decreasing risk of first and subsequent surgeries in

Accepted Manuscript

Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn'sDisease in England From 1994 through 2013

Dr Nicholas E. Burr, Dr Richard Lord, Professor Mark A. Hull, Dr VenkataramanSubramanian

PII: S1542-3565(18)31398-3DOI: https://doi.org/10.1016/j.cgh.2018.12.022Reference: YJCGH 56257

To appear in: Clinical Gastroenterology and HepatologyAccepted Date: 7 December 2018

Please cite this article as: Burr NE, Lord R, Hull MA, Subramanian V, Decreasing Risk of First andSubsequent Surgeries in Patients With Crohn's Disease in England From 1994 through 2013, ClinicalGastroenterology and Hepatology (2019), doi: https://doi.org/10.1016/j.cgh.2018.12.022.

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https://doi.org/10.1016/j.cgh.2018.12.022

https://doi.org/10.1016/j.cgh.2018.12.022

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Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn's Disease in England From

1994 through 2013

Short title: Decreasing risk of surgery in Crohn’s disease.

Dr Nicholas E Burr1, 2

Dr Richard Lord1, 2

Professor Mark A Hull1, 2

Dr Venkataraman Subramanian1, 2

Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United

Kingdom. 1

Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, United

Kingdom. 2

Grant support : The work was funded by a grant from Crohn’s and Colitis UK (Grant

Number - M16-4 and a grant from the Leeds Teaching Hospitals NHS Trust Charitable

Foundation (Grant number 9R01/14-04). These awards were competitive research

grants to fund higher clinical academic training. They had no influence over the design

or conduct of the study.

Abbreviations:

anti-TNF-α Anti-tumour necrosis factor-α

CD Crohn's disease

chi2 Chi-squared

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CI Confidence interval

GI Gastrointestinal

HR Hazard ratio

IMD Index of multiple deprivation

NHS National Health Service

UK United kingdom

Correspondence to: Dr Venkataraman Subramanian, Leeds Institute of Biomedical

and Clinical Sciences, University of Leeds, Leeds, LS9 7TF, United Kingdom.

Tel: +44 113 2068768; Fax:+44 113 2068851

Email: [email protected]

Disclosures, for all authors: None to declare.

Writing assistance: None

Author contributions: NEB, MAH & VS conceived the study. NEB, RL and VS

analyzed the data. All authors commented on drafts of the manuscript and approved the

final version.

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Abstract :

Background & Aims: Gastrointestinal (GI) surgery is an important part of the treatment

algorithm for patients with Crohn’s disease (CD) that is complicated or does not respond

to medical therapy. Cohort studies from Denmark and Canada have shown that the risk

of primary surgery is decreasing but there is a lack of contemporary data on subsequent

resections. We examined trends in first and second GI resections in patients with CD.

Methods: We performed a retrospective cohort study using the United Kingdom primary

care database ResearchOne, collecting data from patients with Crohn’s disease from

1994 through 2013. We compared rates of first and second GI resections with

etiological factors.

Results: Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients

underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an

initial resection, 20% required an additional operation when followed for 10 years after

the initial resection. We found a significant reduction in first surgery, from 44% to 21%

after 10 years of disease, from 1994 to 2003 (�2 for trend, P<.05). There was a

significant reduction in second resections, in a 10–year follow-up period, from 40% in

1994 to 17% in 2003 (�2 for trend, P<.05). Duration of disease, younger age at

diagnosis, smoking, and immunomodulator use were positively associated with first

surgeries. Duration of disease was significantly associated with the risk of undergoing a

second resection.

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Conclusion: In a retrospective analysis of a United Kingdom primary care database,

we observed a significant reduction in first and subsequent GI surgeries among patients

with CD over the past 20 years in England.

KEY WORDS: Operation; epidemiology; IBD; UK

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What You Need to Know

Background: Surgery is an important part of management of patients with Crohn’s

disease. There have been some reports of reductions in first resections over time, but

there are few data on subsequent resections.

