Lifetime Economic Burden of Crohn’s Disease and Ulcerative Colitis by Age at Diagnosis

Clinical Gastroenterology and Hepatology 2019;-:-–-

Lifetime Economic Burden of Crohn’s Disease and Ulcerative Colitis by Age at Diagnosis Gary R. Lichtenstein, MD,* Ahva Shahabi, MPH, PhD,‡ Seth A. Seabury, PhD,‡ Darius N. Lakdawalla, PhD,‡ Oliver Díaz Espinosa, PhD,‡ Sarah Green, BA,‡ Michelle Brauer, BS,‡ and Robert N. Baldassano, MD§ *Gastroenterology Division, Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; ‡Precision Health Economics, Los Angeles, California; and §Center for Pediatric Inflammatory Bowel Disease, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania BACKGROUND & AIMS:

Understanding the burden of Crohn’s disease (CD) and ulcerative colitis (UC) is important for measuring treatment value. We estimated lifetime health care costs incurred by patients with CD or UC by age at diagnosis.

METHODS:

We collected data from 78,620 patients with CD, 85,755 with UC, and propensity score-matched control subjects from the Truven Health MarketScan insurance claims databases (2008‒2015). Total medical (inpatient, outpatient) and pharmacy costs were captured. Cost variations over a lifetime were estimated in cost-state Markov models by age at diagnosis, adjusted to 2016 U.S. dollars and discounted at 3% per annum. We measured lifetime total and lifetime incremental cost (the difference between costs of CD or UC patients vs matched controls).

RESULTS:

For CD, the lifetime incremental cost was $707,711 among patients who received their diagnosis at 0‒11 years, and $177,614 for patients 70 years or older, averaging $416,352 for a diagnosis at any age. Lifetime total cost was $622,056, consisting of outpatient ($273,056), inpatient ($164,298), pharmacy ($163,722), and emergency room (ER) ($20,979) costs. For UC, the lifetime incremental cost was $369,955 among patients who received their diagnosis at 0‒11 years, and $132,396 for individuals 70 years or older, averaging $230,102 for a diagnosis at any age. Lifetime total cost was $405,496, consisting of outpatient ($163,670), inpatient ($123,190), pharmacy ($105,142), and ER ($13,493) costs. Therefore, the prevalent populations of patients with CD or UC in the United States in 2016 are expected to incur lifetime total costs of $498 billion and $377 billion, respectively.

CONCLUSIONS:

Using a Markov model, we estimated lifetime costs for patients with CD or UC to exceed previously published estimates. Individuals who receive a diagnosis of CD or UC at an early age (younger than 11 years) incur the highest lifetime cost burden. Advancing management strategies may significantly improve patient outcomes and reduce lifetime health care spending.

Keywords: Inflammatory Bowel Disease; Patient Costs; Health Care Burden.

rohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases affecting 3 million people in the United States in 2015.1 There are an estimated 70,000 new cases per year, with most patients diagnosed before 35 years of age.2 CD and UC are associated with high morbidity and consist of intermittent periods of hospitalizations, surgery, and pharmacotherapy to manage flare-ups and disease complications throughout a patient’s lifetime. Patients who receive a diagnosis at a younger age (<20 years of age) use more health care resources on average because they experience a longer duration of time with the disease than patients who receive a diagnosis at an older age.3,4

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The extensive care required to manage patients with CD and UC, to say nothing of the stress and negative quality-of-life implications for patients, leads to significant direct and indirect costs throughout patients’ lives. Previous studies used various approaches to estimate direct annual5–9 and lifetime10–13 costs for CD or UC, although results are limited and the estimates range

Abbreviations used in this paper: CD, Crohn’s disease; ER, emergency room; ICD-9-CM, International Classification of Diseases-Ninth RevisionClinical Modification; UC, ulcerative colitis; USD, U.S. dollars. © 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2019.07.022

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broadly from $180,65912 to $310,24211 for adult patients with CD and $237,82013 for pediatric patients with UC (2016 U.S. dollars [USD]). A common limitation of previous studies is that costs are not reported by age at diagnosis, although the expected lifetime burden is likely to be higher for patients diagnosed at younger ages. Furthermore, because of treatment innovation, lifetime health care costs estimated in previous studies, particularly in the prebiologic era, may not accurately reflect the current landscape. This study addresses gaps in the literature by estimating lifetime incremental costs of CD and UC by age at diagnosis using recent data. No single database tracks costs and outcomes for patients with CD or UC over their entire lifetimes, necessitating modeling methods for estimating lifetime costs. Thus, we constructed a Markov model to simulate expected treatment costs from diagnosis to death based on age at diagnosis using administrative claims data from 2008 to 2015. Our methods consider cost differences at diagnosis and allow for fluctuations over time. We focused on incremental lifetime health care costs to estimate the burden of CD and UC for patients inclusive of costs of treatment and disease-related complications.

Materials and Methods To estimate lifetime costs, we developed a Markov model using retrospective medical and pharmacy claims data on patients with CD or UC matched to control subjects without CD or UC to estimate the distribution of incremental costs based on age at diagnosis. To create an age profile of costs, we stratified the data by age and used the cost distribution for each age group to build parameters for the Markov model. Using this information, lifetime costs were constructed for each age group via Markov model simulation. We discuss the details of the analysis in this section, with more detail provided in the Supplementary Material.

Study Population Data from the Truven Health MarketScan Commercial, Claims, and Encounters and Medicare Supplemental databases (Truven Health Analytics [now IBM Watson Health, Cambridge, MA]) from January 2008 to September 2015 were used to identify the study population, including pediatric, adult, and older adult patients. The study included patients with CD (International Classification of Diseases-Ninth Revision-Clinical Modification [ICD-9-CM] code 555.x) and UC (ICD-9-CM code 556.x) with
1 year of continuous follow-up before and after diagnosis. Patients were included if they had received a diagnosis of CD or UC, defined as
1 inpatient or
2 outpatient claims with an ICD-9-CM code for CD or UC that were 30 days apart but not >365 days apart. Patients with multiple instances of ICD-9-CM codes for

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What You Need to Know Background Crohn’s disease (CD) and ulcerative colitis (UC) require lifelong medical management, and lifetime health care costs can be high. Published estimates of lifetime costs for CD and UC are limited and outdated, and costs vary. Findings Using a Markov model analysis of a large insurance database, we found lifetime health care costs to be high among all ages of diagnosis. Differences (incremental) in lifetime costs are particularly high for patients who received a diagnosis of CD or UC at a younger age (younger than 11 years of age). Implications for patient care Improving disease management with more effective therapies and strategies, particularly in the younger population, can reduce the lifetime cost burden facing patients and the health care systems.

