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Transcript
NUMBER 1 OF 1
AUTHOR QUERIES
DATE 8/18/2015
JOB NAME IBD
ARTICLE IBD-15-0022
QUERIES FOR AUTHORS Hovde et al
THIS QUERY FORM MUST BE RETURNED WITH ALL PROOFS FOR CORRECTIONS
AU1) Please check the edits made to the affiliations.
AU2) Please confirm the conflicts of interest statement added.
AU3) Please note that the “Ethics approval” section has been moved from the acknowledgment section and placed below the
“Materials and methods” section. Please check and change if necessary.
AU4) Please spell out “SMR” in the sentence ‘An interesting prospective.” if necessary.
AU5) For references 1; 2; 3; 4; 5; 6; 7; 8; 10; 11; 12; 13; 14; 17 if the total number of authors is 3 or fewer, please provide
names of all the authors. If the number of authors is more than 3, then provide the names of first 3 authors followed by
et al, as per journal style.
AU6) Please note that original references 6 and 11 were identical. Therefore, reference 11 had been deleted and the references
have been renumbered both in text and in list so as to maintain sequential order. Please check.
ORIGINAL ARTICLE
Mortality andCauses of Death in Ulcerative Colitis: Results from 20Years of Follow-up in the IBSEN StudyØistein Hovde, MD,* Milada C. Småstuen, PhD,† Marte L. Høivik, MD, PhD,‡ Tomm Bernklev, PhD,§
Gert Huppertz-Hauss, MD,k Ole Høie, MD, PhD,¶ Jørgen Jahnsen, MD, PhD,** Njaal Stray, MD,††
Magne Henriksen, MD, PhD,‡‡ Inger C. Solberg, MD, PhD,‡ and Bjørn A. Moum, MD, PhD§§
Background: The best way to obtain knowledge about the natural history, including mortality, of ulcerative colitis (UC) is to conduct a longitudinal,population-based, prospective study. The aims of this study were to calculate the mortality rates and causes of death in patients with UC.
Methods: A prospective, population-based, longitudinal cohort study was conducted in South-Eastern Norway. A total of 519 patients (51.4% men)with UC were included over a 4-year period. A gastroenterologist from a university hospital reviewed the clinical information of all of the patients.Mortality data were retrieved from the Cause of Death Registry and from Statistics Norway.
Results: No statistically significant increases in total mortality or cause-specific mortality between the patients with UC and the controls were found.
Conclusions: The present 20-year population-based cohort study revealed a good prognosis regarding the mortality, which partially might be explainedby the patients0 coverage by a generally well-functioning health care system.
(Inflamm Bowel Dis 2015;00:1–5)
Key Words: ulcerative colitis, prospective study, causes of death, mortality
U lcerative colitis (UC) is a chronic relapsing inflammatorybowel disease (IBD) that affects the entire colon or the distal
part of the colon. Currently, the disease etiology is unknown, butenvironmental factors, gut dysbiosis, genetic susceptibility, andinappropriate immune response seem to be contributors to thepathogenesis. The symptoms of UC include diarrhea, blood/mucus in the stool, fatigue and anemia,1 and treatment, bothmedical and surgical, can cause serious side effects. Diseaseonset is usually seen in the patient’s third or fourth decade.2
Because of the age of the patients at the time of diagnosis andthe chronic nature of the disease, patients typically live with the
disease for decades. Previous studies have shown that the overallmortality of patients with UC is not greater than that of thebackground population.3,4
However, better diagnostic tools, more individualizedmedical therapy, and less invasive surgical procedures mighthave changed the clinical course and outcomes of the disease inrecent decades. Treatment with immunomodulators and biologicsmight increase the risk of cancer development in general, whilebetter control of inflammatory activity in the gut mucosa overtime might decrease the risk of developing neoplasms and hencereduce the risk of cancer-related mortality.
Received for publication May 15, 2015; Accepted XX, XXXX.
From the *Department of Gastroenterology, Innlandet Hospital Trust, Gjøvik, Norway, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; †Department ofBiostatistics, Faculty of Medicine, University of Oslo, Oslo, Norway; ‡Department of Gastroenterology, Oslo University Hospital, Oslo, Norway; §Department for Research andDevelopment, Telemark Hospital, Skien, Norway, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; kDepartment of Gastroenterology, Telemark Hospital,Skien, Skien, Norway; ¶Department of Internal Medicine, Sørlandet Hospital, Arendal, Norway; **Department of Gastroenterology, Akershus University Hospital, Lørenskog,Norway, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; ††Department of Internal Medicine, Diakonhjemmet Hospital, Oslo, Norway; ‡‡Department ofGastroenterology, Østfold Hospital, Fredrikstad, Norway; and §§Department of Gastroenterology, Oslo University Hospital, Oslo, Norway, and Institute of Clinical Medicine,University of Oslo, Oslo, NorwayAU1 .