Findings: Using a population dataset, ResearchOne, we found a significant reduction in

first resections from 1994 through 2013 in England; 26% of patients with CD required

surgery after 10 years in 2013. There has also been a significant reduction in the need

for a subsequent resection with 17% of those first operated in 2003 requiring further

surgery.

Implications for patient care: We found evidence for improved management of patients

with CD from 1994 to 2013.

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Background & Aims

Crohn’s disease (CD) is an inflammatory bowel disease which can affect any part

of the gastrointestinal tract. It is characterized by inflammation and ulceration which

most commonly affects the terminal ileum and proximal colon. 1 Treatment of the

disease involves medical therapy to try and control luminal inflammation, achieve

sustained remission and maintain bowel function. More recently, medical treatment has

become individualized through adopting either a “top down” or “step up” approach, with

new medications adding to the clinical armamentarium, and potentially modifying the

disease process. 2 Gastrointestinal (GI) surgery is indicated for disease that hasn’t

responded to medical therapy, or for complications such as internal fistulae, intestinal

obstruction, hemorrhage, toxic dilatation or perforation. 3,4 Surgery remains an important

part of the treatment algorithm, especially for limited terminal-ileal disease, with a recent

randomized controlled trial showing similar outcomes between anti-tumour necrosis

factor-α (anti-TNF-α) and surgically treated disease that had failed to respond to

previous conventional therapy. 5

The most recent systematic review and meta-analysis, in 2013, reported one,

five, and ten-year primary surgery risks of 16%, 33%, and 47% respectively for all

patients with CD. 6 This included a mixture of tertiary-care and population-based

cohorts. Studies from Denmark and Canada have shown a similar reduction in surgical

risk. In Denmark the 5-year risk of primary resection was 19.6% for those diagnosed

between 2003 and 2011.7 The latest study examining surgery in CD from Calgary,

Canada examined the number of surgeries in those with CD and estimated rates of

resection from estimated population prevalence of CD. Here, the estimated rate of

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surgery decreased from 4.4/100 person-years in 2002 to 3.5/100 person-years in 2010.8

There have been few population-based studies on subsequent resections in CD but,

from the available evidence, the risk has been estimated at 16%, 28%, and 35% at five,

ten, and fifteen years after the initial surgery respectively. 1,9 These data are based on

historical cohorts from as far back as 1940, with the most recent data from 2004.

There is a lack of UK population data on primary resections, and contemporary

data on subsequent, resection rates for CD. Exploring etiological factors is important to

identify potentially modifiable risk factors which may be associated with surgery. These

data are important in providing information to patients with CD and clinicians involved in

their care.

Aims

1. Report the risk of first, and second, GI resections in those with CD.

2. Explore associations with first, and second, GI resections in this cohort.

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Materials and Methods

Data source

We used the United Kingdom (UK), National Health Service, population-based,

primary-care database ResearchOne for this study. 10 The ResearchOne database

holds de-identified clinical and administrative records of approximately 6 million

individuals (>10% of the English population), drawn from the larger SystmOne

database, which is used by 34% of practitioners in England. 11 Prescriptions are issued

electronically and clinical data are prospectively entered using Clinical Terms Version 3

codes (Read codes). 12 Individuals are removed, and so not included in data extracts,

when they move to a general practitioner not included in ResearchOne. If somebody

dies their records are retained in the ResearchOne database. These type of datasets

can allow the analysis of representative samples of the English general population, as

98% of residents in England are registered with a general practitioner. 13 We have

previously described this dataset and published prescription data and clinical outcomes

in those with IBD. 14

Validation study

The ResearchOne dataset has not been validated to our knowledge, to date. In order to

confirm the cases of IBD we performed such a study. Full details of the project are

included in the online supplementary materials. Briefly, we consented and recruited 100

individuals with inflammatory bowel disease from out-patient clinic attendances at Leeds

Teaching Hospitals NHS Trust. We compared the hospital confirmed diagnoses with

those held on the ResearchOne general practice computer database.

