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. 2020 Mar 6;99(10):e18925. doi: 10.1097/MD.0000000000018925

Practical strategy for optimizing the timing of anti-tumor necrosis factor-α therapy in Crohn disease

A nationwide population-based study

Min Seob Kwak a,b, Jae Myung Cha a,b,∗, Ji Hyun Ahn b, Min Kyu Chae b, Sara Jeong b, Hun Hee Lee c
Editor: Bülent Kantarçeken
PMCID: PMC7478703  PMID: 32150045

Supplemental Digital Content is available in the text

Keywords: biological therapy, Crohn's disease, Outcome

Abstract

There is little consensus on the optimal timing of anti-tumor necrosis factor (anti-TNF) therapy to decrease the rates of hospitalization and surgery in Crohn disease (CD). We aimed to assess the real-world outcomes of anti-TNF therapy and estimate the optimal timing of anti-TNF therapy in Korean patients with CD.

Claims data were extracted from the Korean Health Insurance Review and Assessment Service database. Incident patients diagnosed with CD between 2009 and 2016, with at least 1 anti-TNF drug prescription, and with follow-up duration > 6 months were stratified according to the number of relapses prior to initiation of anti-TNF therapy: groups A (≤1 relapse), B (2 relapses), C (3 relapses), and D (≥4 relapses). The cumulative survival curves free from emergency hospitalization (EH) and surgery were compared across groups.

Among the 2173 patients analyzed, the best and worst prognoses were noted in groups A and D, respectively. The incidences of EH and surgery decreased significantly as the use of anti-TNF agents increased. The 5-year rate of hospitalization was significantly lower in group A than in groups C and D (P = .004 and .020, respectively), but similar between groups A and B. The 5-year rate of surgery was lower in group A than in group C (P = .024), but similar among groups A, B, and D.

In Asian patients with CD, anti-TNF therapy reduces the risk of EH and surgery and should be considered before three relapses, regardless of disease duration.

1. Introduction

Crohn disease (CD) is a chronic disease with relapsing-remitting course and protracted impact.[1] In CD patients, disease flares and complications may result in the need for hospitalization and even surgery,[2,3] with high direct healthcare costs.[4,5] CD treatment strategies have changed remarkably over the past decades, and the early use of anti-tumor necrosis factor (anti-TNF) therapies is now preferred, with the goal of altering the progressive and destructive course frequently observed in CD.[6–8] However, the most substantial improvement in the rate of CD-related hospitalization and surgery has been achieved since the introduction of biological treatments.[9–12] Population-based studies are typically required in order to obtain general insight into the natural course of a disease and to subsequently issue recommendations for treatment. However, there is insufficient evidence from population level to clarify the natural course of CD in Asian populations.

The optimal timing of anti-TNF therapy represents another important concern in CD. In current clinical practice, most CD patients who start anti-TNF therapy continue to use anti-TNF therapy for a long time, despite the high cost and ongoing safety concerns. The guidelines issued by the European Crohn and Colitis Organization in 2016 recommend trying corticosteroid treatment before starting anti-TNF agents,[13] but no further recommendations are made regarding the timing of anti-TNF therapy. The Korean guidelines issued in 2017[14] also recommend the use of anti-TNF therapy to induce remission of moderate-to-severe CD. However, there is still little agreement on the optimal timing of anti-TNF therapy for CD, especially in Asian populations.

The aim of this nationwide population-based study was to assess the real-world outcomes of anti-TNF treatment in patients with CD, as well as to estimate the optimal timing of anti-TNF therapy to improve the long-term outcomes of CD.

