family history was obtained for 12% and 10% of the patients diagnosed with UC and CD, respectively, similarly to the results reported by Moller et al[27], who published a much larger study. The analysis of the clinical characteristics revealed that the most frequent extra-intestinal manifestation was articular symptoms, with frequencies of 31% and 44% in UC and CD patients, respectively. In previous studies, musculoskeletal manifestations were described as the most common extra-intestinal manifestation, and UC patients are more affected than CD patients. However, the percentage of affected patients was lower than that observed in the present study (20%-30%)[28]. It has been suggested that the risk of developing peripheral arthritis increases with an increase in the extent of IBD activity[29,30], and 70% of patients diagnosed with CD who showed musculoskeletal manifestations had either colonic or ileocolonic involvement, whereas 55% of the patients diagnosed with UC who showed musculoskeletal manifestations had pancolitis. This observation reflects the recognition of this institution as a tertiary referral center that receives complex patients. In addition, the etiology of peripheral arthritis in IBD might reflect a combination of genetic predisposition and exposition to the luminal bacterial bowel contents[30].

The analysis of the extent of UC showed that half of the patients had extensive colitis, different from the frequency described in previous studies, which reported that distal location predominates[9] and that extensive colitis varies between 20 and 40%[7,9,19,22,24,31]. Even a previous study published in Chile, which involved two different institutions, reported 38% and 15% extensive colitis; notably, the frequency of 15% was previously reported at our institution 10 years ago[18], before this institution was recognized as a referral center and before its association with an IBD program. The higher percentage of extensive colitis observed in the population examined in the present study might reflect the fact that it was conducted at a tertiary referral center and included refractory cases that were difficult to treat.

Colonic involvement was more frequent in the CD patients examined in the present cohort, with a frequency of 44%. This finding is consistent with the results of a study conducted in Brazil, which found that colonic involvement predominates, although at a lower frequency (36%)[19]. Non-structuring/non-penetrating behavior was more frequently observed in the cohort examined in the present study, with a frequency of 80%. This value is consistent with the frequency described in previous studies, which showed that inflammatory phenotypes predominate during the first years of the disease[24]. During the disease course, approximately 10% of patients with non-stricturing/non-penetrating behavior exhibited a modification of this characteristic to a more aggressive behavior. However, other studies have reported that 31% to 60% of patients exhibit a disease progression to a more severe behavior[32-34]. Indeed, after 40 years, most patients experience complications and are classified as having a penetrating, or less often, a stricturing disease[16]. These differences might reflect the short follow-up period used in the present study. Additionally, it has been reported that colonic disease remains uncomplicated or inflammatory for many years[24], so predominant colonic involvement found in our study might play a role in this progression. Another factor potentially explaining this difference is that the patients at this institution were aggressively treated upon diagnosis with an “accelerated step-up approach”, involving the initiation of biological therapy a median of one year after diagnosis for patients diagnosed since 2010; thus, patients might have a lower probability to exhibit a change in behavior[35,36].

During the IBD course, 12 patients (2.3%) with an initial diagnosis of UC developed perianal fistulas or showed ileal involvement, changing their diagnosis to CD, as confirmed through histological and image analyses. Previous studies have described a 5%-10% change in diagnosis after 25 years of the disease course[37]. This finding might reflect the short follow-up period in the present study.