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Inclusion

Our cohort comprised adults (>18 years old) with a Read code for CD

(supplementary appendix, table 1) from 01/01/1994 to data extraction on 14th

September 2014. We composed an incident cohort by excluding those with a date of

diagnosis within twelve months of joining a ResearchOne practice to exclude prevalent

cases where the date of diagnosis may be less accurate. This also allows the capture of

continuous prescription data from the date of entry into the ResearchOne database. We

excluded individuals with indeterminate colitis, classified as only having a Read code for

indeterminate colitis or where both codes for ulcerative colitis and CD were present in

the medical record.

Variables of interest.

We investigated two endpoints, namely;

1. First GI surgery, defined as the first Read code entry for a GI surgical

procedure (supplemental appendix, table 2) after a Read code entry for CD.

2. Second GI surgery, defined as a Read code entry for GI surgery at least

twelve months after a primary resection. We used this definition to try and

account for second operations performed as a revision of, or due to

complications from the initial surgery.

We did not include Read codes for perianal operations, including fistula surgery

as these may not be related to Crohn’s disease activity. We also excluded codes for

reversal, or revision, of a previous ileostomy or colostomy as this is likely to represent

planned surgery to repair the stoma site, rather than for disease activity. 15 The time to

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first GI surgery was calculated as the time in days from CD diagnosis to surgery date. In

some cases the diagnosis of CD occurred at the time of the primary resection. Three

time categories were used; surgery within one, five and ten years of diagnosis. Time to

second GI surgery was taken as the time in days from the first operation to the second

operation if longer than one year. We stratified the study subjects into ten, two-year

diagnosis cohorts from 01/01/1994 to 31/12/2013 to examine surgical trends over a

twenty-year follow up period.

For all individuals, we extracted a defined set of data items, including; date of

birth (mm/yyyy), gender, date of death (mm/yyyy) , English Index of Multiple Deprivation

(IMD)16 of residence, diagnoses of CD and relevant comorbidities (including smoking

status), and prescriptions (including repeat prescriptions). British National Formulary

(https://www.evidence.nhs.uk/formulary/bnf/current (accessed April 2014)) headings

and subheadings were used to identify the medication classes. Individuals were

followed up from their CD diagnosis to either death or the extraction date.

Age at diagnosis and duration of CD, from diagnosis to the data extraction date,

and IMD score 16 were used as continuous variables. A lower IMD score equates to

more deprivation and has been shown to correlate with increased morbidity and all-

cause mortality in the UK. 17 To account for co-morbidity we produced an estimate of

the Charlson score 18 using Read codes for each of the seventeen weighted disease

categories included in the original score. We calculated a similar, weighted score and

used a cut off of ≥ two as a modest estimate of co-morbidity. Smoking history was

recorded as ever and never smoked. We adjusted for known surrogate markers of CD

severity including corticosteroid medications given within ninety days of CD diagnosis 9

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and also immunomodulator use, namely azathioprine, 6-mercaptopurine and

methotrexate. 19

Two investigators (NB & RL) searched through the complete list of Read codes

for our variables of interest. Any disagreement was resolved by consensus decision and

the involvement of a third party (VS). A list of the Read term definitions is included in the

supplementary materials.

Statistical analysis

The number of individuals undergoing GI surgery was calculated as a percentage of the

number of alive, diagnosed patients in two-year periods from 1994 to 2013 to produce

surgical rates over a twenty-year period. We used chi-squared (chi2) for trend to identify

any significant change in surgical rates over the study period at one, five and ten years

from diagnosis for the first operation, and two, five, and ten years from this operation for

the second GI surgery cohort. We also calculated the annual percentage change for

each of these rates. As we only had ten-year follow-up data until 2003 we performed an

additional chi2 for trend analysis for the first ten years of follow up to see if there was

any significant change in surgical rates.

Kaplan-Meier failure curves were constructed to display the time taken until the

first GI surgery, in years, from the CD diagnosis date. We produced cumulative hazards

(hazard ratio (HR) with 95% confidence intervals (CI)) of surgery at one, five and ten

years from diagnosis and two, five, and ten years from the first resection. We separated

our cohort into four groups based on the year of diagnosis and plotted the time to

resection for each diagnosis cohort to examine changes over time.