2. Patients and methods

2.1. Data sources and study population

This was a retrospective nationwide population-based cohort study conducted using the database maintained by the Korean Health Insurance Review and Assessment Service (HIRA), which contains all inpatient and outpatient claims data collected nationwide since 1989.[15] HIRA contains the adjusted medical and pharmacy claims for the entire Korean population because all clinics and hospitals in Korea submit claims data to the HIRA in order to obtain reimbursement of medical costs from the Korean Government, which funds public healthcare based on a single-payer system.[15] The HIRA provided de-identified data on socio-demographic characteristics (sex, age, and medical-aid program), information related to the healthcare service provided during a given visit (diagnosis, procedures, treatments, prescriptions), type of healthcare service provider (primary, secondary, or tertiary hospital), and the claim date.[15] The HIRA database records diagnosis information based on the 6th edition of the Korean Classification of Disease, which is a modified version of the International Classification of Disease, 10th revision, adapted for use within the Korean healthcare system.[15]

We extracted all claims data pertaining to incident CD patients and recorded in the HIRA database between 2009 and 2016. Such patients were identified based on the diagnostic code of CD (K50) and a simultaneous prescription of relevant drugs.[16] We only included patients followed up for at least 6 months after diagnosis. In South Korea, anti-TNF agents have been covered by insurance for the treatment of patients with CD since October 2010 with strict criteria for reimbursement coverage. An inadequate response to conventional treatment with corticosteroids and/or thiopurines and moderate or severe disease activity are mandatory for government reimbursement coverage.

Our primary goal was to assess the real-world outcomes of treatment with anti-TNF agents such as infliximab and adalimumab. The secondary goal was to determine the optimal timing of anti-TNF therapy for improving the long-term outcomes of CD in Korean patients. This retrospective cohort study was reviewed and approved by the Institutional Review Board of the Kyung Hee University Hospital at Gangdong (KHNMC IRB 2018-01-014). The need for informed consent was waived on account of the fact that all data used in this study were de-identified.

2.2. Definition of variables

Relapse was defined as the prescription of ≥30 mg oral or intravenous prednisone (or equivalent) per day. In this study, CD patients were divided into 4 groups according to the number of relapses before initiation of anti-TNF therapy: group A, ≤1 relapse; group B, 2 relapses; group C, 3 relapses; and group D, ≥4 relapses. Emergency hospitalization (EH) was defined as hospitalization via the emergency department for symptoms associated with a main diagnosis of CD and requiring > 30 mg prednisolone (or equivalent) per day.[17] Surgery for CD was defined as bowel resection surgery as described within the Current Procedural Terminology code.[18] For each month, the rate of EH or surgery was obtained as the ratio between the number of corresponding events and the total number of CD-related claims in that month. Early use of anti-TNF therapy was defined as initiation of anti-TNF agents (ie, first prescription) within 24 months of the initial diagnosis, per the approach used in previous studies.[19–21]

The regularity of treatment use was based on the frequency of treatment prescription, per the approach employed in previous studies and pharmacokinetics on immunomodulators[22,23] and anti-TNF agents.[24,25] During the follow-up periods after a diagnosis of CD, regular and irregular use of immunomodulators was defined if prescriptions for immunomodulatory drugs covered ≥50% or < 50%, respectively.[22,23] Regarding infliximab therapy, regular and irregular use was defined as the prescription of infliximab at intervals of ≤16 weeks or > 16 weeks, respectively, during the maintenance phase.[24] Regarding adalimumab therapy, regular and irregular use was defined as the prescription of adalimumab at intervals of ≤4 weeks or > 4 weeks, respectively, during the maintenance phase.[25]

2.3. Statistical analyses

We used chi-square tests for categorical variables and independent sample t tests for continuous variables, as appropriate, in the descriptive analysis comparing patient characteristics among non-matched patients stratified according to the number of relapses (groups A–D). After matching, differences between groups were tested using McNemar test for categorical variables and paired t tests for continuous variables.

To account for the potential effect of covariates on each outcome, we created a propensity score combining the covariates of age, sex, regularity of medication use, and severity of pre-existing comorbid conditions, which was quantified using the Charlson Comorbidity Index (CCI), an index adapted for use with health administrative data [26–28]. The cumulative survival curves were compared across groups A–D using the log-rank test. Correlation analyses were performed to quantify the relationship between the prescription of anti-TNF agents and the rates of CD-related EH and surgery, with the results evaluated using Spearman rank correlation test. The statistical analyses were performed using R version 3.5.1.[29,30] All significant thresholds were set at a 2-sided P-value of .05.