Supported by Innlandet Hospital Trust, MSD, Norway, and Janssen Biologics B.V.
The authors have no conflicts of interest to disclose.AU2
All authors contributed substantially to the conception and design of the study as well as to the generation, collection and interpretation of data. All authors alsocontributed to the drafting and revision of the manuscript and to the approval of the final version of the manuscript. M. C. Småstuen had the main responsibility for thestatistical analyses. Ø. Hovde and B. A. Moum were responsible for drafting the article and for its critical revision, for important intellectual content and for the final approvalof the version to be published; they also were partially responsible for the statistical analyses.
Language review: American Journal Experts.
Reprints: Øistein Hovde, MD, Department of Gastroenterology, Innlandet Hospital Trust, Gjøvik, Kyrre Greppsgt. 19, 2819 Gjøvik, Norway (e-mail: [email protected]).
Selection bias is avoided by conducting population-based,longitudinal, prospective studies that include patients who arerepresentative of what is seen in daily clinical practice. Thisapproach is the best way to gaining more knowledge about thetrue nature of the disease.
The aims of this study were to calculate the mortality ratesand risk ratios of all-cause and cause-specific mortality in a well-defined and population-based cohort of patients with UC 20 yearsafter diagnosis.
MATERIALS AND METHODSThe Inflammatory Bowel South-Eastern Norway study has
prospectively followed all patients diagnosed with IBD in the 4-year period from January 1, 1990 to December 31, 1993 in 4geographically well-defined areas (counties) in South-EasternNorway. The cohort included 519 patients with UC.5,6 On January1, 1992, the total population in the area was 966,427. The charac-teristics of the cohort at diagnosis are listed inT1 Table 1. A seniorgastroenterologist at each hospital was responsible for the diagnos-tic procedures and the registration and inclusion of the patients. Thedesign and conduction of the study has been described in detailelsewhere.7,8
Follow-up visits were conducted at 1, 5, 10, and 20 (61)years after inclusion, and the same gastroenterologists at eachcenter were in charge of all of these visits. A clinical examination,a structured interview, and laboratory tests were performed at allof the follow-up visits. Colonoscopies were performed at the 5-,10-, and 20-year visits, unless the patients objected. Mortality datawere retrieved from the Cause of Death Registry, Statistics
Norway, and from hospital records. The causes of deaths weredivided into 4 groups according to the International Classificationof Diseases (ICD)-10: (1) gastrointestinal cancer (ICD-10 diagno-ses C15-C26), (2) all other cancers (ICD-10 diagnoses C00-C97,except C15-C26), (3) cardiovascular diseases (ICD-10 diagnosesI00-I99), and (4) other causes (all other ICD-10 diagnoses).
Ethics Approval AU3
The regional Committee for Medical Ethics approved thestudy. All of the patients attending the 20-year follow-up studyprovided their written informed consent before participating. Theconfidentiality of patient identities was maintained using theguidelines suggested by the National Health Department.
Definitions and Disease ClassificationsThe UC diagnosis was made according to international
criteria9 based on symptoms consistent with IBD that had lastedfor more than 4 weeks. Infections and other non-IBD conditionswere excluded. To establish the diagnosis, at least 3 of the fol-lowing 4 criteria had to be met: (1) a typical history of diarrheaand/or pus/blood in stools, (2) macroscopic appearance, on endos-copy, of continuous mucosal inflammation affecting the rectum incontinuity with some of or the entire colon, (3) microscopic fea-tures on biopsies compatible with UC, and (4) no suspicion ofCrohn’s disease on x-ray of the small bowel, ileocolonoscopy, orbiopsy.6,10 At the prescheduled visits at 1, 5, and 10 years, thediagnoses were systematically reevaluated. Inflammatory changesup to 15 cm from the anus were defined as proctitis, left-sidedcolitis was defined as inflammatory changes up to the splenicflexure, and extensive colitis was defined as inflammation beyondthe splenic flexure.
The status of patients lost to follow-up was reviewed fromhospital records. Any occurrence of colorectal cancer or canceroutside the gastrointestinal system was recorded, and the requiredinformation sources were data from the Norwegian Causes ofDeath Registry, reports from the pathologist, or hospital recordswith the surgical report. At the end of the study, the dates andcauses of death were recorded and cross-checked against datainformation from Statistics Norway.
