The national burden of inflammatory bowel disease in the United States from 1990-2019: results from the Global Burden of Disease study database

Introduction

Inflammatory bowel disease (IBD) is characterized by idiopathic chronic inflammation of the gastrointestinal tract, comprising Crohn’s disease and ulcerative colitis [1]. Although the etiology is yet to be completely understood, it has been hypothesized to be the result of an inappropriate immune response in genetically-prone individuals [2]. IBD is now being found in every population around the globe, shattering ethnic and geographic boundaries. In the absence of a cure, the economic burden of this lifelong disease on healthcare systems and governments worldwide has been rapidly increasing. In the United States (US) alone, annual costs have been estimated to exceed $25 billion dollars in 2016, making IBD one of the top 5 most expensive gastrointestinal conditions [3]. Thus, understanding the epidemiological trends within the US is imperative to effectively address the impact of IBD on both healthcare and economic fronts.

The resultant burden due to IBD can vary considerably by geographic location, sex and age group [4,5]. Accurately assessing the incidence, prevalence and mortality rates of IBD in these demographics remains an ongoing challenge. There remains a paucity of comprehensive data regarding the disease burden specific to geographic location, sex and age at a more granular state level within the US [6]. This information is valuable in order to appropriately and effectively allocate both medical and financial resources throughout the country.

The Global Burden of Disease (GBD) 2019 framework provides comprehensive epidemiological data on incident cases, deaths and disability-adjusted life years (DALYs) of 369 diseases and injuries across a range of 204 countries and territories. While the global IBD burden has been thoroughly described based on the GBD 2019 study [7,8], the available information about its effect on individual states and the recent disease burden trends is notably deficient. Therefore, we aimed to provide a systematic report of the IBD burden, including incidence, prevalence, mortality and DALYs at a state level in the US. Additionally, we aimed to study the age- and sex-specific incidence, prevalence and mortality rates trends of IBD in the US from 1990-2019, using the GBD 2019 database.

Materials and methods

Results

IBD burden in the US

In 2019, there were 762,890 cases (95% confidence interval [CI] 712,357-813,654) of IBD in the US (56.4% were women). Despite an increase in absolute numbers of IBD cases from 1990-2019, age-standardized incidence and prevalence rates decreased between 1990 and 2019. The overall age-standardized incidence rates (ASIRs) of IBD in the US decreased from 35 (95%CI 30-40) per 100,000 population in 1990 to 23 (95%CI 21-25) per 100,000 population in 2019. The decrease in ASIRs was greater in men (-33%) compared to women (-31%). Females had a higher ASIR in 2019 than males, 23.5 (95%CI 21.5-25.5) per 100,000, vs. 22.8 (95%CI 20.8-24.8) per 100,000. The age-standardized mortality rate (ASMR) increased for both sexes by 53% from 1990-2019. Age-standardized DALYs decreased for both sexes, with a larger decrease for men (26% vs. -20%) (Table 1).

Table 1 Total and age-standardized rate of all-age, all-inflammatory bowel disease incidence, prevalence, mortality, DALYs, YLLs, and YLDs and their percentage change by United States State in 1990 and 2019

ASIRs

ASIR by state

Overall, the ASIRs declined in all states from 1990-2019. Initially, rates dropped from 35 (95%CI 30-40) in 1990 to 21 (95%CI 19-23) per 100,000 in 2000. There has been an uptrend since 2000, reaching 23 (95%CI 21-25) per 100,000 in 2019. ASIRs were highest in many Midwestern and Eastern states and lowest across the northern Great Plains and Western states. The highest ASIR was noted in Michigan, 31 (95%CI 28-34) per 100,000, followed by West Virginia and Kentucky (Fig. 1A). There was a wide geographical variation in the percentage of this decline between 1990 and 2019, with the largest percentage change occurring in California (-63.3%) (Fig. 1B). In 2019, incidence rates were nearly similar in men and women (22.89 and 23.53 per 100,000 persons, respectively) (Supplementary Table 1).

Figure 1 (A) Age-standardized incidence rate (ASIR) of inflammatory bowel disease (IBD) per 100,000 population in 2019. (B) Percentage change (%) in ASIRs of IBD between 1990 and 2019

ASIR by sex

Over 30 years, there was an overall decrease in ASIRs among men (AAPC -1.5%, 95%CI -1.6% to -1.4%; P<0.001) and women (AAPC -1.2%, 95%CI -1.3% to -1.1%; P<0.001), with an absolute AAPC difference of 0.2% (95%CI 0.1%-0.4%; P=0.003) (Fig. 2A). Sex-specific trends were non-identical (P<0.001) and not parallel (P<0.001), suggesting that ASIRs were different and decreasing at a greater rate in women compared to men. Interestingly, since 2000 ASIRs have increased in both sexes (Supplementary Table 2).