3. Results

Of the 10,425 incident patients diagnosed with CD between January 2009 and December 2016, 3030 patients had at least 1 claim for anti-TNF agents following diagnosis (Fig. 1). After excluding 328 patients followed up for < 6 months, 2702 CD patients were included in this study and stratified into four groups according to the number of relapses prior to initiation of anti-TNF therapy: group A (n = 2,098), group B (n = 396), group C (n = 119), and group D (n = 89).

Figure 1.

Figure 1

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Patient selection flowchart. The patients were stratified according to the number of relapses experienced from diagnosis until initiation of anti-TNF therapy. TNF, tumor necrosis factor.

3.1. Patient characteristics

In the overall population, the median follow-up duration was 55.7 months (interquartile range, 33.5–77.2 months). The mean time from diagnosis until initiation of anti-TNF therapy ranged from 16.7 to 48.0 months across groups A–D (Tables 1 and 2). The groups were well matched with respect to major characteristics including age, sex distribution, CCI, and regularity of use of immunomodulatory and anti-TNF therapy.

Table 1.

Relationship between patient characteristics and emergency hospitalization in Crohn disease, upon stratification according to the number of relapses.

3.1.

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Table 2.

Relationship between patient characteristics and surgery rates in Crohn disease, upon stratification according to the number of relapses.

3.1.

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The effect of medication use on each outcome (EH and surgery rates) was analyzed after propensity score matching with a ratio of 3:3:1:1 for groups A:B:C:D, using group D as reference. The 4 groups were similar in terms of all parameters analyzed, except regarding the effect of regularity of use of anti-TNF therapy on the rate of EH (group A vs group D: P = .019). Patients in group D (ie, with ≥4 relapses) were older and more likely to be men.

3.2. Relationship between Anti-TNF agent use and major outcomes

Figure 2 illustrates the time trends for the incidences of EH and surgery, as well as those for the prescription of anti-TNF medication in patients with CD. From 2009 to 2016, the frequency of hospital visits for anti-TNF prescription increased 7.7-fold, from 3.8% to 29.3%, whereas the average annual rates of EH and surgery decreased by 2.0% (95% confidence interval [CI] for the change: -4.3% to -1.6%) and 3.0% (95% CI for the change: -3.5% to -0.6%), respectively. There was an inverse and significant relationship between the change in the frequency of visits for anti-TNF prescriptions and the change in the annual rates of EH and surgery during the study period (for EH rates: r =  -0.26, P < .001; for surgery rates: r =  -0.35, P = .004).

Figure 2.

Figure 2

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In Crohn's disease, the use of anti-TNF therapy correlates inversely with the monthly rates of emergency hospitalization and surgery. Data cover the patients diagnosed between 2009 and 2016. TNF= tumor necrosis factor.

3.3. Relationship between the number of relapses and major outcomes

Figure 3 shows the Kaplan-Meier estimates of the probability of survival free from EH and surgery following a diagnosis of CD. In groups A, B, C, and D, respectively, the mean duration of survival free from EH was 30.5 ± 26.3, 40.0 ± 20.7, 55.4 ± 23.4, and 56.1 ± 23.8 months (P < .001) (Fig. 3A), whereas the mean duration of survival free from surgery was 32.0 ± 24.6, 33.0 ± 22.8, 54.2 ± 21.8, and 66.0 ± 19.1 months (P < .001) (Fig. 3B). The 5-year rate of EH was 13.3%, 11.5%, 32.2%, and 25.3% in groups A, B, C, and D, respectively (Fig. 3A), with significantly lower rates in group A than in groups C and D (P = .004 and P = .020, respectively), but with similar rates between groups A and B (P = .780) (Fig. 3A). The 5-year rate of surgery was 8.3%, 12.9%, 21.4%, and 22.1% in groups A, B, C, and D, respectively (Fig. 3B), with significantly lower rates in group A than in group C (P = .024), but with similar rates across groups A, B, and D (A vs B, P = .229; A vs D, P = .159) (Fig. 3B).

Figure 3.