CD and UC were assigned to the condition that appeared most often in the data (eg, a patient with 3 qualifying diagnoses of CD and 1 diagnosis of UC was considered a CD case). Patients with an equal number of qualifying diagnoses of CD and UC throughout their follow-up history were excluded. Identified patients in our study population were diagnosed with CD or UC (diagnoses were mutually exclusive). We distinguished between newly diagnosed (incident) cases and prevalent cases. The index date for incident cases was defined using the date of first observed diagnosis. Each incident case required a “clean period” so that the index date had to be preceded by at least 1 year of observed continuous enrollment without any other diagnoses of CD or UC. Prevalent cases were identified as patients with at least 1 inpatient or 2 outpatient claims with a diagnosis of CD or UC in any or all years of data but with no identified clean period. To calculate the lifetime incremental costs, we matched patients with a diagnosis of CD or UC separately to control subjects with no CD or UC diagnosis. Individuals without CD or UC claims who met the same qualifying continuous enrollment criteria were randomly selected from the data and assigned an index date matching an included case, and were then propensity score matched (one to one, nearest neighbor within specified calipers, without replacement) to each patient based on age, sex, health plan type, and preindex Charlson Comorbidity Index.

Statistical Analysis Health Care Costs. Medical and pharmacy claims were used to determine costs for inpatient stays, outpatient

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visits, emergency room (ER) visits, and outpatient pharmacy services to determine total cost, which constitutes direct CD- or UC-related costs and costs associated with disease-related complications. To maintain granularity of costs, we calculated costs on a quarterly (3-month) basis after the index date. Among medical and pharmacy services, total direct costs included the sum of patient out-of-pocket costs and any insurer- or employer-incurred costs. Costs were adjusted to 2016 USD using the Consumer Price Index and discounted at 3% per annum to obtain present values.14 The population was stratified by age group (0‒11, 12‒ 17, 18‒29, 30‒39, 40‒49, 50‒59, 60‒64, 65‒69, 70 years or older) to determine the cost distribution for each age group, which was used to estimate age-specific cost states and transition probabilities for the Markov model. Cost States. Quarterly cost data were used to derive cost categories that functioned as transition states in the model. To capture heterogeneity in disease severity—which is not directly observable in claims data—we stratified the population according to costs at diagnosis, and then allowed them to transition between costs states over time (severity has been shown to be highly correlated with cost).11 Quarterly total direct costs and costs accruing from each service category (inpatient, outpatient, ER, pharmacy) were stratified by age group and prevalent or incident status for cases with CD or UC and their matched control subjects. Individuals with no costs in a quarter were categorized as zero-cost individuals. For all nonzero costs, the spending distribution in each quarter was evaluated and cost categories (low, moderate, high) were created based on natural breaks in the distribution designed to be consistent with prior literature15: low-cost individuals were in the bottom 70%, moderate-cost individuals were between 70% and 90%, and high-cost individuals were the top 10%. Model Parameters. We used these data to compute the probabilities that a patient with CD or UC in a given cost category today would transition to 1 of the 4 cost categories next quarter. The transition probability matrix records the probability of transitioning from the current state to each of the 4 possible future states. We separately calculated transition probabilities by age of diagnosis, case/control status, and incident/prevalent population status. This resulted in 72 transition probability matrices (4  4) (see Supplementary Tables 1 and 2). An attrition category was created for individuals without claims data after the first year of required continuous enrollment, to account for possible attrition bias. This allowed for maximum data usage without sacrificing accuracy of the transitions. U.S. Life Tables16 were used to estimate agespecific death probabilities, which were included in each transition matrix. The estimating equations and transition probability matrices used in the model are available online (see Supplementary Methods). Once transition probabilities were calculated, a representative cost was assigned for each cost state based on the average cost of

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patients in each cost state across all quarters (Supplementary Table 3). Similar methodology was used to identify the transition probabilities and average costs accruing for patients in each cost state for each health care service category. Markov Model. We used the transition probability matrices and cost state values to parameterize a Markov model of simulated cost for each age group. Model results were stratified by age at diagnosis. For the first year after diagnosis, the incident group transition probabilities and costs were used. For all subsequent years of the patient’s simulated life, the prevalent transition probabilities and costs were used. As patients aged within the model from diagnosis to the next age cohort, transition probabilities for the next age group were applied. The model was run from diagnosis age until all cohort members reached death to determine each patient’s lifetime cost. Similar models were run for each service category to determine the percentage of total costs accruing from each source. The underlying approach for our model is presented in Figure 1. Lifetime incremental costs were calculated by taking the difference in lifetime total costs between cases with CD or UC and their matched control subjects for each age group to estimate the additional costs incurred by patients attributable to their disease. Sensitivity Analyses. We conducted sensitivity analyses to test the robustness of our results by altering the model assumptions. These included (1) using different breaks in the cost distribution to define cost categories (using tertiles instead of natural breaks), (2) applying incident transition probabilities to the model for the first 5 years after diagnosis instead of only the first year, and (3) applying an increase in mortality due to CD (hazard ratio, 1.73)17,18 and UC (hazard ratio, 1.44),17 as shown in prior literature.

Results The characteristics of the population of patients with CD or UC with their 1-to-1 propensity-matched control subjects are shown in Table 1. A total of 78,620 patients with CD (34,692 incident, 43,928 prevalent) and 85,755 patients with UC (48,196 incident, 37,559 prevalent) and their respective 78,620 and 85,755 matched control subjects were included. Cases with CD or UC and their matched control subjects were similar based on characteristics, with no statistically significant differences in matched characteristics. Lifetime total and incremental costs for a patient with CD compared with individuals without CD or UC are presented by age group at diagnosis (Figure 2A). Pediatric CD patients had the highest incremental lifetime costs of all age groups (0‒11 years of age: $707,711; 12‒ 17 years of age: $624,632). Incremental costs ranged from $177,614 (70 years of age or older) to $707,711 (0‒11 years of age). In a similar manner, total lifetime

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Figure 1. Schematic of the Markov model using cost states. Each branch represents the probability of being a high-, moderate-, low-, or zero-cost individual, given the age group, in the specific time frame. Death is a static state; probabilities were included from the U.S. Life Tables.16 Table 1. Summary Statistics of the Study Population Used to Derive Model Parameters Incident

Prevalent

Incident

Prevalent

CD Control CD Control UC Control UC Control patients subjects patients subjects patients subjects patients subjects (n ¼ 34,692) (n ¼ 34,692) (n ¼ 43,928) (n ¼ 43,928) (n ¼ 48,196) (n ¼ 48,196) (n ¼ 37,559) (n ¼ 37,559) Age group at index 0–11 y 2.5 12–17 y 5.5 18–29 y 12.4 30–39 y 13.8 40–49 y 18.3 50–59 y 22.1 60–64 y 10.0 65–69 y 5.0 70þ y 10.5 Female 56.2 Charlson Comorbidity Index 0 73.8 1 12.4 2 8.3 3þ 5.5 Health plan type PPO 60.6 HMO 13.7 Other 25.7 U.S. region of residence Northeast 20.5 North Central 27.0 South 35.4 West 15.9 Unknown 1.3 Follow-up time, y 2.89  1.47

