ORIGINAL ARTICLE

Changes in medical treatment and surgery ratesin inflammatory bowel disease: a nationwidecohort study 1979–2011Christine Rungoe,1 Ebbe Langholz,2 Mikael Andersson,1 Saima Basit,1

Nete M Nielsen,1 Jan Wohlfahrt,1 Tine Jess1

▸ Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/gutjnl-2013-305607).1Department of EpidemiologyResearch, National Center forHealth Data and DiseaseControl, Copenhagen, Denmark2Department of InternalMedicine, Gentofte UniversityHospital, Hellerup, Denmark

Correspondence toDr Christine Rungø,Department of EpidemiologyResearch, National Center forHealth Data and DiseaseControl, Artillerivej 5,Copenhagen 2300, Denmark;cxr@ssi.dk

Received 5 July 2013Revised 3 September 2013Accepted 4 September 2013Published Online First20 September 2013

▸ http://dx.doi.org/10.1136/gutjnl-2013-306045

To cite: Rungoe C,Langholz E, Andersson M,et al. Gut 2014;63:1607–1616.

ABSTRACTIntroduction Treatment possibilities have changed ininflammatory bowel disease (IBD). We assessed changesin medical treatment and surgery over time and impactof medications on risk of surgery in a population-basedcohort.Methods 48 967 individuals were diagnosed with IBD(Crohn’s disease (CD), 13 185; ulcerative colitis (UC),35 782) during 1979–2011. Cumulative probability ofreceiving 5-aminosalicylic acids (5-ASA), topical, oralcorticosteroids, thiopurines, and tumour necrosis factor-α(TNF-α) blockers, and of first minor or major surgeryaccording to period of diagnosis, was estimated.Medication use and risk of surgery was examined by Coxregression.Results 5-year cumulative probability of first majorsurgery decreased from 44.7% in cohort (1979–1986)to 19.6% in cohort (2003–2011) (p < 0.001) for CD,and from 11.7% in cohort (1979–1986) to 7.5% incohort (2003–2011) (p < 0.001) for UC. Minor surgeryrisk decreased significantly in CD. From cohort(1995–2002) to cohort (2003–2011), a significantincrease in use of thiopurines and TNF-α blockers wasobserved, paralleled by a significant decrease in use of5-ASA and corticosteroids. Comparing use ofazathioprine (or oral corticosteroids) to never-use, noconvincing surgery-sparing effect was found. Comparinguse in 3+ months of a given drug with use <3 months,only 3+ months use of oral corticosteroids reduced therisk of surgery in patients with disease duration of>1 year.Conclusions Parallel to an increasing use ofthiopurines and TNF-α blockers in IBD over time, apersistent significant decrease in surgery rates wasobserved along with a significant decrease in use of5-ASA and corticosteroids. However, no convincingsurgery-sparing effect of newer medications was found.

INTRODUCTIONInflammatory bowel diseases (IBD) are multifactor-ial chronic diseases, where severe disease complica-tions often result in surgery. Primary indications forsurgical interventions are emergency and failure torespond to medical therapy. However, in the past30 years, major advances in the treatment of IBDhave been made, latest with the introduction oftumour necrosis factor-α (TNF-α) blockers which,in Denmark, have been in use since late 1998.Randomised controlled trials, referral centrestudies, short-term follow-up studies of IBD

cohorts1–3 have indicated that introduction ofimmune modulators early in the disease course mayreduce the need for surgery in patients with IBD.A study published in 2008 found that treatmentwith azathioprine in combination with TNF-αblockers early in the course of Crohn’s disease(CD) was superior to current strategies with corti-costeroids in inducing mucosal healing and avoid-ing surgery during the following 2 years.1 This is inaccordance with studies from different centres sug-gesting that early introduction of especially thio-purines reduces the risk of surgery, particularly inCD.2 4–6 Likewise, two former regional Danish

Significance of this study

What is already known about this subject?▸ Treatment options in inflammatory bowel

disease have changed through the lastdecades.

▸ Whether these changes have had an impact onlong-term need of surgery remains unknown.

What are the new findings?▸ We observed a significant decrease in need of

surgery over the last three decades in patientswith ulcerative colitis or Crohn’s disease.

▸ The decrease in need of surgery was paralleledby an increase in use of azathioprine andanti-TNF-α blockers along with a decrease inuse of 5-aminosalicylates (5-ASA) and topicalcorticosteroids in both diseases, and a decreasein use of oral corticosteroids in Crohn’s disease.

▸ Of all medications, only long-term use of oralcorticosteroids in patients with disease durationof ≥1 year, was associated with a reduced riskof surgery.

How might it impact on clinical practice inthe foreseeable future?▸ The study provides clinicians with long-term

population-based data on risk of surgery andtrends in medication use in patients withinflammatory bowel disease.

▸ The study underscores the complexity ininterpreting the impact of medicine use on riskof surgery in inflammatory bowel disease.

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population-based studies have reported a decreased need ofsurgery within the first year after diagnosis of IBD amongpatients diagnosed in the era of immune-suppressive treatmentwhen compared to older Danish cohorts.7 8 However, due toshort follow-up time in the mentioned studies, it remains uncer-tain whether the potential decrease in risk of surgery is persist-ing over time, or whether the need for surgery is just postponedin patients exposed to immunosuppressive and biologics.