Figure 3

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Kaplan-Meier survival analysis for emergency hospitalization (A) and surgery (B) in patients with Crohn disease. The patients were stratified according to the number of relapses until initiation of anti-tumor necrosis factor therapy: group A, ≤1 relapse; group B, 2 relapses; group C, 3 relapses; group D, ≥4 relapses. TNF = tumor necrosis factor.

3.4. Optimal timing of anti-TNF therapy

To clarify the efficacy of early anti-TNF therapy, the patients with ≤2 relapses (ie, groups A and B) were divided into subgroups according to the time interval from diagnosis until initiation of anti-TNF therapy (early vs late use) (Supplementary Table 1). After propensity score matching, most baseline parameters were comparable between the two subgroups. However, regular use of anti-TNF therapy was more common among patients who started anti-TNF therapy at > 24 months after diagnosis than among those who started such therapy early, although the difference did not reach statistical significance. The probability of survival free from EH and surgery did not differ between the 2 subgroups (early vs late initiation of anti-TNF therapy) (P = .798 and P = .334, respectively) (Supplementary Fig. 1).

4. Discussion

To our knowledge, this was the largest nationwide population-based study to assess the natural course of CD and focus on major outcomes such as EH and surgery. Moreover, we covered the period from 2009 to 2016, during which there was a substantial increase in the use of anti-TNF agents in South Korea. Our results suggest that anti-TNF therapy may decrease the risk of EH and surgery. Indeed, during the study period, the rates of EH and surgery decreased despite an increase in the prevalence of CD.[16] The present results have also helped us identify a practical strategy for optimal timing of anti-TNF therapy in CD patients, which focuses on the number of relapses rather than on disease duration. These findings can be used to inform clinical decision making, improve patient care, and increase the efficiency of healthcare services provided to CD patients.

Studies conducted after the introduction of biologics have reported inconsistent results regarding hospital utilization among patients with inflammatory bowel disease (IBD), likely because hospital utilization is a multifactorial issue. A report based on a European inception cohort reported an inverse relationship between healthcare utilization and the use of anti-TNF agents in CD patients.[31] On the contrary, other studies reported that the emergency department utilization rate among IBD patients increased even after the introduction of biologics.[11,32] Similar inconsistencies are noted among reports regarding surgery rates in IBD patients after the introduction of anti-TNF therapy.[33–37] These inconsistent findings regarding both emergency department utilization and surgery rates may be influenced by factors other than anti-TNF therapy, such as improved disease detection capabilities, introduction of practice guidelines, continuing medical education on IBD, and a shift in care from surgeons to gastroenterologists.[33] The present nationwide cohort study suggests that, in South Korea, both emergency department utilization and surgery rates have decreased significantly since the introduction of anti-TNF therapy. Although the improved clinical outcomes noted in our study can be partly explained by other factors such as improved access to specialized IBD care in tertiary centers.[12] the efficacy of anti-TNF therapy is likely the main explanation in the Korean population, in which the prevalence of CD is low. In fact, there was little effort to promote awareness of CD in South Korea before 2010, and no framework for educating the patients in this direction was implemented, yet the rates of EH and surgery have decreased continuously since the introduction of anti-TNF agents, as revealed by our nationwide population-based study.

Current guidelines strongly recommend that, in CD patients, anti-TNF therapy should be used when other medications are either poorly tolerated or insufficiently effective.[38–40] Furthermore, continued long-term use of anti-TNF agents is recommended in even those who attain remission, because there is little consensus on when to de-escalate or stop anti-TNF agents.[41,42] There is an increasing preference for the early initiation of anti-TNF therapy after diagnosis, with the goal to prevent the development of complications and to decrease corticosteroid exposure.[6] However, there is no universal definition for “early anti-TNF use” in the literature. In many studies, “early anti-TNF use” was described either with respect to the disease course (time since diagnosis)[19–21,43] or with respect to the treatment course (use in patients naïve to immunomodulators, or earlier use than would be done in the conventional step-up treatment approach).[6,44–46] These definitions were mostly based on clinical trials supporting the role of anti-TNF drugs in improving the natural course of the disease.[6,47,48] The current study is the first nationwide population-based study supporting such a claim based on real-world data, especially in an Asian population.