Figure 2 (A) Sex-specific trends in age-standardized incidence rates (ASIRs) of inflammatory bowel disease (IBD). (B) Age-specific trends in ASIRs of IBD

ASIR by age

Similarly, age-specific trends were decreasing among younger adults (AAPC -1.5%, 95%CI -1.6% to -1.4%; P<0.001) and older adults (AAPC -1.5%, 95%CI -1.7% to -1.4%; P<0.001), without a significant difference (P=0.46) (Fig. 2B). The major decrease in ASIR among both age groups and sexes was from 1990-1999, followed by an overall increase from 2000-2019 (Supplementary Table 2).

ASMRs

ASMR with geographic variation

A total of 5910 patients died due to IBD (60.1% women) in 2019 compared to 2171 in 1990. There was a wide geographic variation in the ASMR of IBD in 2019 across the states. The lowest ASMRs were noted in Hawaii and California (0.7 and 0.8 deaths per 100,000), while nearly double that rate was observed in Vermont (1.4 cases per 100,000) (Fig. 3A, Supplementary Table 3). The ASMR increased in all the states from 1990-2019, with the largest relative growth in West Virginia, Kentucky and Iowa (+86.9%, +83.2%, and +82.7%) (Fig. 3B).

Figure 3 (A) Age-standardized mortality rate (ASMR) of inflammatory bowel disease (IBD) per 100,000 population in 2019. (B) Percentage change (%) in ASMRs of IBD between 1990 and 2019

ASMR by sex

Overall, between 1990 and 2019, sex-specific ASMRs were increasing in men (AAPC 1.3%, 95%CI 1.2-1.4%; P<0.001) and women (AAPC 1.7%, 95%CI 1.4-1.9%; P<0.001) with an absolute AAPC difference of 0.4% (95%CI 0.1-0.6%; P=0.008) (Fig. 4A). While females’ ASMRs decreased during 2009-2019 (APC -0.5%, 95%CI -0.8% to -0.2%; P<0.001), there was an increase in males’ rates (APC 0.1, 95%CI 0.0-0.2%; P=0.01). Sex-specific trends were neither parallel (P<0.001) nor identical (P<0.001), suggesting that ASMRs among women are different and relatively increasing at a greater rate than men (Supplementary Table 4).

Figure 4 (A) Sex-specific trends in age-standardized mortality rates (ASMRs) of inflammatory bowel disease (IBD). (B) Age-specific trends in ASMRs of IBD

ASMR with age variation

Similar to the younger adults (AAPC 1.4, 95%CI 1.2-1.6%; P<0.001), older adults had an overall increase in ASMR (AAPC 1.5, 95%CI 1.3-1.7%; P<0.001), with a steady increase from 2001-2019 (APC 1.3, 95%CI 1.3-1.4%; P<0.001) (Fig. 4B). However, no significant absolute AAPC difference was observed (P=0.41) (Supplementary Table 4).

Age-standardized prevalence rates (ASPRs)

ASPRs with geographic variation

There were an estimated 762,889 prevalent cases of IBD during 2019 in the US, less than in 1990, when there were 982,981 cases. There was wide geographic variation in the ASPR among US states in 2019. The highest ASPR was in Rhode Island, 287 (95%CI 264-310) per 100,000, followed by Massachusetts and Connecticut (Fig. 5A). Interestingly, all states saw a significant decrease in prevalent cases from 1990-2019. The most notable decrease was in California, which decreased from 462 (95%CI 404-528) in 1990 to 169 (95%CI 157-181) per 100,000 in 2019 (Fig. 5B). Although all age groups saw a decrease in prevalence rates, people aged 50-74 had the most notable decrease, from 718 per 100,000 in 1990 to 332 per 100,000 in 2019, with a relative decrease of 53.7% (Supplementary Table 5).