The aim of the present study was to conduct a nationwidepopulation-based cohort study of changes in exposure to clas-sical and newer IBD medications as well as changes in short-term and long-term risk of major and minor surgery amongDanish patients diagnosed with IBD during the last threedecades. Also, we evaluated the association between exposure to5-aminosalicylates (5-ASA), corticosteroids and thiopurines andrisk of first major intestinal surgery in IBD.

METHODSStudy populationWe included patients 16 years or older at their first diagnosis ofIBD in the Danish National Patient Register (NPR), which containsindividual-level healthcare information on inpatient hospital con-tacts, diagnoses, surgical and other procedures performed inDanish hospitals since 1977, and in ambulatory outpatient settingssince 1995.9 Linkage between registers was possible by use of theDanish Civil Registration System10 where all Danes are registeredunder a unique 10-digit identification number.

The cohort was defined by patients with a first diagnosis ofIBD after 1978 (thereby excluding prevalent cases) using theinternational classification of diseases (ICD) 8th and 10th revi-sion codes for CD (563.00–563.09 and K50) and ulcerativecolitis (UC) (563.19, 569.04 and K51). The diagnoses of IBD inNPR are found to be correct and almost complete with validityestimates for registered CD and UC of, respectively, 97% and90%, using a pathology register as reference.11 To avoid diag-nostic ambiguity, patients with a diagnosis of UC and CD(n=5861) recorded in NPR were not included in this study.Patients who underwent major intestinal surgery before (mediantime 3.3 years) diagnosis of IBD (n=1393) were also excluded(with a similar proportion of patients excluded in each

subcohort). The final study cohort consisted of 35 782 incidentcases with UC and 13 185 with CD diagnosed during 1979–2011. We divided the study cohort, according to era of IBDdiagnosis, into four groups; Cohort I (diagnosed 1979–1986),Cohort II (1987–1994), Cohort III (1995–2002), and CohortIV (2003–2011) (table 1) for UC and CD, respectively.

Medical treatmentDetailed individual-level information on medical treatment for IBDwas extracted from the Danish Prescription Database (DPD),12

which contains information on all prescriptions redeemed fromDanish pharmacies since 1995, including the personal identifica-tion number, dispensing date, anatomic therapeutic chemical code,number of packages, and number of defined daily doses. AsIBD-relevant medications (see online supplementary table S1), weincluded azathioprine (the primary thiopurine used in Denmark),5-ASA/sulfasalazine, oral- and topical corticosteroids. Treatmentwith TNF-α blockers was identified by combining data from theDPD; NPR (administration in inpatient and outpatient settings)and the Danish Crohn Colitis Database (DCCD).13

SurgeryWe defined surgical procedures for IBD as first major or firstminor surgery. Major surgery included colectomies, resectionsand other unspecified major intestinal operations, according tothe Danish Classification of Surgical Procedures and Therapies(including 1995) and, thereafter, codes from the Danish versionof the Nordic Medico-Statistical Committee classification (seeonline supplementary table S2). Minor surgery was defined asintra-abdominal abscess-fistulas drainage and surgery for peri-anal complications (see online supplementary table S2).

Vital status and covariatesInformation on age, gender and vital status was obtained fromthe Danish Civil Registration system10 which contains continu-ously updated information on birth, sex, place of birth, address,marital status, as well as dates of immigration, emigration, anddeath of citizens.

Information on comorbidities during follow-up was obtainedfrom NPR. Comorbidities were categorised as cardiovascular

Table 1 Characteristics of patients with Crohn’s disease or ulcerative colitis diagnosed in Denmark during 1979–2011 by year of diagnosis

Year of diagnosis

Cohort I (1979–1986) Cohort II (1987–1994) Cohort III (1995–2002) Cohort IV (2003–2011)

Crohn’s diseaseNumber of patients 1603 2312 3718 5552Male (n, %) 652 (40.7) 915 (39.6) 1581 (42.5) 2254 (40.6)Median age at diagnosis (range) 39.7 (16–90) 37.1 (16–93) 38.2 (16–98) 41.4 (16–105)Age at diagnosis (years) (n, %)16–39 810 (50.5) 1259 (54.5) 1968 (52.9) 2679 (48.3)40–59 411 (25.6) 547 (23.7) 939 (25.3) 1427 (25.7)60 + 382 (23.8) 506 (21.9) 811 (21.8) 1446 (26.0)

Ulcerative colitisNumber of patients 4845 5587 10 155 15 195Male (n, %) 2359 (48.6) 2734 (48.9) 4721 (46.5) 7009 (46.1)Median age at diagnosis (range) 45.7 (16–96) 43.6 (16–93) 45.4 (16–97) 48.5 (16–101)Age at diagnosis (years) (n, %)16–39 2060 (42.52) 2465 (44.12) 4197 (41.33) 5581 (36.73)40–59 1226 (25.30) 1557 (27.87) 3109 (30.62) 4571 (30.08)60 + 1559 (32.18) 1565 (28.01) 2849 (28.06) 5043 (33.19)

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disease, cerebral infarction, renal disease, chronic lung disease,liver disease, rheumatic disease, cancer, anaemia, coagulationdisorders, immune disorders, human immune deficit virus infec-tion, tuberculosis and senile dementia (see online supplementarytable S3). Comorbidities were selected a priori and included inthe analysis as potential confounders, and treated as 13 time-dependent binary variables.