The availability of anti-TNF agents for CD may differ across countries due to differences in healthcare systems and national guidelines. Therefore, the optimal timing for initiation of anti-TNF therapy may also differ across countries. In this context, it is highly desirable to develop a simplified, objective, and practical suggestion for determining the optimal starting time of anti-TNF therapy. Based on our study, which employed real-world data, the optimal outcomes can be obtained when anti-TNF agents are started before three relapses. Basing the decision only on disease duration is not expected to be as effective, as we observed no difference between the outcomes of early and late anti-TNF therapy among patients with ≤2 relapses. Therefore, the present observations may lay the foundation of a new framework for deciding the optimal timing for starting anti-TNF therapy in CD patients. Nevertheless, prospective clinical trials are warranted to clarify this aspect.

Several limitations of our study merit discussion. First, an important weakness of the study is related to the accuracy of CD diagnosis. Because of the nature of claims data, we could not exclude the bias of inadequate diagnosis. However, the reliability of identifying IBD patients using information from the HIRA database was validated in a previous study.[16] Second, we cannot exclude the effect of unmeasured confounders in the descriptive analysis, and cannot clarify the causal relationship between the clinical outcomes and anti-TNF therapy in CD. Third, the lack of clinical information, such as a disease activity, on individual patients represents another major drawback of claims data. Patients with predictors of poor prognosis (extensive small-bowel involvement, perianal involvement, or extra-intestinal manifestations) may have been included in the subgroup with early initiation of anti-TNF therapy.[6,49] In the light of these limitations, it is important to establish larger, nationwide prospective registries for CD cohorts in order to address the specific questions raised by the present study.

5. Conclusion

The present study not only confirms the beneficial effects of anti-TNF therapy for reducing the rates of hospitalization and surgery due to CD, but also suggests that the decision to start anti-TNF therapy should take into consideration the number of relapses rather than disease duration. Anti-TNF agents should be considered in patients who have had 2 relapses, regardless of disease duration.

Author contributions

Conceptualization: Jae Myung Cha, Min Seob Kwak.

Data curation: Min Seob Kwak, Ji Hyun Ahn.

Formal analysis: Min Seob Kwak, Min Kyu Chae, Hun Hee Lee.

Investigation: Sara Jeong, Hun Hee Lee.

Writing – original draft: Jae Myung Cha, Min Seob Kwak.

Supplementary Material

Supplemental Digital Content
medi-99-e18925-s001.docx (65.7KB, docx)

Supplementary Material

Supplemental Digital Content
medi-99-e18925-s002.doc (110.5KB, doc)

Footnotes

Abbreviations: anti-TNF = anti-tumor necrosis factor, CD = Crohn disease, EH = Emergency hospitalization, HIRA = Health Insurance Review and Assessment Service.

How to cite this article: Kwak MS, Cha JM, Ahn JH, Chae MK, Jeong S, Lee HH. Practical strategy for optimizing the timing of anti-tumor necrosis factor-α therapy in Crohn's disease: A nationwide population-based study. Medicine. 2020;99:10(e18925).

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), which is funded by the Korean Ministry of Science, ICT and Future Planning [grant number NRF-2017R1E1A1A01076359]. This work was also supported by a grant from Kyung Hee University in 2018 (KHU-20180930).

The authors have no conflicts of interest to disclose.

Supplemental Digital Content is available for this article.