The analysis of IBD treatment revealed that mesalamine was the most used drug in UC treatment (98%), whereas corticosteroids, mesalamine and immunosuppressive agents were used at equal frequencies (67%-68%) in CD treatment. In the present study, despite the frequent use of mesalamine for patients with CD, the use of this agent in CD is controversial. Indeed, the European Crohn’s and Colitis Organization Consensus recently stated that oral aminosalicylates are not recommended for the treatment of mild to moderate CD[38]. However, both the American and British National Gastroenterology Associations recommend the use of high-dose 5-aminosalicylic acid as the first-line treatment of mild ileal, ileocolonic or colonic CD[38]. Because we had a high percentage of patients with colonic involvement, treatment with mesalamine could have had some implications because the action of mesalamine is predominantly topical at the site of inflammation, particularly within the colon[38]. However, many of these patients received mesalamine, regardless of the severity of the disease, prior to evaluation at this institution, possibly resulting from misinformation regarding the role of mesalamine in CD. On the other hand, according to the latest clinical guidelines, the use of immunosuppressive and biological therapies is significantly higher in CD patients compared with UC patients, as observed in the present study. In the series examined in the present study, the use of infliximab in UC treatment (7%) was similar to that reported in other countries[31,39,40]; however, the use of this drug in CD treatment (34%) was considerably higher than that detailed in Saudi Arabia, Israel and some European countries, which report frequencies between 2% and 10%[31,40]. Similarly, the use of immunomodulators was considerably higher in both groups compared with that observed in some European countries[31]. This discrepancy reflects the type of center where the present study was conducted, i.e., a tertiary center that treats patients with more complex diseases. Unfortunately, the use of adalimumab and certolizumab pegol was extremely low in the cohort examined in the present study, reflecting the low coverage of these therapies by insurance companies. In addition, vedolizumab is still not available for use in Chile.

The investigation of the use of surgery for IBD treatment revealed that 38% of the CD patients required surgery for either intestinal resection or perianal disease. The frequency of intestinal resection was significantly higher in CD patients (25%) compared with that of colectomy in UC patients (5%), a result consistent with the findings reported by Niewiadomski et al[41], who showed that the risk of intestinal resection in CD was 13% after one year and 26% after five years. However, the colectomy rates in UC obtained in this study were 2% and 13% after one and five years, respectively. Notably, the early use of immunomodulators and biological therapies during the disease course could reduce the risk of surgery[24,42], particularly for those patients who achieve mucosal healing[43].

Relatively few data are available regarding the hospitalization rates in population-based cohorts[44,45]. The CD patients in the cohort examined in the present study had significantly more hospitalizations than the UC patients; however, higher percentages of patients belonging to both groups in this cohort were affected compared with the frequencies obtained in previous studies[41,46]. Nevertheless, it has previously been reported that more than one-third of UC patients require hospitalization within one year after diagnosis in the biological era[44]. Among the UC patients examined in the present study, 35% required hospitalization at some point during the disease course. The disease extent at diagnosis and the need for steroids and anti-TNF therapy were associated with the risk of UC-related hospitalization[44]. For CD, a 52.7% cumulative risk of hospitalization within ten years of diagnosis has previously been described[45]. Among the CD patients in the present study, 55% required hospitalization at some point during the disease course.

The analysis of our data concerning IBD and C. difficile infection demonstrated that this bacterium was equally prevalent in patients with UC and patients with CD (5%). Notably, it is difficult to clinically distinguish between C. difficile infections and IBD flare-ups because both pathologies have similar presentations, i.e., diarrhea and abdominal pain. Indeed, C. difficile might mimic or even trigger an IBD flare-up, and screening is therefore recommended at every flare-up experienced by these patients[47]. Because IBD patients with concomitant C. difficile infections have been associated with longer hospital stays, colectomy and even higher mortality, the diagnosis of this bacterial infection is important[48]. The data obtained in the present study differ from those detailed in previous publications, which reported that UC patients exhibit increased susceptibility to C. difficile compared with CD patients[48-50]; however, previous studies have reported that one of the major risk factors for C. difficile infection in patients with IBD is colonic IBD[51], and 44% of the patients with CD in the present study showed colonic involvement. Importantly, only patients with moderate-to-severe activity were examined for C. difficile infections, and hence, these data might be underestimated because patients with mild activity were not examined.

In conclusion, IBD has continued to increase in the present cohort, slowly approaching the levels reported in developed countries. The association of this institution with a multidisciplinary IBD program has improved the characterization of these patients and had therefore improved management options.

We wanted to thank Magdalena Castro biomedical statistician and member of the Academic Research Unit from Clínica Las Condes who conducted the statistical review of this study.