Statistical analysisIn all analyses, including Kaplan–Meier curves, patients werefollowed from diagnosis of IBD until the outcome of interest,

death, emigration, or end of follow-up, 31 December 2011,whichever occurred first.

Kaplan–Meier plots were used to estimate the cumulativeprobability of ever filling a prescription of 5-ASA, oral cortico-steroid, azathioprine or TNF-α blockers or of ever undergoingfirst major or minor surgery according to time since diagnosis ofIBD. Kaplan–Meier curves were compared by log rank test,comparing rates within the first year, 1–4 years, and 5–8 yearsafter diagnosis. Estimating the cumulative probability withoutassuming independent competing risks14 gave only slightlyhigher estimates. To assess any association of use of medication(5-ASA, corticosteroids, azathioprine) on risk of surgery, we

Figure 1 (A-H) Cumulativeprobability (CP) of ever medicine useby time since diagnosis according tocohort of diagnosis in patients withCrohn’s disease (left) and ulcerativecolitis (right) black line; Cohort III(1995-02) black dash line; Cohort IV(2003-11). CP of (A) 5-ASA, (C) oralcorticosteroids, (E) azathioprine, (G)TNF-α-antagonists in patients withCrohn’s disease. CP of (B) 5 -ASA,(D) oral corticosteroids,(F) azathioprine, (H) TNF-α-antagonistsin patients with ulcerative colitis135×245mm (300×300 DPI).

80

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Crohn’s disease Ulcerative colitis

Cohort III (1995-2002)Cohort IV (2003-2011)

Cumulative probability of 5-ASA use (%)

Cumulative probability oral steroids use (%)

Cumulative probability azathioprine use (%)

Cumulative probability of anti-TNF-alpha use (%) Cumulative probability of anti-TNF-alpha use (%)

Cumulative probability azathioprine use (%)

Cumulative probability oral steroids use (%)

Cumulative probability of 5-ASA use (%)

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used Cox proportional hazards regression to estimate HRs with95% CIs using days since IBD diagnosis as the underlying timescale. In the first type of comparison we compared the twoexposure groups, current users with never users by time sincediagnosis. In the second type of comparison including currentusers only, we compared long-term current users (3–11 months,12+ months, 3+ months) with short-term current users(<3 months) by time since diagnosis (<1 year, ≥1 year). TheHRs for medication were adjusted for gender, age, calendarperiod (divided into 2-year intervals), diagnosing hospitalgrouped in six groups according to region of Denmark (North,Middle and South Jutland, Funen, Zealand, and the capitalregion including Bornholm), IBD-related drugs (5-ASA, corti-costeroids (oral or topical), azathioprine and anti-TNF-α block-ers) and comorbidities (13 different main groups, see above). Allvariables were chosen a priori and were time dependent exceptgender and diagnosing hospital.

Medication use was treated as time-dependent variables cate-gorised as ‘current’ users, ‘past’ users and ‘never’ users in the fol-lowing manner: a patient was a current user from the date of firstredeemed prescription, a gap between consecutive prescriptionsof up to 100% of the duration of the preceding prescription (indefined daily doses) was accepted to leave room for variations indrug intake (using 50% or 150% gave similar results, data notshown). If two consecutive prescriptions overlapped, the overlapwas disregarded and exposure time was counted from the dis-pensing day of the most recent prescription. Users of the drug inquestion who subsequently stopped treatment were recategorisedto a distinct group of past user-patients and contributed person-time to this group from the day the maximum time gap after aprescription was exceeded. However, if a past user later refilled aprescription, they would contribute person-time to the currentuser group. Only cumulative probability for current users andnever users was visualised in Kaplan Meier curves.

In an alternative analytic approach, we used stratified Coxregression with propensity score matched (1:1 with replace-ment) pairs as strata. We compared ever users and never userswith follow-up from 1 year after diagnosis, and with medicationstatus defined at start of follow-up. Propensity scores expressedthe likelihood of being treated with a given IBD-specific medica-tion within the first year after diagnosis. The propensity wasestimated using logistic regression including the same adjustmentvariables described above plus use of other IBD-related medica-tions than the drug in question within the first year afterdiagnosis.

Data were analysed using SAS V.9.3 (SAS Institute, Cary,North Carolina, USA).

RESULTSThe cohort consisted of 48 967 patients with IBD (CD,n=13 185; UC, n=35 782) diagnosed from 1979 to 2011.Cohort members were followed for up to 32 years or 134 167person-years in CD and 364 306 person-years in UC. Patientswere divided into four subcohorts according to calendar periodof diagnosis as outlined in table 1.

Medication useData on medication use was available for Cohort III (1995–2002) and Cohort IV (2003–2011).