References

  • [1].Loftus EV., Jr Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126:1504–17. [DOI] [PubMed] [Google Scholar]
  • [2].Longobardi T, Bernstein CN. Utilization of health-care resources by patients with IBD in Manitoba: a profile of time since diagnosis. Am J Gastroenterol 2007;102:1683–91. [DOI] [PubMed] [Google Scholar]
  • [3].Longobardi T, Jacobs P, Bernstein CN. Utilization of health care resources by individuals with inflammatory bowel disease in the United States: a profile of time since diagnosis. Am J Gastroenterol 2004;99:650–5. [DOI] [PubMed] [Google Scholar]
  • [4].Bernstein CN, Nabalamba A. Hospitalization, surgery, and readmission rates of IBD in Canada: a population-based study. Am J Gastroenterol 2006;101:110–8. [DOI] [PubMed] [Google Scholar]
  • [5].Xu J, Tang M, Shen J. Trends and factors affecting hospitalization costs in patients with inflammatory bowel disease: a two-center study over the past decade. Gastroenterol Res Pract 2013;2013:267630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660–7. [DOI] [PubMed] [Google Scholar]
  • [7].Baert F, Caprilli R, Angelucci E. Medical therapy for Crohn's disease: top-down or step-up? Dig Dis 2007;25:260–6. [DOI] [PubMed] [Google Scholar]
  • [8].Ghazi LJ, Patil SA, Rustgi A, et al. Step up versus early biologic therapy for Crohn's disease in clinical practice. Inflamm Bowel Dis 2013;19:1397–403. [DOI] [PubMed] [Google Scholar]
  • [9].Ramadas AV, Gunesh S, Thomas GA, et al. Natural history of Crohn's disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates. Gut 2010;59:1200–6. [DOI] [PubMed] [Google Scholar]
  • [10].Samuel S, Ingle SB, Dhillon S, et al. Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis. Inflamm Bowel Dis 2013;19:1858–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Nguyen GC, Tuskey A, Dassopoulos T, et al. Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004. Inflamm Bowel Dis 2007;13:1529–35. [DOI] [PubMed] [Google Scholar]
  • [12].Nguyen GC, Nugent Z, Shaw S, et al. Outcomes of patients with Crohn's disease improved from 1988 to 2008 and were associated with increased specialist care. Gastroenterology 2011;141:90–7. [DOI] [PubMed] [Google Scholar]
  • [13].Gomollon F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management. J Crohns Colitis 2017;11:3–25. [DOI] [PubMed] [Google Scholar]
  • [14].Park JJ, Yang SK, Ye BD, et al. Second Korean guidelines for the management of Crohn's disease. Intest Res 2017;15:38–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Kim J-A, Yoon S, Kim L-Y, et al. Towards actualizing the value potential of Korea Health Insurance Review and Assessment (HIRA) data as a resource for health research: strengths, limitations, applications, and strategies for optimal use of HIRA data. J Korean Med Sci 2017;32:718–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Kwak MS, Cha JM, Lee HH, et al. Emerging trends of inflammatory bowel disease in South Korea: a nationwide population-based study. J Gastroenterol Hepatol 2018. [DOI] [PubMed] [Google Scholar]
  • [17].Carter MJ, Lobo AJ, Travis SPL. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53: suppl 5: v1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Hirsch JA, Leslie-Mazwi TM, Nicola GN, et al. Current procedural terminology; a primer. J Neurointerv Surg 2015;7:309–12. [DOI] [PubMed] [Google Scholar]
  • [19].Oh EH, Oh K, Han M, et al. Early anti-TNF/immunomodulator therapy is associated with better long-term clinical outcomes in Asian patients with Crohn's disease with poor prognostic factors. PLoS One 2017;12:e0177479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Schreiber S, Reinisch W, Colombel JF, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns Colitis 2013;7:213–21. [DOI] [PubMed] [Google Scholar]
  • [21].Ma C, Beilman CL, Huang VW, et al. Anti-TNF therapy within 2 years of Crohn's disease diagnosis improves patient outcomes: a retrospective cohort study. Inflamm Bowel Dis 2016;22:870–9. [DOI] [PubMed] [Google Scholar]
  • [22].Haynes RB, McDonald HP, Garg AX. Helping patients follow prescribed treatment: clinical applications. Jama 2002;288:2880–3. [DOI] [PubMed] [Google Scholar]
  • [23].Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Arch Intern Med 1990;150:841–5. [PubMed] [Google Scholar]
  • [24].Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis 2009;15:1264–75. [DOI] [PubMed] [Google Scholar]