Statistical AnalysisContinuous variables are described as the medians and
ranges and categorical variables as proportions and percentages.Crude differences between categorical variables were assessedwith the chi-square test.
Each patient in the Inflammatory Bowel South-EasternNorway cohort was age and sex matched with 25 controls fromthe same geographical area.
Thus, each patient and his/her controls formed a unitreferred to as matched set. Crude cumulative mortality, both forthe entire cohort and separately for each sex, was calculated usingthe Kaplan–Meier method.
The risk ratios of all-cause and cause-specific mortality(gastrointestinal cancer, all other cancers, heart disease, and
TABLE 1. Characteristics at Diagnosis and TreatmentGiven at Diagnosis, Patients with UC (n ¼ 519,Including 10 Patients Lost to Follow-up)
Age, men, median 38.6, yr
Age, females, median 37.4, yr
Gender (females/males) 252/267
Proctitis, n (%) 171 (33)
Left-sided colitis, n (%) 182 (35)
Extensive colitis, n (%) 166 (32)
Never smoked, n (%) 292 (56)
Smoker, n (%) 68 (13.3)Ex smoker, n (%) 156 (30.1)
Missing data, smoking, n (%) 2 (0.4)
Oral 5-ASA/SASP,a n (%) 327 (63)
Oral GC,b n (%) 12 (2.3)
Local 5-ASA/GC 140 (27)
Three patients (0.6%) were treated surgically immediately after diagnosis. Thirty-sevenpatients (7.1%) did not need medical/surgical treatment at diagnosis.aWith or without oral GC/local 5-ASA/GC/oral metronidazole.bWith or without local 5-ASA/GC.5-ASA, 5-aminosalicylic acid; GC, glucocorticosteroids; SASP, sulfasalazine.
Hovde et al Inflamm Bowel Dis � Volume 00, Number 00, Month 2015
AU3: You can keep "Ethics Approval" here, but remove the section "Ethics" on nest page since the text is equal to what is written under "Ethics Approval".
oeihov
Notat
Unmarked angitt av oeihov
oeihov
Notat
Add (%) after "Local 5-ASA/GC in the table.
“other”) for the patients, compared to matched controls, weremodeled with Cox regression analyses stratified by matched sets.The results are expressed as hazard ratios and are presented with95% confidence intervals. P-values , 0.05 were considered sta-tistically significant.
Data analyses were performed using the Statistical Packagefor the Social Sciences (SPSS, version 16.0 for Windows; SPSS,Chicago, IL) and Stata software, version 13 (StataCorp 2013,Stata Statistical Software: Release 13; Stat Corp LP, CollegeStation, TX).
EthicsThe Regional Committee for Medical Ethics approved the
study. All of the patients attending the 20-year follow-up studyprovide their written informed consent before participating. Theconfidentiality of patient identities and records was maintainedusing the guidelines suggested by the National Health Department.
RESULTSA total of 519 patients were diagnosed with UC; 267
(51.4%) were male and 252 were female patients. Ten patientswere lost to follow-up; the patients available for analysis werematched with 25 controls according to age, sex, and county ofresidence. The mean age at diagnosis was 42 years (median agewas 37.4 yr).2 For men, the mean age was 42.7 years, and forwomen, the mean age was 41.9 years. The extent of colitis atdiagnosis and the initial treatment given are shown in Table 1.
Twenty years later, a total of 129 (29%) of the 445 patientswith information about medication were treated with 5-ASA, 9patients were on azathioprine, and 12 patients had been treatedwith tumor necrosis factor–a inhibitors in the period between 10and 20 years after diagnosis. In the first 10 years of the Inflam-matory Bowel South-Eastern Norway study, no patients weretreated with tumor necrosis factor–a inhibitors. There were nodeaths in the tumor necrosis factor–a inhibitor treated group. Inthe whole cohort, 61 of 263 (23%) men and 47 of 246 (19%)women had died.T2 Table 2 shows the causes of deaths in the
patients with UC, compared with their matched controls. No sig-nificant differences in deaths from any of the causes were revealedbetween patients and controls.