2.5 5.3 12.4 13.8 18.3 22.0 10.1 5.0 10.5 56.2

1.2 4.9 15.9 18.0 20.1 21.7 8.8 3.7 5.7 55.7

1.1 4.8 16.1 18.0 20.2 21.6 8.7 3.7 5.7 55.8

0.7 2.3 9.0 13.0 19.2 24.7 11.2 5.9 14.1 55.4

0.7 2.2 8.8 13.1 19.2 24.7 11.3 6.0 14.0 55.1

0.7 2.1 11.5 17.0 21.2 24.1 10.0 4.5 8.7 51.9

0.7 2.1 11.6 17.2 21.2 24.2 10.1 4.5 8.5 51.8

73.9 12.5 8.3 5.2

77.7 11.2 7.2 3.9

77.5 11.7 7.0 3.9

73.2 11.6 8.6 6.6

73.2 11.7 8.5 6.6

78.7 10.2 7.6 3.6

78.7 10.2 7.5 3.6

60.9 13.8 25.3

66.1 13.1 20.8

66.7 12.9 20.4

58.7 14.6 26.7

59.0 14.8 26.2

64.9 14.1 21.0

65.3 14.0 20.7

20.1 27.4 35.4 15.8 1.2 3.04  1.54

20.5 27.8 35.1 14.3 2.3 3.26  1.70

20.7 27.9 35.1 14.1 2.3 3.43  1.73

20.3 25.7 33.7 19.2 1.0 2.91  1.47

20.3 25.8 33.8 19.2 1.0 3.06  1.53

22.2 24.1 33.5 18.5 1.8 3.28  1.68

22.2 24.1 33.5 18.3 1.8 3.43  1.71

Vales are % or mean  SD. P values comparing characteristics of CD and UC patients to matched control subjects were all not statistically significant at a ¼ 0.05. CD, Crohn’s disease; HMO, health maintenance organization; PPO, preferred provider organization; UC, ulcerative colitis.

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Figure 2. Lifetime and incremental costs for (A) a patient with Crohn’s disease (CD) stratified by age at diagnosis and (B) a patient with ulcerative colitis (UC) stratified by age at diagnosis. Costs shown are discounted at 3% per annum. Younger control subjects in the data are very healthy and do not start accruing medical costs until they become older in the model. Therefore, the cumulative discounting is higher than for an older patient just entering the model. This explains the lower discounted lifetime costs for younger control subjects (effect is not seen in nondiscounted costs). USD, U.S. dollars.

costs for patients with CD ranged from $371,264 (70 years of age or older) to $848,084 (0‒11 years of age). Figure 2B shows the lifetime total and incremental costs by age group for a patient with UC compared with individuals without CD or UC. Similar to patients with

CD, pediatric patients with UC incurred the highest incremental cost (0‒11 years of age: $341,603; 12‒17 years of age: $299,311). Incremental and total lifetime costs for UC are approximately half of what is seen for CD. Incremental costs for UC ranged from $89,884 (70

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Figure 3. Average lifetime cost and incremental cost for a patient with Crohn’s disease (CD) and a patient with ulcerative colitis (UC). ER, emergency room; USD, U.S. dollars.

years of age or older) to $341,603 (0‒11 years of age), approximately half of the estimates seen for CD. Total lifetime costs for patients with UC ranged from $290,948 (70 years of age or older) to $475,580 (0‒11 years of age). The primary cost driver was outpatient visits, accounting for 46.5% (50‒59 years) to 52.1% (0‒11 years of age) of total costs for the CD population and 44.6% (18‒29 years of age) to 46.4% (0‒11 years of age) of the UC population (see Supplementary Tables 4 and 5). Using the lifetime costs for each age group, ageadjusted average lifetime costs and the source of these costs (outpatient visit, inpatient, pharmacy, and ER) were calculated for patients with CD or UC and their matched control subjects (Figure 3). Incidence rates for CD and UC by age from the literature19 were multiplied with the corresponding lifetime cost and incremental cost to derive an age-adjusted average for each condition. The difference in the age-adjusted estimates of patients with CD or UC and their matched control subjects is the incremental cost (cost burden), which is $416,352 for CD and $195,799 for UC. Details on costs by age and by health care service type for CD and UC can be found in the Supplementary Material. Results of 3 sensitivity analyses for CD and UC are shown in Table 2. For CD, incremental lifetime costs from all sensitivity analyses ranged from $377,793 to $397,963, compared with our main result of $416,352; incremental lifetime costs for UC ranged from $189,462

to $190,014 compared with our main result of $195,799. Compared with the main results, the largest differences in incremental cost seen was for the sensitivity analysis incorporating an increase in mortality due to CD or UC, a difference of $38,559 (CD) and $6336 (UC). For each age group, we estimated incremental lifetime costs if a patient with CD or UC in the model starts at a zero, low, moderate, or high cost at diagnosis (see Supplementary Figures 1 and 2). This assessment estimated the cost range for each age group if baseline cost categories were used as proxies for baseline severity status. Younger age groups continued to have the highest incremental lifetime costs, regardless of status at baseline; CD patients who received their diagnosis at 0‒11 years of age had an incremental lifetime cost range of $669,907 (zero cost at diagnosis) to $767,223 (high cost at diagnosis) and patients with UC had a range of $317,239 to $384,130.

Discussion This study estimated lifetime total and incremental costs by age at diagnosis for patients with CD or UC compared with their matched control subjects using a large health care claims database. The average patient faces an additional $416,352 or $195,799 for CD or UC,

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Table 2. Sensitivity Analyses Lifetime cost per patient (2016 USD) Analysis CD: main results Sensitivity #1 Sensitivity #2 Sensitivity #3 UC: main results Sensitivity #1 Sensitivity #2 Sensitivity #3

Description Cost category cutoffs at equal thirds (tertiles) Incident transition probabilities applied for the first 5 y after diagnosis instead of only the first year in the model Applied an increase in mortality due to CDa Cost category cutoffs at equal thirds (tertiles) Incident transition probabilities applied for the first 5 y after diagnosis instead of only the first year in the model Applied an increase in mortality due to UCa

Per CD/UC patient

Per non-CD/UC control subject

Incremental cost

$622,056 $596,616 $601,373

$205,704 $198,654 $206,477

$416,352 $397,963 $394,896

$570,805 $405,496 $392,577 $404,903

$205,704 $209,697 $202,563 $209,682

$365,101 $195,799 $190,014 $195,221

$379,390

$209,697

$169,693

CD, Crohn’s disease; UC, ulcerative colitis; USD, U.S. dollars. a Hazard ratios comparing hazard rates of CD and UC patients with the general population were applied to the model: 1.73 for CD and 1.44 for UC.17,18

respectively, in total lifetime health care costs due to their disease. The majority of lifetime costs for CD and UC patients were attributed to outpatient visits, while inpatient and pharmacy were the next largest cost drivers. Patients who received a diagnosis of CD or UC at 0‒11 years of age have the highest incremental costs compared with groups who received a diagnosis at older ages, with an added $707,711 in health care costs due to CD and $341,603 due to UC. The differences in lifetime cost by age indicate that a single average lifetime cost estimate does not apply across the spectrum of patients and likely understates the burden for those who received a diagnosis at younger ages. Furthermore, we show higher lifetime total costs for the average patient compared with previous studies.