  • [25].Weisman MH, Moreland LW, Furst DE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther 2003;25:1700–21. [DOI] [PubMed] [Google Scholar]
  • [26].Sundararajan V, Henderson T, Perry C, et al. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol 2004;57:1288–94. [DOI] [PubMed] [Google Scholar]
  • [27].Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43:1130–9. [DOI] [PubMed] [Google Scholar]
  • [28].Thygesen SK, Christiansen CF, Christensen S, et al. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish national registry of patients. BMC Med Res Methodol 2011;11:83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Venables W, Smith D. An Introduction to R. Available online at https://www.R-project.org/. [Google Scholar]
  • [30].Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 2016 Available online at https://www.R-project.org/. [Google Scholar]
  • [31].Vegh Z, Burisch J, Pedersen N, et al. Treatment steps, surgery, and hospitalization rates during the first year of follow-up in patients with inflammatory bowel diseases from the 2011 ECCO-Epicom inception Cohort. J Crohns Colitis 2015;9:747–53. [DOI] [PubMed] [Google Scholar]
  • [32].Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46–54.e42. [DOI] [PubMed] [Google Scholar]
  • [33].Frolkis AD, Dykeman J, Negron ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology 2013;145:996–1006. [DOI] [PubMed] [Google Scholar]
  • [34].Ma C, Moran GW, Benchimol EI, et al. Surgical rates for Crohn's disease are decreasing: a population-based time trend analysis and validation study. Am J Gastroenterol 2017;112:1840–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Jones DW, Finlayson SR. Trends in surgery for Crohn's disease in the era of infliximab. Ann Surg 2010;252:307–12. [DOI] [PubMed] [Google Scholar]
  • [36].Rungoe C, Langholz E, Andersson M, et al. Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011. Gut 2014;63:1607–16. [DOI] [PubMed] [Google Scholar]
  • [37].Geltzeiler CB, Hart KD, Lu KC, et al. Trends in the surgical management of Crohn's disease. J Gastrointest Surg 2015;19:1862–8. [DOI] [PubMed] [Google Scholar]
  • [38].Cury DB, Moss AC. Ocular manifestations in a community-based cohort of patients with inflammatory bowel disease. Inflamm Bowel Dis 2010;16:1393–6. [DOI] [PubMed] [Google Scholar]
  • [39].Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571–607. [DOI] [PubMed] [Google Scholar]
  • [40].Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:501–23. [DOI] [PubMed] [Google Scholar]
  • [41].Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies. Inflamm Bowel Dis 2012;18:201–11. [DOI] [PubMed] [Google Scholar]
  • [42].Chaparro M, Panes J, Garcia V, et al. Long-term durability of infliximab treatment in Crohn's disease and efficacy of dose “escalation” in patients losing response. J Clin Gastroenterol 2011;45:113–8. [DOI] [PubMed] [Google Scholar]
  • [43].Schreiber S, Colombel JF, Bloomfield R, et al. Increased response and remission rates in short-duration Crohn's disease with subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial data. Am J Gastroenterol 2010;105:1574–82. [DOI] [PubMed] [Google Scholar]
  • [44].Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. Lancet 2015;386:1825–34. [DOI] [PubMed] [Google Scholar]
  • [45].Marchetti M, Liberato NL, Di Sabatino A, et al. Cost-effectiveness analysis of top-down versus step-up strategies in patients with newly diagnosed active luminal Crohn's disease. Eur J Health Econ 2013;14:853–61. [DOI] [PubMed] [Google Scholar]
  • [46].Hoekman DR, Stibbe JA, Baert FJ, et al. Long-term outcome of early combined immunosuppression versus conventional management in newly diagnosed Crohn's disease. J Crohns Colitis 2018;12:517–24. [DOI] [PubMed] [Google Scholar]
  • [47].Peyrin-Biroulet L, Oussalah A, Williet N, et al. Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease. Gut 2011;60:930–6. [DOI] [PubMed] [Google Scholar]
  • [48].Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 2010;138:463–8. [DOI] [PubMed] [Google Scholar]
  • [49].Harbord M, Annese V, Vavricka SR, et al. The first European evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease. J Crohns Colitis 2016;10:239–54. [DOI] [PMC free article] [PubMed] [Google Scholar]

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