Figure 5 (A) Age-standardized prevalence rate (ASPR) of inflammatory bowel disease (IBD) per 100,000 population in 2019. (B) Percentage change (%) in ASPRs of IBD between 1990 and 2019

ASPR by sex

Overall, sex-specific ASPR was decreasing in men (AAPC -1.8%, 95%CI -1.9% to -1.7%; P<0.001) and women (AAPC -2.2%, 95%CI -2.3% to -2.1%; P<0.001), showing an absolute difference of 0.4 (95%CI 0.3-0.5; P<0.001) with non-parallel trends, suggesting that ASPRs among women are different and decreasing at a greater rate than in men (Fig. 6A). The largest drop in ASPRs among both sexes was observed during 1996-1999, in males (APC -7.15, 95%CI -6.5 to -7.6; P<0.001) and females (APC -6.61, 95%CI -5.9 to -7.3; P<0.001) (Supplementary Table 6).

Figure 6 (A) Sex-specific trends in age-standardized prevalence rates (ASPRs) of inflammatory bowel disease (IBD). (B) Age-specific trends in ASPRs of IBD

ASPR with age variation

Compared to the younger adults (AAPC -1.6%, 95%CI 1.8% to -1.4%; P<0.001), older adults had a greater decrease in ASPR (AAPC -2.6%, 95%CI 2.8% to -2.4%; P<0.001), with an absolute AAPC difference of 1% (95%CI 0.9-1.1%; P<0.001) (Fig. 6B). Age-specific trends were non-identical (P<0.001) and not parallel (P<0.001), suggesting that ASPRs among older adults are different and decreasing at a greater rate than in younger adults (Supplementary Table 6).

Discussion

In this study, we demonstrated that, according to our analysis of GBD 2019, there was an overall decrease in ASIRs and ASPRs in the US from 1990-2019, whereas there was a simultaneous increase in the overall ASMRs. The ASPR dropped from 343 (95%CI 295-395) per 100,000 in 1990 to 193 (95%CI 179-207) per 100,000 in 2019. However, a distinct trend emerged of increasing incidence and prevalence rates starting in 2000, with ASIRs rising from 21 (95%CI 19-23) per 100,000 in 2000 to 23 (95%CI 21-25) per 100,000 in 2019. A study by Park et al showed that the decrease in US ASPRs during the past 3 decades was the biggest worldwide [7]. Notably, our data showed that the period 1990-2000 had the most pronounced decrease in incidence and prevalence rates. Although the exact reason for this decrease in incidence and prevalence has not been identified, it was probably due to an array of factors. Among these, exercise, nutritional awareness, migration trends, and saturation of genetic and environmental factors contributing to the development of IBD are likely to have played major roles [15-17]. These may provide some insight into the potential reasons that the state of California experienced the largest decline in the incidence and prevalence of IBD throughout the US.

California is distinguished by its substantial Latino population, which exhibits a higher growth rate than any other state [18]. This trend is largely due to the influx of Latinos and other ethnic minorities migrating into California, thereby contributing to the state’s largest immigrant population nationwide [19]. Studies have consistently shown lower levels of IBD within these populations, further reinforcing the potential influence of migration trends and demographic factors on disease prevalence [5,20,21]. In addition, recent population-level changes in diet may be more pronounced in some states, contributing to the different rates of IBD. The California state government, for example, regularly funds large healthy eating initiatives. One example is the Healthy Eating, Active Communities (HEAC) Program, a 4-year, $26 million investment to help prevent childhood obesity and diabetes that has consistently shown positive results [22]. In a study by Ye et al, diets that were richer in soluble fibers were found to be protective against IBD [23].

On the other hand, our results indicate a lower incidence of IBD in the Northern Great Plains and Western states, while Midwestern and Northeastern states struggle with higher incidence and prevalence rates. These results are supported by studies by Sonnenberg et al and Kappelman et al, which both demonstrated higher incidence and prevalence rates of IBD in the Midwestern and Northeastern states [24,25]. Considering the predominantly white demographics in these regions [26], studies demonstrating the association between being white and the development of IBD [25,27] provide insight into the elevated rates of incidence and prevalence observed in these states [21].

When investigating the propensity of the disease to affect different sexes, we report that both males and females had a major decline in both incidence and prevalence between the years 1990 and 1999, followed by a steady rise in incidence and prevalence rates until 2019. This trend was followed by both the younger and older age groups. The reason for this more recent increase in incidence is unclear, but it could be due to increased awareness of patients and healthcare providers about IBD and better access to diagnostic tools such as endoscopy, imaging, and stool testing for intestinal inflammation. Another factor that could explain changes in IBD epidemiology is trends in early-life exposure to various microbes. As industrialization and modernization continue in the US and in nations around the world, children are exposed to a more sterilized environment and may not develop immune tolerance, thus leading to an inappropriate immune response to harmless intestinal microbes later in life [28]. Moreover, increased early-life exposure to antibiotics may result in decreased intestinal microbial diversity and species richness, a factor known to be strongly associated with IBD [29].