Crohn’s diseasePatients diagnosed with CD in recent years (Cohort IV) used5-ASA to a lesser extent than patients in Cohort III, within the firstyear (p<0.001) and 1–4 years (p<0.001) after diagnosis (overallp<0.001). The visual difference between the two cohorts 5–8 years after diagnosis (figure 1A) was explained by the differencein the first years (table 2). For oral corticosteroids, the overall pvalue was 0.029, but no difference in use between Cohorts III and

Table 2 Cumulative probability of ever medical use within the first, fifth and ninth years of diagnosis in patients with Crohn’s diseasediagnosed in Cohorts III and IV

Cohort III (1995–2002)n=3718

Cohort IV (2003–2011)n=5552 Homogeneity test for rates within

<1,1–4, 5–8 years*Users Cumulative probability (%) Users Cumulative probability (%)

Use† within first year of diagnosis p<1 year5-ASA‡ 1866 51 1021 19 <0.001Topical corticosteroids 618 17 987 19 0.02Oral corticosteroids 1335 37 1855 35 0.29Azathioprine 547 15 1323 25 <0.001TNF-α blockers§ 1 0.1 456 9 <0.001

Use within first 5 years of diagnosis p1–4 years5-ASA‡ 2024 56 1151 23 <0.001Topical corticosteroids 953 27 1225 26 <0.001Oral corticosteroids 1774 49 2212 46 0.006Azathioprine 986 28 1681 36 0.18TNF-α blockers§ 46 3 783 19 <0.001

Use within first 9 years of diagnosis p5–8 years5-ASA‡ 2057 56 1164 24 0.43Topical corticosteroids 1071 31 1264 30 0.82Oral corticosteroids 1996 56 2280 53 0.45Azathioprine 1126 32 1719 39 0.70TNF-α blockers§ 164 10 839 23 0.35

*p Value for homogeneity performed by log rank test, p value compares rates within first year of diagnosis (p<1 year) from 1–4 years (p1–4 years) and 5–8 years of diagnosis (p5–8 years).†Use defined as ever use of the drug in question.‡5-aminosalicylates/sulfasalazine.§Users of TNF-α blockers in Cohort III contains only patients diagnosed after 1998 (n=2381).

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IV was observed within the first year after diagnosis (p=0.29),whereas a significantly lower use of oral corticosteroids in CohortIV as compared with Cohort III was seen 1–4 year after diagnosis(p=0.006) (figure 1B, table 2). For azathioprine, patients inCohort IV had a significantly higher use within the first year afterdiagnosis as compared with Cohort III (p<0.001), whereas thelong-term differences seen in Kaplan–Meier plots (figure 1C) wereentirely explained by the difference in the first years (1–4 years(p=.18) and 5–8 years (p=0.70))(overall p<0.001). Use ofTNF-α blockers in Cohort III was only estimated for the propor-tion of patients diagnosed after introduction of the drug inDenmark in late 1998. Patients diagnosed in Cohort IV had a sig-nificantly higher use of TNF-α blockers within the first year(p<0.001) and 1–4 years (p<0.001) after diagnosis than patientsin Cohort III, whereas the cumulative probability of use 5–8 yearsafter diagnosis tended to equalise (p=0.35) (figure 1D, table 2)(overall p<0.001).

Ulcerative colitisIn patients with UC, the cumulative probability of using 5-ASAwithin the first (p<0.001) and 1–4 years (p<0.001) after diag-nosis decreased significantly from Cohort III to Cohort IV;whereas the observed differences between curves 5–8 years(p=0.21) after diagnosis was explained by the difference in thefirst year (figure 1E, table 3) (overall p<0.001). Also, a signifi-cant decrease in use of topical corticosteroids was observedfrom Cohort III to Cohort IV within the first (p<0.001) and 1–4 years (p<0.001) after diagnosis (table 3, (not visualised in afigure)) (overall p<0.001). Contradictory to this, no differencein use of oral corticosteroids was observed from Cohort III toCohort IV within the first year (p=0.97), 1–4 years (p=0.2) or5–8 years (p=0.2) after diagnosis (figure 1F) (overall p=0.32).Patients in Cohort IV had a higher probability than patients inCohort III of being exposed to azathioprine within the first year

(p<0.001) and 1–4 years (p<0.001) after diagnosis, whereasthe long-term difference observed (figure 1G) 5–8 years afterdiagnosis was explained by the initial differences in use (table 3)(overall p<0.001). Restricting Cohort III to include patientsdiagnosed after the introduction of TNF-α antagonist only, weobserved a significantly higher probability of receiving TNF-αblockers in Cohort IV than in Cohort III within the first(p<0.001), 1–4 years (p<0.001), and 5–8 years (p<0.001)after diagnosis (overall p<0.001) (table 3, figure 1H).