F1Figures 1 and 2 display the cumulative mortality risk foreach sex separately. When comparing overall mortality, patientswith UC had a slightly higher overall mortality risk than controls.However, the risk ratio did not reach statistical significance(hazard ratio ¼ 1.14, 95% confidence interval, 0.93–1.40, P ¼0.20). Ten years after the diagnosis, 49 patients had been colec-tomized; 25 of these colectomies were performed the first 2 yearsafter diagnosis.6 Between 11 and 20 years after the diagnosis, 8more patients were colectomized. The colectomized patients werenot excluded from the statistical analyses after the surgery becausewe wanted to follow all initial cases classified with UC for 20years whether they had their colon intact or not. No mortality wasfound 30 days postoperatively. No statistically significant differ-ences in cause-specific mortality risk between the patients with
TABLE 2. Causes of Death in the UC Group Comparedwith Sex- and Age-Matched Controls in the GeneralPopulation from the Same Geographical Area
UC and the controls were found when analyzed separately foreach of the 4 main causes of death (data not shown).
DISCUSSIONThe present population-based cohort study revealed that
patients with UC had good prognoses regarding mortality 20years after diagnosis. Moreover, there were no more deaths fromcancer in the UC group than in a comparable age-, gender-, andresidency-matched Norwegian population.
The proportion of deceased individuals was slightly higherin the patients with UC, compared with their matched controls(the crude difference was 6.2%), but there were no statisticallysignificant differences in cumulative mortality rates between thegroups. Thus, our results suggested no need for restrictionsregarding health or life insurance for patients with UC.
The natural course of UC is best described in population-based, long-term studies that include patients with the wholerange of disease activity, from remission to mild proctitis toextensive, severe colitis. This study fulfilled these criteria.
By law, medical doctors in Norway must report any deathand complete a death certificate. These certificates are sent to theCause of Death Registry for the coding of information. In somecases, the underlying causes of death might be difficult toestablish and consequently can lead to a registration that is notalways accurate. There is, however, no reason to assume differ-ences in the classification of causes of deaths in the UC group,compared with deaths in the general population.
In a recent study from Denmark, the authors showed thatpatients older than 50 years with extensive colitis at diagnosis hadincreased mortality during the first 2 years after diagnosis,compared with the general population. All of the causes of deathwere reported to be colitis associated and of great importancewere postoperative complications.4 A study from 1982,11 in which676 patients with UC underwent a long-term review, reporteda mortality risk 1.7 times that of the general population. Thisstudy revealed a heavy mortality burden during the first year afterdiagnosis and during the first year after colectomy.
Selinger and Leong,12 in a recent review article of cohort-and population-based mortality studies, found that the majority ofstudies did not demonstrate increased mortality in patients withUC, compared with the general population. They also found thatstudies with patients with UC diagnosed from the 1940s to 1960sand studies with high-surgical rates were associated withincreased mortality rates. Age at diagnosis and extent of the dis-ease, in contrast, did not influence the mortality rate.
When searching for postoperative mortality in this study,we could not find any patients who died within the first 30 daysafter surgery, in contrast with the findings of a meta-analysis from2007, in which 44% of UC-related deaths were due to compli-cations directly related to surgery (peritonitis, perforations, andother postoperative complications).13 Bernstein et al14 found thatstandard mortality rates in UC were at the same level as those inthe general population, but older patients with UC were found to
have more comorbidities and greater mortality than the generalpopulation.
Mortality data from 21 different countries, from 1951 to2005,15 showed a 6-fold greater mortality rate in patients with UCfor the entire period compared with patients with Crohn’s disease,but from the mid-seventies, the mortality risk associated withthese 2 diseases reached a similar level. The introduction of cor-ticosteroids in the treatment of UC in the middle of the 1950scontributed to a decrease in mortality,16 and the use of moreindividualized treatment in past decades with newer therapeuticapproaches might constitute part of the explanation for the favor-able developments in mortality. The increasing use of less inva-sive surgical procedures might also have contributed to thedecreased mortality rate. An interesting prospective AU4, registry-based study from Finland,17 in which 1254 patients with UC werefollowed for 13.5 years, showed that the overall mortality ratewas, in fact, decreased (but not significantly), compared with whatwas expected (SMR 0.90, 95% confidence interval, 0.77–1.06). Inparticular, there were fewer deaths from mental and behavioraldisorders due to alcohol use in the UC group, compared with thegeneral population.
Strengths and LimitationsMajor strengths of this study included the longitudinal
follow-up of a well-defined inception cohort in a well-characterized geographical area. The limited time during whichinclusion occurred, combined with dedicated specialists, andhospitals being responsible for the diagnostic procedures werefactors that contributed to a uniform diagnostic and therapeuticapproach. Norwegians do not tend to move very often, and it istherefore easy to conduct prospective studies that last for manyyears. The duration of follow-up was the same for all of thepatients. Owing to a complete national death cause registry, wewere able to match each patient with age- and sex-matchedindividuals from the same geographical area. Each individual bornin Norway is assigned a unique ID number that enables easy andaccurate identification and linkage of medical and death certificaterecords. This fact constituted a substantial strength of this study.