For CD lifetime costs, Malone et al11 reported $310,242 (2016 USD) and Silverstein et al12 reported $180,659, compared with our result of $622,056. For UC, Park et al13 reported a $237,820 lifetime cost for a patient who received a new diagnosis at 10 years, which was approximately half of our result for the 0‒11 years of age group at $475,580. Rough approximations suggest lifetime costs would be higher if they were to be imputed from more recent annual cost figures published in the literature (see Supplementary Methods). The departure from prior findings could be due to the following factors that distinguish our study from previous work: (1) more recent data; (2) pediatric, adult, and older adult populations included by age at diagnosis; and (3) differentiating patients by cost states

Figure 4. Comparison of published lifetime cost estimates for a patient across different diseases. Estimates of Crohn’s disease and ulcerative colitis are from this study. Lifetime cost estimates were previously modeled and published for other diseases: type 2 diabetes,21 rheumatoid arthritis,22 and care after heart failure.23 USD, U.S. dollars.

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rather than health states, which captures costs explicitly recorded rather than severity status not easily captured in claims. Using our total lifetime cost estimates, we estimated the projected lifetime costs for the prevalent populations of patients with CD or UC in 2016. With the approximate size of these populations (computed by applying the estimated prevalence of CD [246.7 cases per 100,000] and UC [286.3 cases per 100,000] reported by Shivashankar et al20 to the 2016 U.S. population of approximately 324 million), the lifetime cost burden for the prevalent populations of patients with CD and UC in 2016 in the United States are expected to be $498 billion and $377 billion, respectively. Our estimates of lifetime costs for CD and UC are significant compared with other chronic diseases with published lifetime cost estimates (Figure 4). Zhuo et al21 simulated lifetime costs of type 2 diabetes and estimated the age- and sex-weighted average of lifetime medical cost at $89,064 (2016 USD). For rheumatoid arthritis, the most recent lifetime medical care cost estimate is $100,273 (in 2016 USD, but based on older data).22 The lifetime cost for CD or UC is also higher than lifetime costs for medical care after heart failure, estimated at $122,110 (2016 USD).23 Additional studies evaluating lifetime costs of chronic diseases that are more similar to CD and UC and affect patients over their lifetimes are warranted. Our study has several limitations. First, as is common in the literature, future treatment innovations are not considered and all medical technology is held constant. This study is designed to simulate the thought experiment of calculating lifetime costs at today’s prices and technological possibilities. Our estimates serve as a measure of today’s cost burden, incorporating spending at all ages, but they cannot predict the future lifetime course of today’s young patients. Second, we were not able to assess clinical measures of disease severity in claims data. While prior studies have used an algorithm to derive severity,11,12 the actual clinical severity status in claims data is unknown and also nuanced. However, cost is strongly associated with severity.11,24,25 Allowing lifetime costs to differ based on the distribution of costs at diagnosis, we capture important variations in severity. Third, while we use the timing of diagnosis to determine incidence, patients may begin exhibiting symptoms long before being diagnosed and treated. This potential misclassification may cause our model to underestimate costs that some patients may incur if they seek care before being diagnosed. Conversely, patients with comparatively minor cases who seek only intermittent care within the time horizon of our inclusion criteria could be falsely excluded because of the requirement of 2 outpatient claims within a calendar year. Therefore, our cost estimates may be more applicable to prevalent patients who seek care more often and have more moderate to severe disease.

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An additional limitation is that while diagnoses based on ICD-9-CM codes in claims data have been widely used and validated in past work, we lack clinical detail from the medical records that would help to confirm the validity of the diagnosis and identify disease severity. Also, the use of administrative claims data limits the generalizability of the results to populations covered by employer-sponsored health insurance or supplemental Medicare plans. Finally, our study does not consider the significant indirect costs that impose additional burden on patients with CD or UC. Further work on the economic burden should consider the productivity and quality-oflife effects of the disease in addition to treatment costs. Despite these limitations, we believe this study provides the most accurate estimates to date of the lifetime medical costs associated with CD or UC. With the arrival of new therapies in recent years and evolving treatment paradigm for CD and UC, costs of care may be impacted; as more data on patients are collected, continued efforts should include assessing health care costs considering both short- and long-term patient outcomes and potential drivers of cost that can be used to further validate our findings. The high lifetime cost burden in CD and UC highlights the urgent need for continued efforts to improve treatments and disease management leading to better patient outcomes, particularly in younger patients diagnosed with CD or UC.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2019.07.022.

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18 years - United States, 2015. MMWR Morb Mortal Wkly Rep 2016;65:1166–1169. 2. Crohn’s & Colitis Foundation of America. The facts about inflammatory bowel diseases. Available at: http://www. crohnscolitisfoundation.org/assets/pdfs/updatedibdfactbook.pdf. Accessed January 15, 2019. 3. Kappelman MD, Porter CQ, Galanko JA, et al. Utilization of healthcare resources by U.S. children and adults with inflammatory bowel disease. Inflamm Bowel Dis 2011;17:62–68. 4. Park KT, Bass D. Inflammatory bowel disease-attributable costs and cost-effective strategies in the United States: a review. Inflamm Bowel Dis 2011;17:1603–1609. 5. Ganz ML, Sugarman R, Wang R, et al. The economic and healthrelated impact of Crohn’s disease in the United States: evidence from a nationally representative survey. Inflamm Bowel Dis 2016;22:1032–1041. 6. Gibson TB, Ng E, Ozminkowski RJ, et al. The direct and indirect cost burden of Crohn’s disease and ulcerative colitis. J Occup Environ Med 2008;50:1261–1272. 7. Gunnarsson C, Chen J, Rizzo JA, et al. Direct health care insurer and out-of-pocket expenditures of inflammatory bowel disease:

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evidence from a US national survey. Dig Dis Sci 2012; 57:3080–3091. 8. Kappelman MD, Rifas-Shiman SL, Porter CQ, et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology 2008;135: 1907–1913. 9. Bickston SJ, Waters HC, Dabbous O, et al. Administrative claims analysis of all-cause annual costs of care and resource utilization by age category for ulcerative colitis patients. J Manag Care Pharm 2008;14:352–362. 10. Bodger K, Kikuchi T, Hughes D. Cost-effectiveness of biological therapy for Crohn’s disease: Markov cohort analyses incorporating United Kingdom patient-level cost data. Aliment Pharmacol Ther 2009;30:265–274. 11. Malone DC, Waters HC, Van Den Bos J, et al. A claims-based Markov model for Crohn’s disease. Aliment Pharmacol Ther 2010;32:448–458. 12. Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn’s disease: Markov model analysis of a population-based cohort. Gastroenterology 1999; 117:49–57. 13. Park KT, Perez F, Tsai R, et al. Cost-effectiveness analysis of adjunct VSL#3 therapy versus standard medical therapy in pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2011; 53:489–496. 14. Sanders GD, Neumann PJ, Basu A, et al. Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on costeffectiveness in health and medicine. JAMA 2016; 316:1093–1103. 15. Forget EL, Roos LL, Deber RB, et al. Variations in lifetime healthcare costs across a population. Healthc Policy 2008; 4:e148–e167.