Risk of surgeryCrohn’s diseaseA total of 4146 CD patients underwent a first major surgeryduring follow-up, 863 in Cohort I (1977–1986), 1148 in CohortII (1987–1994), 1166 in Cohort III (1995–2002) and 969 inCohort IV (2003–2011). Risk of first major surgery decreasedover calendar time (comparing all four cohorts; figure 2). Thiswas observed within the first year (p<0.001) and also 5 years(p<0.001) and 9 years (p<0.001) after diagnosis. Likewise, thecumulative probability of undergoing first major surgery waslowest in the most recent Cohorts (Cohorts III and IV) within thefirst year, 5 years and 9 years after diagnosis (overall p=0.004,figure 3). Restricting analysis either to intra-abdominal fistulas orperianal complications, the same significant decrease in surgeryover time was observed in both groups (overall p values,p<0.001 and p<0.001). Restricting analyses to inpatients atdiagnosis only, revealed nearly identical results (data not shown).

Ulcerative colitisA total of 4037 UC patients underwent a first major surgeryduring follow-up, 943 in Cohort I (1979–1986), 1004 in CohortII (1987–1994), 1128 in Cohort III (1995–2002) and 962 inCohort IV (2003–2011). As for CD, risk of first major surgerydecreased significantly over calendar time (comparing all four

Table 3 Cumulative probability of ever medical use within the first, fifth and ninth years of diagnosis of patients with ulcerative colitisdiagnosed in Cohorts III and IV

Cohort III (1995–2002)n=10 155

Cohort IV (2003–2011)n=15 195 Homogeneity test for rates within

<1,1–4, 5–8 years*Users Cumulative probability (%) Users Cumulative probability (%)

Use† within first year of diagnosis p<1 year5-ASA‡ 6388 63 7565 51 <0.001Topical corticosteroids 3118 31 3546 24 <0.001Oral corticosteroids 2587 26 3746 26 0.97Azathioprine 405 4 1028 7 <0.001TNF-α blockers§ 0 – 356 3 <0.001

Use† within first 5 years of diagnosis p1–4 ears

5-ASA‡ 6777 68 7943 55 <0.001Topical corticosteroids 4044 41 4397 33 <0.001Oral corticosteroids 3906 39 5109 40 0.23Azathioprine 960 10 1732 15 <0.001TNF-α blockers§ 12 0.2 697 6 <0.001

Use† within first 9 years of diagnosis p5–8 years5-ASA‡ 6884 69 7975 57 0.21Topical corticosteroids 4382 45 4496 37 0.07Oral corticosteroids 4635 47 5355 48 0.21Azathioprine 1194 13 1809 17 0.56TNF-α blockers§ 82 2 760 9 0.001

*p Value for homogeneity performed by log rank test, p value compares rates within first year after diagnosis, from 1–4 years and 5–8 years after diagnosis.†Use defined as ever use of the drug in question.‡5-aminosalicylates/sulfasalazine.§Use of TNF-α blockers in Cohort III contains only patients diagnosed after 1998 (n=6805).

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cohorts; figure 4). The decrease was found in 1, 5 and 9 yearsafter diagnosis (all p<0.001). Restricting analysis to inpatients atdiagnosis only, revealed similar results (data not shown).

Use of medications and risk of surgeryIn the following, we first present the impact of current versusnever use of azathioprine and oral corticosteroids on risk ofsurgery. Second, we present the differences in short-term andlong-term use of 5-ASA, topical and oral corticosteroids, andazathioprine on risk of surgery.

Crohn’s diseaseFigure 5A shows the cumulative probability of first major intes-tinal surgery in CD according to time since diagnosis of CD(Cohorts III and IV combined) in current users and never users

of azathioprine. Dividing the first year into intervals of3 months, only in the first 3 months after diagnosis of CD alower surgery rate was observed in current users compared to

Figure 5 (A) Cumulative probability of first major surgery in Crohn’sdisease by time since diagnosis according to use of azathioprine (AZA),in Cohort III and Cohort IV combined. Black line; Current use of AZAlight grey line; never use of AZA. (B) Cumulative probability of firstmajor surgery in ulcerative colitis by time since diagnosis according touse of AZA, in Cohort III and Cohort IV combined. Black line; Currentuse of AZA, light grey line; never use of AZA.

Figure 3 Cumulative probability of first minor surgery among 13 185patients with Crohn’s disease by time since diagnosis according tocohort at diagnosis. Minor surgery defined as; intra-abdominalabscess-fistulas drainage and surgery for perianal complications. Greyline; Cohort I (1979–1986), grey dotted line; Cohort II (1987–1994),black line; Cohort III (1995–2002), black dotted line Cohort IV(2003–2011). p Value for homogeneity performed by log rank test,p value compares rates within first year after diagnosis, from 1–4 yearsand 5–8 years after diagnosis.

Figure 2 Cumulative probability of first major intestinal surgeryamong 13 185 patients with Crohn’s disease by time since diagnosisaccording to cohort at diagnosis. Grey line; Cohort I (1979–1986), greydotted line; Cohort II (1987–1994), black line; Cohort III (1995–2002),black dotted line Cohort IV (2003–2011). p Value for homogeneityperformed by log rank test, p value compares rates within first yearafter diagnosis, from 1–4 years and 5–8 years after diagnosis.