There were some limitations to the study. The relatively smallnumber of deaths in this population-based cohort implied limitedstatistical power. Because of a limited number of patients,stratification according to disease extension at diagnosis was notperformed. At diagnosis, the median age of the patients was 37.4years,2 indicating that the patients were relatively young, even 20years later. Thus, it is impossible to exclude that a longer observationperiod might have revealed increased mortality in the UC group.
CONCLUSIONSThe present population-based inception cohort study of
newly diagnosed patients with UC revealed a good prognosisregarding mortality 20 years after diagnosis. There were nostatistically significant differences in mortality or deaths fromcancer compared with the general Norwegian population. This
Hovde et al Inflamm Bowel Dis � Volume 00, Number 00, Month 2015
outcome might be explained by the inclusion of an unselectedpatient cohort in a generally well-functioning, public health caresystem during these 2 decades of follow-up. The sample size,however, was relatively small indicating a possibility ofunderpowering.
ACKNOWLEDGMENTSThe authors thank all of the following members of the
Inflammatory Bowel South-Eastern Norway (IBSEN) study groupfor participating in this study: Morten Vatn, Akershus UniversityHospital; Iril Kempski-Monstad, Idar Lygren, Øyvind Palm, andErling Aadland, Oslo University Hospital; Jostein Sauar, BorgarFlaaten, and Øystein Kjellevold, Telemark Hospital; and ArneRøseth and Finn Strøm, Lovisenberg Diakonale Hospital.
Author contributions: All of the authors made substantialcontributions to the conception and design of the study, as well asthe generation, collection, and interpretation of the data. All of theauthors also contributed to the drafting and revision of the articleand approved the final version of the article. M. C. Småstuen hadthe main responsibility for the statistical analyses. Ø. Hovde andB. A. Moum were responsible for drafting the article, for revisingit critically, for important intellectual content, and for the finalapproval of the version to be published. They also were partiallyresponsible for the statistical analyses.
REFERENCES1. Kim B, et al. Proximal disease extension and related predicting factors in
2. Moum B, et al. Incidence of ulcerative colitis and indeterminate colitis infour counties of southeastern Norway, 1990-93. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN)
Study Group of Gastroenterologists. Scand J Gastroenterol. 1996;31:362–366.
3. Cosnes J, et al. Epidemiology and natural history of inflammatory boweldiseases. Gastroenterology. 2011;140:1785–1794.e4.
4. Winther KV, et al. Survival and cause-specific mortality in ulcerativecolitis: follow-up of a population-based cohort in Copenhagen County.Gastroenterology. 2003;125:1576–1582.
5. Solberg IC, et al. Clinical course in Crohn’s disease: results of a Norwe-gian population-based ten-year follow-up study. Clin GastroenterolHepatol. 2007;5:1430–1438.
6. Solberg IC, et al. Clinical course during the first 10 years of ulcerativecolitis: results from a population-based inception cohort (IBSEN Study).Scand J Gastroenterol. 2009;44:431–440. AU6
7. Moum B, et al. Incidence of inflammatory bowel disease in southeasternNorway: evaluation of methods after 1 year of registration. Digestion.1995;56:377–381.
8. Henriksen M, et al. Change of diagnosis during the first five years afteronset of inflammatory bowel disease: results of a prospective follow-upstudy (the IBSEN Study). Scand J Gastroenterol. 2006;41:1037–1043.
10. Henriksen M, et al. Ulcerative colitis and clinical course: results ofa 5-year population-based follow-up study (the IBSEN study). InflammBowel Dis. 2006;12:543–550.
11. Gyde S, et al. Mortality in ulcerative colitis. Gastroenterology. 1982;83:36–43.
13. Jess T, et al. Overall and cause-specific mortality in ulcerative colitis:meta-analysis of population-based inception cohort studies. Am J Gastro-enterol. 2007;102:609–617.
14. Bernstein CN, et al. A review of mortality and surgery in ulcerative colitis:milestones of the seriousness of the disease. Inflamm Bowel Dis. 2013;19:2001–2010.
15. Sonnenberg A. Time trends of mortality from Crohn’s disease and ulcer-ative colitis. Int J Epidemiol. 2007;36:890–899.
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Inflamm Bowel Dis � Volume 00, Number 00, Month 2015 Mortality and Causes of Death in UC