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We compared the characteristics of those who had or hadn’t undergone first and

second GI surgery, using the chi2 test for categorical data, the two sampled t-test for

continuous, parametric variables and Mann-Whitney U test for non-parametric variables.

Ethical statement

ResearchOne has received a favourable opinion from National Health Service

(NHS) Research Ethics Committee (REC) (11/NE/0184) and the UK National

Information Governance Board for Health and Social Care. Our study has NHS REC

(14/WM/01/26) and local research and development (GA14/11077) approval.

Results

We included 3,059 incident cases of CD in our final analyses. There were 611

(20%) who had a resection. Of these, 75 (12%) underwent one, or more subsequent

operations. The first surgery was an ileo-colonic resection in 322 (53%), isolated small

bowel resection in 183 (30%), and an isolated colonic resection in 106 (17%). The

median time to first resection was 189 days (interquartile range 1 to 1,017 days). On

univariate analysis, younger age at diagnosis, duration of CD, ever having smoked or

having been prescribed an immunomodulator were significantly associated with first GI

surgery (p <0.05). There was no significant association for sex, deprivation score or

Charlson co-morbidity score. For second surgery, defined as > 1 year from the initial

operation, the operation was an ileo-colonic resection in 29 (39%), isolated colonic

resection in 25 (33%), and an isolated small bowel resection in 21 (28%). Only longer

duration of disease, until the second resection, showed a significant association with

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undergoing repeat surgery (table 1). The median time to the second resection was

1,184 days (interquartile range 558 to 2,192 days).

Validation study

We recruited, and consented 100 patients with IBD from outpatient clinics at Leeds

Teaching Hospitals NHS Trust (supplementary materials, table 1) who were registered

with a relevant GP. From the hospital histological diagnoses there were 62 patients with

CD, 35 with UC and 3 with indeterminate colitis. There were 23 individuals who had

undergone a GI surgical resection for IBD, 61% of these were ileo-colonic resections.

IBD diagnosis was recorded in 98 (98%) individuals’ GP records (supplementary

materials, table 2). The type of IBD was correct in 93%, and date of diagnosis was

within 6 months for 76% and within 12 months for 85%. Individuals who had undergone

surgery was recorded in 91% of patient’s primary care records. The surgery type was

correct in 81% of cases. The surgery date was accurate within 6 months in 90% of

cases and within 12 months in 95% of cases.

First GI surgery trends

We found a significant decrease in the proportion of those requiring a first GI

operation ten years from diagnosis from those diagnosed in 1994 to 1995 (44%) to

those diagnosed in to 2002 to 2003 (21%), chi2 for trend (p <0.05) . There was a

reduction in surgical rates for one and five years after diagnosis but this did not reach

statistical significance between the years 1993 to 2013 (figure 1). When analysing the

trend data over the first ten years from 1993 there was a significant reduction in one,

five and ten year rates of surgery. From the 1998 to 1999 cohort there has been a

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plateau in the rate of surgery after one, five and ten years from diagnosis. The annual

percentage change in first surgery rates were -1.2%, -2.5% and -5.4% after 1, 5, and 10

years from diagnosis respectively. For second surgery the annual percentage change in

rates were -0.2%, -0.7% and -4.8 % for resections 2 years, 5 years and 10 years from

the initial resection respectively.

We separated the study cohort into four groups based on the year of diagnosis.

The cumulative hazards of undergoing surgery after one, five and 10 years from

diagnosis are shown in table 2. The hazard of primary surgery after 10 years of

diagnosis falls from 0.58 (95% CI 0.40 to 0.86) for those diagnosed in 1990 to 1995 to

0.25 (95% CI 0.22 to 0.29) for those diagnosed in 2002 to 2007. We constructed a

Kaplan-Meier failure curve displays the increasing number of those undergoing surgery

since diagnosis in figure 2, again stratifying by year of diagnosis in 4 groups. The risk of

surgery was greatest for the early diagnosis cohort (1990 to 1995).

Second GI surgery trends

There has been a significant reduction in second GI surgery rates, up to ten

years after the initial operation, from 40% for those first operated in 1994 to 17% in

2003 (chi2 for trend p < 0.05) (figure 3). There has been no significant reduction in

second GI surgery rates two, or five years after the primary operation. This was

consistent with results from the first ten years after surgery, 1993-2003.