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20. Shivashankar R, Tremaine WJ, Harmsen WS, et al. Incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010. Clin Gastroenterol Hepatol 2017;15:857–863. 21. Zhuo X, Zhang P, Hoerger TJ. Lifetime direct medical costs of treating type 2 diabetes and diabetic complications. Am J Prev Med 2013;45:253–261. 22. Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality, and economics of rheumatoid arthritis. Arthritis Rheum 2001; 44:2746–2749. 23. Dunlay SM, Shah ND, Shi Q, et al. Lifetime costs of medical care after heart failure diagnosis. Circ Cardiovasc Qual Outcomes 2011;4:68–75. 24. Floyd DN, Langham S, Severac HC, et al. The economic and quality-of-life burden of Crohn’s disease in Europe and the United States, 2000 to 2013: a systematic review. Dig Dis Sci 2015;60:299–312. 25. Yu AP, Cabanilla LA, Wu EQ, et al. The costs of Crohn’s disease in the United States and other Western countries: a systematic review. Curr Med Res Opin 2008;24:319–328. Reprint requests Address requests for reprints to: Gary R. Lichtenstein, MD, University of Pennsylvania School of Medicine, Gastroenterology Division, Department of Internal Medicine, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, Pennsylvania 19104-4283. e-mail: [email protected]; fax: (215) 349-5915. Acknowledgments The authors would like thank the following individuals for their advice and assistance during the study: Thanh G. N. Ton, Adrienne Chung, Devin Incerti, Karen Mulligan, Noe Marquez, and Sarah Beers.

18. Jess T, Frisch M, Simonsen J. Trends in overall and causespecific mortality among patients with inflammatory bowel disease from 1982 to 2010. Clin Gastroenterol Hepatol 2013; 11:43–48.

Conflicts of interest These authors disclose the following: Gary R. Lichtenstein is a consultant for AbbVie, American Regent, Celgene Corporation, CellCeutrix, Eli Lilly, Endo Pharmaceuticals, Ferring, Gilead, Janssen Biotech, Merck, Morphic Therapeutics, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/ Valeant, Shire Pharmaceuticals, Takeda, and UCB, and has received grant/ research support from Janssen Biotech. Gary R. Lichtenstein and Robert N. Baldassano received a grant from Celgene Corporation as consultants to cover costs for this research. Ahva Shahabi, Oliver Díaz Espinosa, Sarah Green, and Michelle Brauer are employees of Precision Health Economics (PHE), a research consultancy that received financial support from Celgene Corporation to conduct this study. Seth A. Seabury is a consultant to PHE and a faculty member at the University of Southern California. Darius N. Lakdawalla is a faculty member at the University of Southern California, a consulting Scientific Advisor at PHE, and an investor in Precision Medicine Group, the parent company of PHE.

19. Loftus CG, Loftus EV Jr, Harmsen WS, et al. Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. Inflamm Bowel Dis 2007;13:254–261.

Funding This study was funded by Celgene Corporation. Seth A. Seabury acknowledges partial support from an unrestricted departmental grant to the Department of Ophthalmology at the University of Southern California.

16. Arias E, Heron M, Xu J. United States Life Tables, 2012. Natl Vital Stat Rep 2016;65:1–65. 17. Card T, Hubbard R, Logan RF. Mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology 2003;125:1583–1590.

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Supplementary Methods Estimating Parameters for the Total Lifetime Cost Markov Model Transition Probabilities. To estimate the transition probability between two stages, we counted the number mTij of transitions from state i to state j that occurred between each consecutive quarter T  1 to T, and the number of individuals in state i at the beginning of each period. The transition probability estimate was computed as:

b p ij ¼

m1ij þ / þ mTij

; T

m1i þ / þ mi

where i and j take values over states Z (zero cost), L (low cost), M (moderate cost), H (high cost), or A (attrition). Attrition occurred after the required first 12 months of continuous enrollment and the effect was eliminated by considering only the following adjusted transition probabilities: ~ij ¼ p

b p ij 1b p iA

where i; j take value over Z, L, M, or H. The previous equation is the probability that an individual is at state j at quarter T given that at quarter T  1, the individual is at state i and there was no attrition. In the Markov model, when an individual started at any of the age or risk groups described previously, we used the calculated transition probability estimates for the incident population for the first year in the model. After the first year, we switched to prevalence transitions. As individuals in a given age group were aged to the next age bracket, transition probabilities were also switched accordingly. To account for aging and therefore death of individuals, we added a final state, D (death). Each quarter, as individuals aged, we computed the probability  q x; x þ14

that an individual of age x died before she

turned xþ1/4 based on annual U.S. Life Tables1 and a simple actuarial interpolation technique.2 This means that transition probabilities were further adjusted to include death as follows:    1 ~ij 1  q x; x þ pxij ¼ p 4 Transition probabilities for the cost states (zero, low, moderate, high) were calculated by age group, further stratified by (1) Crohn’s disease (CD) or ulcerative colitis (UC) and matched control status and (2) incident vs

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prevalent groups. For the nonzero cost states, to remove any strong outliers that can significantly skew the costs used for the high and low categories, costs were trimmed at the top and bottom 0.1% of the distribution. Supplementary Table 1 shows the transition probability matrices for the CD population and control subjects. Supplementary Table 2 shows the transition probability matrices for the UC population and control subjects.

Average Costs per Quarter (Supplementary Table 3) After transition probabilities, the second parameter that entered into the model was the representative costs for each of the states in the model. For individuals in the zero-cost state and for those who died (and therefore will remain in the Death state afterward), the cost $.00 was assigned. For the low-, moderate-, and high-cost states, we took the average over all quarters of the mean costs in each state. Other estimates, such as median or the 75th percentile, were evaluated for diagnostics as a sensitivity analysis; however, the changes were not significant to favor one over the other, particularly as the change in lifetime cost for both cases and control subjects changed by the same order of magnitude. The incremental cost using any of the metrics would be similar. Just as with the transition probabilities, the average costs were grouped by disease (CD/UC), incidence or prevalence status, case or control status, and age-risk group. Supplementary Table 3 shows the representative average costs for each of the stratifications applied with the transition probabilities within the model. It is important to note that when an individual of a certain age transitioned into the next age group in the model, we concurrently switched to the corresponding transition probabilities and average costs for that age group of the prevalent population.

Decomposition of Lifetime Cost by Type of Health Care Cost As our approach to assign a representative quarterly cost for each level (low, moderate, high) is based on quantile decomposition, and quantiles do not have additive properties, we estimate lifetime costs for each health care component by building separate Markov models for type of cost: inpatient, outpatient visit, emergency room, and pharmacy. The lifetime costs obtained for each source of cost are used to estimate the contribution that each type of health care cost has on the total cost. The net contribution (in U.S. dollars) is then obtained by direct application of these proportions to the total lifetime cost. Supplementary Tables 4 and 5 show the contribution of each cost type to the total lifetime cost (discounted) for each disease by age at diagnosis.

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Average Lifetime Cost by Age at Diagnosis and Cost Source By decomposing the lifetime total cost of CD and UC into the source of costs (outpatient visit, inpatient, pharmacy, and emergency room), we could simulate the total lifetime costs by source accruing to CD or UC patients and the matched individuals without CD or UC for patients diagnosed in each age group. Supplementary Figure 1 shows the average lifetime cost of CD patients and the matched individuals without CD or UC, by age at diagnosis. Similarly, Supplementary Figure 2 shows the average lifetime cost of UC patients and the matched individuals without CD or UC, by age at diagnosis.

baseline (Supplementary Figures 3 and 4). Younger age groups continue to have the highest incremental lifetime costs, regardless of status at baseline. The percent difference between the lifetime costs of a patient starting as a high-cost vs zero-cost patient, per age group, is highest among patients who received a diagnosis of CD at 65‒ ‒69 years of age at 16% and similarly at 15% for patients who received a diagnosis of CD at 0‒ ‒11 years of age; the lowest is at 8% for age groups 18‒ ‒29, 30‒ ‒39, and 40‒ ‒49 years of age. For UC, the highest percentage difference is among the pediatric and young adult groups at 21% for patients who received a diagnosis of CD at 0‒ ‒11 years of age and 17% for patients who received a diagnosis of CD at 12‒17 years of age, with the lowest at 9% among those with a diagnosis at 65‒69 years of age.