Figure 4 Cumulative probability of first major intestinal surgery in35 782 patients with ulcerative colitis by time since diagnosis accordingto cohort at diagnosis. Grey line; Cohort I (1979–1986), grey dottedline; Cohort II (1987–1994), black line; Cohort III (1995–2002), blackdotted line Cohort IV (2003–2011). p Value for homogeneity performedby log rank test, p value compares rates within first year afterdiagnosis, from 1–4 years and 5–8 years after diagnosis.

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never users of azathioprine (HR, 0.50; 95% CI 0.31 to 0.82),whereas an increased surgery rate was observed in current usersat all other time intervals (eg, HR 6–8 months afterdx=1.95;95% CI 1.03 to 2.96; HR 12–14 months afterdx=1.85;95% CI 0.97 to 3.52). Risk of surgery in current usersof oral corticosteroids was increased at all times compared withnon-users, figure 6A. Propensity-score matching did not changeresults (see online supplementary table S4).

As the higher surgery rate found in users could be due to con-founding by indication, that is, the most ill patients were theones receiving medication, we also examined rate of surgeryamong current drug users according to duration of use (table 4).In these analyses we looked separately at patients initiating treat-ment with a given drug <1 year, respectively, 1+ year afterdiagnosis. In patients initiating treatment with 5-ASA, topical ororal corticosteroids, or azathioprine within the first year afterdiagnosis, those with a current use for 3–11 months were at sig-nificantly higher risk of surgery than those with a current use of<3 months (table 4). In patients initiating treatment with5-ASA, topical corticosteroids or oral corticosteroids, orazathioprine more than 1 year after diagnosis, only use of oralcorticosteroids for 3+ months versus less than 3 months (HR,0.42; 95% CI 0.26 to 0.69) significantly reduced the risk ofsurgery (table 4).

Ulcerative colitisFigure 5B shows the cumulative probability of major intestinalsurgery in UC according to time since diagnosis of UC (CohortIII and IV combined) in current users and never users ofazathioprine. The risk of surgery, at any time, was higher incurrent users of azathioprine, compared to the risk in non-users(p<0.001). Likewise, current use (vs never use) of oral corticos-teroids was associated with increased risk of surgery (p<0.001)(figure 6B). Again, propensity-score matching did not changeresults (see online supplementary table S4).

Next we analysed the risk of surgery according to duration ofcurrent drug use and disease duration. In patients initiatingtreatment within a year from diagnosis, a significantly increasedrisk of surgery was observed in those with a current use of5-ASA or oral corticosteroids for 3–11 months (vs <3 months),and a similar tendency was observed for azathioprine (table 5).In patients with UC, initiating treatment with a given drug morethan a year from diagnosis, a significantly reduced risk ofsurgery was observed only for those with a long-term use oforal corticosteroids (table 5).

DISCUSSIONIn this nationwide population-based cohort study of 48 967patients diagnosed with IBD over a 32-year period, we found adecrease in risk of first major intestinal surgery over calendartime, most noticeable in CD. The decrease continued long-term,suggesting that surgery is postponed not only in patients diag-nosed in recent years. A significant decrease in risk of minorsurgery in patients with CD was also observed in recent cohorts.Comparing the two latest cohorts, we further found a decreasein use of 5-ASA and topical corticosteroids (and oral corticoster-oid in CD) paralleled by an increasing use of azathioprine andTNF-α blockers. Examining the risk of surgery according tocurrent use of medications (compared with never users), wefound, that only patients with CD using azathioprine within thefirst 3 months after diagnosis had a reduced risk of surgery.Considering risk of surgery among current medication usersonly, patients initiating treatment of 5-ASA, topical corticoster-oids, oral corticosteroids, or azathioprine within the first year ofdiagnosis and receiving the treatment for 3–11 months had anincreased risk of surgery compared to those with a current useof <3 months. In patients initiating treatment with 5-ASA,topical or oral corticosteroids, or azathioprine more than 1 yearafter diagnosis, only long-term use of oral corticosteroids signifi-cantly reduced the risk of surgery.

The major strength of this study was the assessment of a largenational and, hence, unselected cohort of patients with IBDdiagnosed over three decades. IBD diagnoses are found to be ofhigh completeness and validity in the Danish National PatientsRegister.11 As access to medical services (hospitalisation, controlvisits, and treatment) in Denmark is independent of race, socio-economic status and participation in health assurance pro-grammes due to free and easy access to healthcare, the studypopulation should represent the complete and broad spectrumof IBD. The availability of nationwide individual-level registra-tion of all redeemed prescriptions from all pharmacies inDenmark from 1995 and onwards further strengthens thisstudy. A potential limitation could be that redeemed prescriptionmay not fully reflect actual drug intake, but these data are stillassumed to be superior to self-reported drug intake. Anotherpossible limitation is the use of defined daily doses and accept-ance of gaps between prescriptions when estimating status ofcurrent or past use. This limitation however is judged to be

Figure 6 (A) Cumulative probability of first major surgery in Crohn’sdisease by time since diagnosis according to use of oral corticosteroidin Cohort III and Cohort IV combined. Black line; Current use of oralcorticosteroids, light grey line; never use of oral corticosteroids.(B) Cumulative probability of first major surgery in ulcerative colitis bytime since diagnosis according to use of oral corticosteroids in CohortIII and Cohort IV combined. Black line; Current use of oralcorticosteroids, light grey line; never use of oral corticosteroids.