We calculated the cumulative hazard for undergoing second surgery for four

groups based on diagnosis cohort. As for first resection there was a reduction for later

diagnosis cohorts with the cumulative hazard falling from 0.48 (95% CI 0.27 to 0.88) for

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those diagnosed in 1990 to 1995 to 0.16 (95% CI 0.11 to 0.24) for those diagnosed in

2002 to 2007. A Kaplan-Meier failure curve displays the increasing number of those

having surgery in figure 4, stratified by the four groups based on year of diagnosis.

Discussion

Here we have shown a significant reduction in the risk of surgery after ten years

of CD in a UK population-based cohort since 1994. We have also shown a reduction in

the risk of subsequent operation risk within ten years of the initial surgery. The duration

of CD, younger age at diagnosis, smoking and immunomodulator use were significantly

associated with undergoing initial GI surgery. We would expect disease duration to be

associated with surgery as CD is a life-long relapsing and remitting condition. 20 Whilst

immunomodulators are used to try and prevent disease progression and complications

such as surgery, 21 the use of these medications is likely to be associated with a more

severe disease phenotype and thus the possibility of needing an operation. Smoking is

an established risk factor for adverse outcomes, including first and subsequent surgery

in CD. 22 Smoking rates worldwide are decreasing, 23 so this may account for some of

the reduction seen in the number of operations. Interestingly, we found no association

between deprivation score and the need for surgery which may reflect the current

universal access, free at the point of care model provided by the UK National Health

Service.

International guidelines from 2017 quote the surgical risk at much greater than

we have shown at up to 90% for certain individuals with CD, 24 and second operation

risk at up to 50%. These estimates are drawn from historic cohorts from the 1980’s and

1990’s. 3,25,26 The latest systematic review and meta-analysis with pooled data from

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primary and secondary care since 1990, quotes a lower risk of primary resection ten

years after diagnosis at 39% (95% CI 31% - 48%). 6 The largest recent cohort from

Rungoe et al in 2017 examined patients from a Danish national cohort and showed a

reduction in the 9-year incidence of surgery from 50.3% in those diagnosed in 1979-86

to 23.3% in those diagnosed in 2003-11. 7 These results are consistent with our own.

They did not report the risk of subsequent GI resection. A recent study by Ma et al. in

2017 examined trends in all GI surgery for those with a hospital admission diagnosis

code for CD and found a reduction in rate from 4.4/100 person years of disease in 2002

to 3.5/100 person years of disease in 2010. 8 This study used admission codes for

surgery and calculated the annual operation rate as a proportion of the estimated local

prevalence of CD. There was not sufficient detail in the dataset to estimate the risk of

resection from date of diagnosis. The authors were also unable to determine whether

the operations were primary or subsequent surgeries, or performed as a revision of the

initial operation. There is a lack of population-based data on the incidence of

subsequent GI surgery for CD. In a cohort from Olmsted County from 1970 to 2004 the

risk of two, or more resections was 9% after ten years. 9 A Danish cohort study from the

1980’s found a risk of 13% after 10 years of disease. 27 A more recent study from 26

specialist CD units in Spain reported a five-year re-operation incidence of 14% for those

with a primary resection from 2007 to 2010. 28 Our re-operation cohort is likely to be

similar to this study, as after a primary resection for CD most individuals are likely to be

followed up in a specialist centre, and our five-year re-operation rate of 12% (95% CI 9

– 15%) is in-line with results from this study.