Incremental Lifetime Cost Differences of Zero- and High-Cost Patients at Baseline For each age group, incremental lifetime costs were calculated for a patient who entered the model at diagnosis as a zero-, low-, moderate-, or high-cost patient at

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References 1.

Arias E, Heron M, Xu J. United States Life Tables, 2012. Natl Vital Stat Rep 2016;65:1–65.

2.

Bowers N, Gerber H, Hickamn J, et al. Actuarial mathematics. 2nd ed. Schaumburg, IL: Society of Actuaries, 1997.

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Supplementary Table 1. Transition Probabilities for Crohn’s Disease Patients and Matched Control Subjects by Age Group and Incident/Prevalent Groups Incident Crohn’s disease patient Age group at diagnosis 0–11 y

12–17 y

18–29 y

30–39 y

40–49 y

50–59 y

60–64 y

65–69 y

70þ y

Prevalent Crohn’s disease patient

Control subject

Control subject

Cost Category

Z

L

M

H

Z

L

M

H

Z

L

M

H

Z

L

M

H

Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H

.472 .078 .020 .014 .530 .074 .029 .022 .570 .121 .042 .036 .510 .101 .038 .035 .515 .076 .028 .027 .490 .056 .020 .017 .463 .045 .021 .019 .371 .032 .011 .015 .538 .024 .014 .031

.517 .793 .392 .175 .441 .792 .383 .222 .395 .744 .369 .279 .447 .757 .375 .280 .435 .779 .403 .257 .470 .791 .423 .264 .495 .798 .427 .285 .602 .814 .415 .283 .406 .793 .477 .333

.008 .104 .450 .293 .018 .104 .427 .329 .022 .096 .447 .299 .033 .103 .440 .290 .035 .111 .421 .292 .027 .117 .417 .279 .028 .118 .414 .271 .014 .115 .432 .280 .028 .133 .374 .270

.003 .025 .139 .518 .011 .030 .161 .427 .013 .038 .142 .386 .010 .039 .147 .394 .015 .034 .147 .425 .014 .036 .140 .440 .014 .039 .138 .425 .014 .040 .142 .422 .028 .049 .136 .366

.610 .383 .175 .134 .651 .328 .168 .121 .712 .256 .137 .121 .652 .214 .091 .093 .651 .159 .068 .048 .644 .110 .040 .030 .634 .086 .027 .026 .610 .054 .019 .023 .649 .039 .015 .029

.326 .466 .428 .274 .286 .519 .433 .275 .236 .584 .421 .327 .291 .625 .422 .337 .299 .682 .435 .287 .308 .731 .442 .277 .324 .758 .435 .275 .347 .788 .423 .288 .311 .794 .443 .300

.048 .110 .290 .214 .046 .113 .287 .241 .041 .114 .320 .220 .042 .116 .348 .246 .037 .122 .366 .249 .035 .120 .390 .264 .027 .115 .407 .282 .032 .116 .414 .290 .020 .119 .404 .306

.016 .041 .106 .378 .017 .040 .112 .364 .012 .046 .122 .332 .015 .045 .139 .324 .013 .038 .131 .416 .014 .039 .128 .429 .015 .040 .130 .417 .012 .042 .143 .400 .020 .049 .137 .364

.314 .050 .017 .012 .479 .062 .024 .022 .519 .078 .029 .023 .454 .060 .019 .021 .459 .047 .013 .014 .446 .035 .010 .012 .453 .032 .014 .017 .428 .024 .008 .018 .585 .016 .013 .032

.657 .822 .377 .179 .485 .801 .388 .217 .440 .773 .418 .273 .512 .795 .397 .266 .508 .818 .373 .247 .521 .837 .348 .242 .509 .836 .352 .261 .538 .829 .383 .288 .379 .813 .438 .306

.020 .103 .445 .314 .022 .108 .436 .301 .026 .115 .405 .284 .021 .110 .433 .289 .020 .105 .463 .282 .020 .096 .494 .289 .022 .096 .483 .295 .022 .108 .455 .285 .019 .123 .404 .290

.010 .025 .161 .495 .014 .029 .152 .461 .014 .034 .148 .420 .012 .035 .150 .424 .014 .031 .151 .457 .013 .032 .148 .457 .015 .035 .150 .427 .013 .039 .154 .409 .016 .047 .145 .372

.559 .407 .236 .120 .668 .329 .161 .123 .713 .260 .132 .122 .648 .215 .094 .082 .638 .165 .063 .049 .636 .106 .038 .027 .617 .083 .027 .028 .615 .054 .014 .021 .662 .038 .016 .030

.351 .440 .454 .278 .267 .518 .440 .309 .234 .582 .423 .315 .298 .625 .417 .323 .312 .676 .429 .291 .321 .733 .436 .277 .334 .755 .441 .292 .357 .787 .429 .275 .301 .797 .430 .294

.067 .115 .201 .226 .047 .111 .283 .240 .039 .113 .321 .237 .041 .118 .354 .237 .035 .120 .377 .255 .029 .123 .395 .260 .033 .121 .400 .263 .021 .119 .413 .286 .024 .119 .407 .298

.023 .038 .109 .376 .018 .042 .115 .328 .013 .045 .124 .327 .014 .042 .135 .357 .014 .039 .131 .405 .015 .038 .130 .435 .016 .041 .132 .417 .007 .040 .144 .418 .012 .045 .147 .378

H, high; L, low; M, moderate; Z, zero.

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Supplementary Table 2. Transition Probabilities for Ulcerative Colitis Patients and Matched Control Subjects by Age Group and Incident/Prevalent Groups Incident Ulcerative colitis patient Age group at diagnosis 0–11 y

12–17 y

18–29 y

30–39 y

40–49 y

50–59 y

60–64 y

65–69 y

70þ y

Prevalent Ulcerative colitis patient

Control subject

Control subject

Cost Category

Z

L

M

H

Z

L

M

H

Z

L

M

H

Z

L

M

H

Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H Z L M H

.506 .095 .033 .013 .484 .103 .049 .039 .544 .116 .061 .046 .474 .101 .047 .035 .461 .080 .034 .024 .458 .054 .020 .019 .458 .044 .018 .017 .420 .029 .011 .016 .614 .022 .013 .029

.461 .766 .422 .183 .465 .741 .445 .225 .406 .723 .450 .257 .465 .728 .472 .290 .483 .753 .468 .271 .487 .775 .479 .283 .493 .784 .472 .302 .537 .798 .467 .302 .347 .799 .467 .334

.030 .115 .400 .267 .036 .125 .371 .265 .037 .126 .365 .251 .049 .132 .356 .240 .043 .131 .372 .244 .037 .134 .370 .255 .034 .131 .376 .263 .028 .131 .381 .270 .026 .129 .379 .286