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minor as sensitivity analyses testing various lengths of gaps didnot change results. Information on disease behaviour, diseaseextent at diagnosis or smoking status was not available, whichlimited the possibility to control for disease severity. However,from regional Danish cohort studies we know that changes inphenotypes have been minor over time.15 Furthermore, usingpropensity score matching as an alternative analytic approachdid not change results. However, although intended to capture

disease severity, propensity scores did not include direct vari-ables of severity and behaviour, but only surrogate measures ofseverity. We found an increase in use of azathioprine and TNF-αblockers over time, especially in patients with CD. This is partlyin accordance with observations made by Herrinton and collea-gues on the potentially more selected Kaiser Permanente insur-ance database of 8787 patients with IBD, although TNF-αblockers had not been introduced for UC at the time of that

Table 5 HR of first major surgery in patients with ulcerative colitis according to duration of current use of 5-ASA, oral and topicalcorticosteroids or azathioprine by disease duration

Medications

Duration of current use HR (95% CI) n*

<3 months 3–11 months 12+ months 3+ months

Disease duration <1 year5-ASA 1 (Ref)

1242.55 (1.87 to 3.46)120

– –

Oral corticosteroid 1 (Ref)150

1.94 (1.45 to 2.60)125

– –

Topical corticosteroid 1 (Ref)35

1.49 (0.35 to 6.22)2

– –

Azathioprine 1 (Ref)41

1.45 (0.89 to 2.36)28

– –

Disease duration ≥1 year5-ASA 1 (Ref)

30.74 (0.21 to 2.57)15

0.66 (0.21 to 2.07)191

0.67 (0.21 to 2.08)206

Oral corticosteroid 1 (Ref)56

0.55 (0.38 to 0.78)34

0.31 (0.21 to 0.44)69

0.40 (0.29 to 0.55)143

Topical corticosteroid 1 (Ref)8

1.17 (0.25 to 5.53)2

0 (–)0

0.67 (0.14 to 3.15)2

Azathioprine 1 (Ref)36

1.01 (0.67 to 1.53)61

0.71 (0.45 to 1.10)46

0.86 (0.59 to 1.26)107

HRs are adjusted for gender, age, calendar period, hospital location at diagnosis, comorbidities and use of medications other than the drug in question (5-ASA, oral steroid, localsteroid, azathioprine) and never/ever users of TNF-α blockers.*N represents medicine users who had surgery within the specific time period.5-ASA, 5-aminosalicylates.

Table 4 HR of first major surgery in patients with Crohn’s disease according to duration of current use of 5-ASA, oral and topicalcorticosteroids or azathioprine by disease duration

Medications

Duration of current use, HR (95% CI), n*

<3 months 3–11 months 12+ months 3+ months

Disease duration <1 year5-ASA 1 (Ref)

1001.70 (1.25 to 2.32)95

– –

Oral corticosteroid 1 (Ref)171

1.60 (1.22 to 2.09)127

– –

Topical corticosteroid 1 (Ref)65

2.70 (1.72 to 4.23)29

–- –

Azathioprine 1 (Ref)52

1.79 (1.16 to 2.74)39

– –

Disease duration ≥1 year5-ASA 1 (Ref)

21.46 (0.33 to 6.38)16

1.21 (0.30 to 4.93)108

1.25 (0.31 to 5.04)124

Oral corticosteroid 1 (Ref)23

0.61 (0.36 to 1.05)34

0.32 (0.18 to 0.55)31

0.42 (0.26 to 0.69)65

Topical corticosteroid 1 (Ref)16

1.58 (0.82 to 3.03)21

0.39 (0.11 to 1.35)3

1.14 (0.61 to 2.16)24

Azathioprine 1 (Ref)17

0.95 (0.52 to 1.71)32

0.73 (0.41 to 1.28)45

0.81 (0.48 to 1.38)77

HRs are adjusted for gender, age, calendar period, hospital location at diagnosis, comorbidities and use of medications other than the drug in question (5-ASA, oral steroid, localsteroid, azathioprine) and never/ever users of TNF-α blockers.*N represents medicine users who had surgery within the specific time period.5-ASA, 5-aminosalicylates.

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study.16 Likewise, Kaplan and colleagues found an increase inuse of immune modulators and biologicals among 775 patientswith UC during 1997–2009.17

Interestingly, in the present study, the increasing use ofazathioprine and TNF-α blockers was paralleled by a decrease inuse of 5-ASA, topical corticosteroids and oral corticosteroids inCD. Whereas the decrease in use of 5-ASA in CD patients maybe explained by changed clinical guidelines no longer support-ing its use as maintenance therapy, the decreasing use of 5-ASAin patients with UC and of topical corticosteroids in bothpatient groups remains unexplained, although paralleled by theincrease in use of immune-modulators and biological treatment.The reduced use of oral corticosteroids in patients with CD isan interesting and novel finding as it may point towards asteroid-reducing effect of newer drugs as observed in paediatricpatients with CD.18

Along with the significant changes in use of classical andnewer treatments for IBD, we found a persisting decrease inneed of first major surgery in CD and UC, which was present inthe first year after diagnosis, as shown previously,15 and was alsofound to persist in the long term. In UC, the 9-year riskdecreased from 14.5% in Cohort I to 9.1% in Cohort IV. Thefirst estimate is in accordance with regional Danish data from acohort of patients with UC diagnosed In 1962–1987,19 whereasthe current probability of 9.1% is in accordance with morerecent results from a European cohort,20 hence suggesting thatlong-term colectomy rates in UC have decreased significantlyover time, and that Danish rates are also approaching those ofother European countries.