A closer look at the results also reveals a significant upswing in the incidence of IBD among females over the years 2017 and 2019, in contrast to males, who continued to maintain only a steady increase in incidence. Notably, the existing literature has reported an increase in the incidence of autoimmune diseases over the past decades [30]. These conditions have been hypothesized to stem from various factors, including genetic predisposition and environmental exposures, such as diet and stress, ultimately resulting in an impaired immune response [31]. Evidence from a recent study suggests that adopting a “Western diet,” which is typically high in saturated fats and sucrose, coupled with a low intake of dietary fibers, may precipitate the development and exacerbation of autoimmune conditions such as IBD [32]. Furthermore, multiple studies have consistently provided evidence supporting a clear sex-related bias in autoimmune diseases, specifically towards women, with some reporting a risk up to 4 times greater in women than men [33].

In regard to mortality related to IBD, our results illustrated an overall increase over the last 30 years. Although the mortality rates in all age groups and sexes were similar in 2019, our data illustrated a downtrend of the rate in females between 2009 and 2019, while it increased in males during this time period. The differences in environmental factors between males and females resulting from biological, social, and economic exposures may be implicated in this trend discrepancy between the 2 sexes. Of these factors, the increasing, and ultimately higher, prevalence of smoking in males is likely to have contributed to this uptick in mortality, given that it has been one of the most examined environmental factors in patients with IBD [4]. Simultaneously, smoking prevalence was both lower and down-trending in females during this period [34,35]. Moreover, smoking significantly increases the risk of cancer and mortality in these individuals, further underscoring the adverse consequences associated with smoking in this patient population [36].

Moreover, while we witnessed an increase in the mortality rate in all states throughout the US, the largest relative increase was seen in Mideastern states. In recent years, these states have experienced an aging population, with a greater proportion of their residents falling into the older age group [37], which, according to the data from our study, had significantly higher mortality rates than the younger age group. A long-term outcome study by Jess et al has highlighted the association between older age and a higher IBD-related mortality rate. The results from this study indicated that there may be an increased likelihood of dying with IBD from secondary comorbidities such as cardiovascular disease or chronic lung disease [38]. Furthermore, emerging evidence suggests that the significant increase in the risk of both intestinal and extraintestinal malignancies observed in IBD patients may be attributed to several factors, including the presence of extraintestinal manifestations of IBD, comorbidities, and the use of immunosuppressive drugs [39].

This study possesses various noteworthy strengths. To the best of our knowledge, our study represents the most recent estimates of IBD prevalence, incidence and mortality rates throughout the US population, specifically looking at these trends at the state level. Moreover, the major strength of this study is its comprehensive coverage over the last 3 decades, surpassing the scope of most previous studies. In addition, this study provides valuable information and insight into the mortality rates attributed to IBD, an aspect of IBD that has been addressed by relatively few studies in the existing literature. Several limitations should also be noted. First, the study estimated rates of IBD as a whole, overlooking the potential differences in rates between ulcerative colitis and Crohn’s disease. If Crohn’s disease and ulcerative colitis were reported separately, variations in the incidence and prevalence rates between males and females might be revealed. Second, the study could not determine the cause of increased mortality in IBD patients, thus making it difficult to suggest a course of corrective action.

Overall, IBD has a protracted disease course, and associated mortality is low relative to other chronic diseases. However, as the absolute number of patients with IBD cases increases, a compound prevalence phenomenon will continue to weigh heavily on the US healthcare system. Moreover, despite their effectiveness, the cost of biological drugs poses a significant financial burden on both the patients and the healthcare system. Emerging reports have suggested that up to 25% of adults experience financial difficulties due to IBD-related medical expenses, and around 16% of adults are burdened by cost-related nonadherence to their prescribed medication [40]. As a result, it is imperative to conduct more comprehensive epidemiological studies on IBD, aiming to learn more about its etiology and geographic distribution so that we can continue to intelligently allocate medical, educational, and financial resources to areas predicted to have the most need.