.003 .024 .145 .537 .015 .032 .136 .472 .013 .035 .125 .446 .012 .039 .124 .435 .013 .036 .126 .461 .019 .038 .131 .444 .015 .041 .134 .418 .015 .041 .141 .412 .013 .051 .141 .350

.619 .428 .216 .133 .654 .346 .159 .125 .720 .263 .150 .133 .655 .225 .097 .097 .644 .170 .073 .055 .639 .111 .043 .029 .632 .087 .029 .025 .621 .058 .016 .021 .681 .037 .015 .028

.311 .437 .418 .224 .280 .507 .433 .293 .224 .580 .418 .325 .288 .621 .406 .319 .302 .675 .421 .289 .316 .731 .434 .267 .327 .756 .437 .274 .343 .790 .415 .273 .282 .794 .446 .305

.053 .098 .283 .181 .046 .103 .303 .254 .042 .114 .307 .216 .043 .111 .358 .249 .039 .117 .379 .241 .032 .121 .392 .264 .029 .119 .407 .259 .024 .113 .433 .278 .020 .120 .402 .301

.017 .037 .084 .462 .020 .044 .105 .329 .014 .043 .125 .326 .014 .043 .139 .335 .015 .038 .126 .416 .013 .037 .130 .440 .012 .038 .127 .441 .013 .039 .137 .428 .017 .049 .137 .366

.404 .081 .032 .009 .513 .091 .030 .034 .528 .095 .038 .036 .429 .075 .030 .024 .439 .060 .025 .017 .414 .043 .016 .014 .436 .038 .017 .018 .374 .024 .010 .013 .516 .018 .010 .025

.534 .756 .469 .236 .442 .759 .440 .213 .426 .767 .382 .244 .515 .775 .426 .235 .502 .776 .469 .242 .534 .791 .470 .250 .528 .791 .474 .285 .577 .804 .461 .307 .447 .803 .460 .337

.049 .126 .372 .264 .032 .117 .402 .272 .035 .105 .435 .281 .044 .119 .402 .273 .046 .133 .371 .257 .039 .132 .377 .269 .024 .131 .379 .264 .040 .130 .383 .278 .024 .128 .390 .282

.014 .038 .126 .491 .014 .033 .129 .481 .011 .033 .145 .439 .013 .031 .142 .468 .013 .031 .135 .485 .014 .034 .137 .467 .012 .040 .130 .434 .009 .042 .146 .402 .013 .051 .139 .356

.605 .380 .243 .175 .659 .323 .149 .104 .706 .265 .129 .117 .655 .219 .096 .082 .650 .169 .070 .054 .635 .112 .042 .034 .640 .084 .030 .028 .622 .051 .012 .025 .681 .038 .015 .030

.317 .462 .386 .299 .284 .531 .408 .286 .241 .581 .412 .327 .291 .623 .418 .318 .299 .675 .428 .271 .317 .729 .436 .277 .316 .756 .435 .293 .347 .792 .414 .280 .280 .789 .450 .320

.053 .111 .240 .237 .040 .104 .334 .246 .040 .109 .328 .247 .042 .116 .353 .237 .036 .118 .381 .247 .034 .120 .397 .258 .027 .120 .399 .274 .018 .117 .426 .283 .021 .123 .399 .291

.026 .047 .132 .289 .018 .042 .109 .364 .013 .046 .132 .309 .013 .043 .132 .363 .015 .038 .121 .428 .014 .039 .126 .432 .016 .040 .136 .405 .012 .040 .148 .413 .018 .050 .136 .360

H, high; L, low; M, moderate; Z, zero.

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Supplementary Table 3. Average Cost for Each Cost Category Applied to the Model Age Group (y) Cost Group

0‒11

12‒17

18‒29

30‒39

Incident CD population Zero $0 $0 $0 $0 Low $1979 $2406 $1695 $1173 Moderate $13,052 $12,838 $9744 $7571 High $44,310 $38,461 $31,843 $28,051 Matched non-CD/UC population to the incident CD population Zero $0 $0 $0 $0 Low $217 $235 $258 $303 Moderate $888 $1156 $1462 $1763 High $5867 $10,392 $14,307 $12,548 Prevalent CD population Zero $0 $0 $0 $0 Low $2380 $2976 $2678 $2472 Moderate $12,103 $13,669 $11,724 $11,261 High $35,530 $42,206 $33,945 $31,132 Matched non-CD/UC population to the prevalent CD population Zero $0 $0 $0 $0 Low $207 $244 $266 $308 Moderate $801 $1232 $1497 $1793 High $7279 $7406 $11,359 $12,818 Incident UC population Zero $0 $0 $0 $0 Low $1058 $1025 $955 $953 Moderate $6720 $5693 $5056 $4604 High $33,082 $28,893 $24,975 $22,893 Matched non-CD/UC population to the incident UC population Zero $0 $0 $0 $0 Low $200 $232 $244 $290 Moderate $770 $1142 $1356 $1659 High $5605 $6766 $10,828 $11,777 Prevalent UC population Zero $0 $0 $0 $0 Low $757 $975 $1181 $1199 Moderate $4213 $5246 $6297 $5891 High $25,034 $26,273 $22,733 $22,682 Matched non-CD/UC population to the prevalent UC population Zero $0 $0 $0 $0 Low $213 $238 $259 $308 Moderate $762 $1158 $1458 $1777 High $5195 $8168 $10,695 $12,582

40‒49

50‒59

60‒64

65‒69

70þ

$0 $1214 $7450 $30,532

$0 $1383 $7861 $36,116

$0 $1455 $7627 $38,291

$0 $1726 $8784 $42,393

$0 $1824 $8890 $38,491

$0 $376 $2145 $15,705

$0 $503 $2777 $20,484

$0 $603 $3239 $25,338

$0 $754 $3939 $24,587

$0 $866 $4449 $28,540

$0 $2270 $10,906 $34,519

$0 $2101 $10,258 $35,955

$0 $2069 $10,041 $37,712

$0 $2126 $9750 $39,815

$0 $2253 $10,256 $45,134

$0 $390 $2186 $15,331

$0 $513 $2750 $20,098

$0 $607 $3055 $20,714

$0 $748 $3707 $26,803

$0 $897 $4412 $28,281

$0 $1006 $4955 $26,140

$0 $1212 $5724 $31,736

$0 $1362 $6265 $34,803

$0 $1472 $6513 $34,186

$0 $1671 $7579 $37,437

$0 $371 $2122 $15,639

$0 $495 $2750 $19,942

$0 $605 $3244 $23,532

$0 $749 $3890 $27,172

$0 $892 $4509 $29,164

$0 $1193 $5263 $22,590

$0 $1375 $5896 $26,066

$0 $1470 $6054 $28,305

$0 $1574 $6090 $28,646

$0 $1738 $7056 $35,952

$0 $370 $2111 $14,037

$0 $492 $2620 $19,396

$0 $583 $3081 $23,368

$0 $739 $3745 $24,724

$0 $907 $4559 $29,901

CD, Crohn’s disease; UC, ulcerative colitis.