In CD, surgery rates also decreased significantly, even in thelong term, from 50.3% 9 years after diagnosis in Cohort I to23.3% in Cohort IV. Current surgery rates among Danishpatients with CD appear to be slightly lower than thosereported from Cardiff, Wales (25% at 5 years),6 and fromEastern Europe (approximately 30% at 7 years after diagnosis).5

The risk of minor surgery due to intra-abdominal fistulas orperianal complications was also significantly decreased inpatients with CD, potentially due to increased use of drugs withknown efficacy on penetrating disease. The decrease in need ofmajor and minor surgery in IBD over time may also beexplained by a milder disease course in patients diagnosed inrecent decades,5 or by changes in smoking habits in the generalpopulation21 and, hence, potentially also in IBD. However, inDenmark, the phenotype of IBD has not been found to changemarkedly over time,15 nor have smoking patterns in patientswith CD and UC changed significantly.8

Whether the introduction of immunosuppressive and bio-logical drugs has had a direct effect on risk of surgery amongpatients with IBD remains debateable.22 We looked prospect-ively at the risk of first major surgery according to current dur-ation of medicine use and time since diagnosis of IBD andobserved an increased risk of surgery among users of medica-tions prescribed within the first year of diagnosis. This is inter-esting, as previous studies of various methodologies2 5 6 23

suggest that initiating treatment early in disease course couldreduce surgery rates. Ramadas et al6 found in multivariate ana-lysis that patients with CD using thiopurines within the firstyear of diagnosis had a reduced risk of surgery, while Lakatosand colleagues5 observed that patients with CD using azathiopr-ine for 6 months within the first 3 years after diagnosis hadreduced risk of surgery. In a French referral centre study2 ofnewly diagnosed patients with CD, duration of treatment wasalso associated with surgery risk, whereas no such associationwas observed in patients with UC.24 Provided that the initiation

of medical treatment per se causes delay of surgery, it is likely,that the increased risk of surgery we found within the first yearafter diagnosis in current users to some extent reflects failure torespond to medical treatment, as discussed by Vernier–Massouille.25 This leads to the concern that our results arereflecting confounding by indication, that is, that use ofimmunotherapy and oral corticosteroids reflect more severedisease. This may, to some extent, be the case despitepropensity-score matching. Further, the concern raised is chal-lenged by the reduced risk of surgery observed in patients withlonger-term use of oral corticosteroids. Hence, the observedpersistent decrease in surgery rates paralleled by an increase inuse of immunosuppressive and biological treatment, our resultsdo not point clearly towards a surgery-reducing effect of thesetreatments.

CONCLUSIONIn this nationwide cohort study on patients with IBD diagnosedfrom 1979 to 2011 we found an increased use of azathioprineand TNF-α blockers over time parallel to a decrease in use of5-ASA and local corticosteroids. Also, a parallel decrease inneed of major and minor surgery was observed. However, aconvincing surgery-sparing effect of use of newer medicationswas not found.

Acknowledgements We thank Doctor Björn Pasternak for his useful comments inhandling medical data.

Contributors CR: Conception and design of the study, generation andinterpretation of data, drafting the manuscript and approval of the final version ofthe manuscript. SB: generation, analysis and interpretation of data. Revision andapproval of the final version of the manuscript. MA: analysis and interpretation ofdata. Revision and approval of the final version of the manuscript. NMN. Generationand interpretation of data. Revision and approval of the final version of themanuscript. JW: Design of the study, analysis and interpretation of data, revisionand approval of the final version of the manuscript. EL: Conception and design ofthe study, interpretation of data, revision and approval of the final version of themanuscript. TJ: Conception and design of the study, generation and interpretation ofdata, drafting and critical revision of the manuscript and approval of the finalversion of the manuscript.

Funding Dr Tine Jess was financially supported through a Female Research Leadergrant (no. 09-066323) from the Danish Council of Independent Research and thestudy was further supported by the Danish Cancer Society, grant (no.R40-A1737-11-S2).

Competing interests None.

Ethics approval The study was register based and has been approved by DanishData Protection Agency.

Provenance and peer review Not commissioned; externally peer reviewed.

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doi: 10.1136/gutjnl-2013-3056072013

2014 63: 1607-1616 originally published online September 20,Gut Christine Rungoe, Ebbe Langholz, Mikael Andersson, et al. 

2011−nationwide cohort study 1979 rates in inflammatory bowel disease: a

Changes in medical treatment and surgery

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