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Supplementary Table 4. Decomposition of Average Lifetime Costs for CD Patients by Age at Diagnosis Age at diagnosis

Inpatient (%)

Outpatient visit (%)

CD population 0–11 y 18.7 12–17 y 20.1 18–29 y 20.5 30–39 y 21.3 40–49 y 23.0 50–59 y 25.2 60–64 y 27.6 65–69 y 28.8 70þ y 29.9 Matched non-CD/UC population 0–11 y 23.5 12–17 y 25.1 18–29 y 25.8 30–39 y 25.4 40–49 y 26.4 50–59 y 28.5 60–64 y 30.9 65–69 y 32.2 70þ y 33.2

ER (%)

Pharmacy (%)

52.1 48.5 46.9 46.9 46.8 46.5 46.7 47.0 47.3

2.6 3.2 3.3 3.1 2.8 2.7 2.7 2.8 3.0

26.6 28.3 29.3 28.8 27.4 25.6 23.0 21.4 19.9

50.7 50.5 50.4 50.8 50.2 49.0 47.7 46.9 46.3

6.1 5.6 4.9 4.2 3.7 3.4 3.2 3.4 3.7

19.7 18.8 19.0 19.5 19.7 19.1 18.2 17.5 16.8

CD, Crohn’s disease; ER, emergency room; UC, ulcerative colitis.

Supplementary Table 5. Decomposition of Average Total Lifetime Costs for UC Patients by Age at Diagnosis Age at diagnosis

Inpatient (%)

Outpatient visit (%)

UC population 0–11 y 23.1 12–17 y 21.7 18–29 y 21.4 30–39 y 21.4 40–49 y 22.7 50–59 y 24.9 60–64 y 27.5 65–69 y 28.9 70þ y 30.6 Matched non-CD/UC population 0–11 y 24.4 12–17 y 26.2 18–29 y 26.1 30–39 y 25.2 40–49 y 26.2 50–59 y 28.7 60–64 y 31.0 65–69 y 32.1 70þ y 33.7

ER (%)

Pharmacy (%)

46.4 44.9 44.6 45.5 45.7 45.3 45.1 45.1 44.8

3.0 3.3 3.2 2.9 2.8 2.7 2.8 2.9 3.0

27.4 30.1 30.7 30.2 28.8 27.1 24.6 23.2 21.6

51.5 49.6 50.2 51.3 50.8 49.6 48.5 48.1 47.6

6.0 5.4 4.8 4.2 3.7 3.3 3.2 3.3 3.5

18.0 18.8 18.8 19.4 19.3 18.4 17.3 16.5 15.2

CD, Crohn’s disease; ER, emergency room; UC, ulcerative colitis.

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$9,00,000 $8,48,084 $7,93,309

$8,00,000

$7,24,151 $6,73,920 $6,23,002 $6,00,000

$5,54,684 $4,72,984

$5,00,000

$4,32,181 $3,71,264

$4,00,000

$3,00,000

$2,00,000 $1,40,372

$1,68,678

$1,89,319

$2,11,025

$2,30,390 $2,40,528 $2,30,650 $2,18,492

$1,93,650

$1,00,000

0-11

12-17

18-29

30-39

40-49

50-59

60-64

65-69

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

CD paent

Matched control

$CD paent

Average Lifeme Cost (2016 USD)

$7,00,000

70+

Age at diagnosis (years) Outpaent visit

Inpaent

Pharmacy

ER

FLA 5.6.0 DTD
YJCGH56628_proof
5 November 2019
10:50 pm
ce OB

Supplementary Figure 1. Average lifetime costs of Crohn’s disease (CD) by age at diagnosis and cost source. Matched control subjects include individuals without CD or ulcerative colitis randomly selected during propensity score matching. ER, emergency room; USD, U.S. dollars.

-

2019

Lifetime Cost of Inflammatory Bowel Disease

9.e8

$9,00,000

$8,00,000

Average Lifeme Cost (2016 USD)

$7,00,000

$6,00,000

$5,00,000 $4,75,580

$4,62,711 $4,47,579 $4,34,431

$4,17,612 $3,99,207

$4,00,000

$3,55,073

$3,26,596 $2,90,948

$3,00,000

$2,00,000

$1,88,950 $1,91,918 $1,86,922 $1,94,458 $1,85,927 $1,88,485 $1,73,902 $1,66,334

$1,42,920

$1,00,000

0-11

12-17

18-29

30-39

40-49

50-59

60-64

65-69

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

UC paent

Matched control

$UC paent

Supplementary Figure 2. Average lifetime costs of ulcerative colitis (UC) by age at diagnosis and cost source. Matched control subjects include individuals without Crohn’s disease or UC randomly selected during propensity score matching ER, emergency room; USD, U.S. dollars.

70+

Age at diagnosis (years) Outpaent visit

Inpaent

Pharmacy

ER

Supplementary Figure 3. The incremental lifetime costs by age group for a Crohn’s disease patient who starts the model as a zero-, low-, moderate-, or high-cost patient. USD, U.S. dollars. FLA 5.6.0 DTD
YJCGH56628_proof
5 November 2019
10:50 pm
ce OB

9.e9

Lichtenstein et al

Clinical Gastroenterology and Hepatology Vol.

-,

No.

-

Age at diagnosis (years)

Supplementary Figure 4. The incremental lifetime costs by age group for an ulcerative colitis patient who starts the model as a zero-, low-, moderate-, or high-cost patient. USD, U.S. dollars.

70+

$14,000

65-69

$13,659

$14,562

$-

$26,065

$21,635

$4,430

0-11

$25,649

$20,134

$5,515

12-17

$24,633

$18,232

$6,401

18-29

$24,690

$16,978

$7,711

30-39

$25,519 $25,100

$15,886

$9,214

40-49

$26,473

$13,789

$10,957

50-59

$27,372

$13,713

$12,684

60-64

$27,792

$13,792

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

Average Lifeme Cost (2016 USD) Matched individual without CD/UC

Incremental lifeme cost for CD paent

FLA 5.6.0 DTD
YJCGH56628_proof
5 November 2019
10:50 pm
ce OB

Supplementary Figure 5. The average annual lifetime costs by age at diagnosis for Crohn’s disease (CD) patients and matched nonCD/ulcerative colitis (UC) individuals.

-

2019

Lifetime Cost of Inflammatory Bowel Disease

$9,541

$5,398

Age at diagnosis (years)

12-17

Supplementary Figure 6. The average annual lifetime costs by age at diagnosis for ulcerative colitis (UC) patients and matched non-Crohn’s disease (CD)/UC individuals.

$8,942

$6,224

18-29

$10,246

$4,224

0-11 $-

$5,000

$15,859

$8,327

$7,532

30-39

$16,731

$7,683

$9,048

40-49

$18,290

$7,307

$10,983

50-59

$19,719

$6,776

$12,944

60-64

$20,676

$6,728

$13,947

65-69

$21,286

$6,774

$14,512

70+

$10,000

$15,165 $14,940 $14,470 $15,000

$20,000

Average Lifeme Cost (2016 USD) Matched individual without CD/UC

9.e10

Incremental lifeme cost for UC paent

FLA 5.6.0 DTD
YJCGH56628_proof
5 November 2019
10:50 pm
ce OB

$25,000