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There are several plausible explanations for the reduced risk of surgery in our

study time period. It is likely that improved clinical care and patient education will

improve outcomes in CD over our study period. Studies have shown that early use of

immunomodulator medication, 29,30 or anti-TNF alpha therapy 31,32 can reduce the need

for early surgery in CD. However there is evidence that the risk of surgery is similar

between those who continue, or discontinue anti-TNF alpha therapy beyond twelve

months. 33 In the UK, CD treatment is increasingly delivered from secondary care by

specialists with an interest in inflammatory bowel disease. There is also increased multi-

disciplinary team involvement, specialist nurse support and resources available to

improve patient education and offer more personalised care. These measures may

have improved long-term outcomes with early use of medications, and prompt

escalations for non-responsive disease. With the implementation of National Institute for

Clinical Heath and Excellence quality standards for CD in 2015, there may be further

improvements to come. 34

There are several strengths to our study. Over 98% of UK residents are

registered with a GP so the study cohort is likely to be representative of the full clinical

spectrum of CD. 13 Studies using secondary, or tertiary care data are likely to have

inherent referral bias, typically including those with more severe disease. We have

confirmed previously established risk factors for GI surgery with duration of CD,

smoking and immunomodulator use. 30,35 This adds to the validity of the data source

used in this study.

There are several important limitations to our study which must be considered

when interpreting the results. Our diagnoses are drawn from primary care data which

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relies on computer entries derived from secondary care correspondence and results.

This could lead to an under, or over-estimation in our results. We believe this risk to be

small. Previous studies have shown that Read code entries were > 90% accurate in an

analysis of CD in the UK primary care database, the General Practice Research

Datalink (now called the Clinical Practice Research Datalink). 36 Further validation

studies of UK primary care datasets have consistently shown average accuracy rates of

> 85%. 37 Our own validation study, reported here, reflects similar accuracy of the

ResearchOne database. We did not have phenotypic data on disease location, or

extent. This information would be useful to advise patients on surgical risk as the need

for surgery in ileo-colonic, colonic, peri-anal and isolated small bowel CD are likely to be

different. We also do not have information on the use of anti-TNF-α medication which is

typically used in more severe disease. It is administered from hospital specialists, so

prescribing data is not consistently available in primary care databases. However,

widespread use for maintenance therapy was not adopted in the UK until 2010 38 and

between 2002 and 2010 episodic treatment was available but uptake was low. Less

than 3% of those with CD in the UK were prescribed an anti-TNF alpha in 2010. 39

The incidence of CD is increasing. 40 It is important for clinicians and patients to

be aware of the risks of surgery to help inform discussions about long-term

management and patient expectations. Our data suggest a significant reduction in the

incidence of first and second GI surgery since 1994. Whether this reduction is due to

improved, co-ordinated clinical care, patient education, reduction in smoking or

alternative factors is uncertain, but the disease course appears to have changed, with

newly diagnosed individuals being less likely to need surgery than those in the past.

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Funding

The work was supported by a grant from Crohn’s and Colitis UK (Grant Number -

M16-4 and a grant from the Leeds Teaching Hospitals NHS Trust Charitable Foundation

(Grant number 9R01/14-04). These are both competitive grant awards and the funders

did not have any influence over the study design or results.

Acknowledgments

We would like to thank Dr Chris Bates and Samantha Crossfield at The Phoenix

Partnership (TPP, ResearchOne) for their help with the study.

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Surgical management and special situations. J Crohn’s Colitis 2017;11:135-149.

25. Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s

disease. Gastroenterology 1985;88:1818-1825.

26. Shivananda S, Hordijk M, Pena A, et al. Crohn’s disease: Risk of recurrence and

reoperation in a defined population. Gut 1989;30:990-995.

27. Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn’s disease--based on

results from a regional patient group from the county of Copenhagen. Gut

1985;26:146-150.

28. Domènech E, Garcia V, Iborra M, et al. Incidence and Management of

Recurrence in Patients with Crohn ’ s Disease Who Have Undergone Intestinal

Resection : The Practicrohn Study. Inflamm Bowel Dis 2017;23:1-7.

29. Lakatos PL, Golovics PA, David G, et al. Has There Been a Change in the Natural

History of Crohn’s Disease? Surgical Rates and Medical Management in a

Population-Based Inception Cohort from Western Hungary Between 1977–2009.

Am J Gastroenterol 2012;107:579-588.

30. Ramadas A V., Gunesh S, Thomas GAO, et al. Natural history of Crohn’s disease

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in a population-based cohort from Cardiff (1986-2003): a study of changes in

medical treatment and surgical resection rates. Gut 2010;59:1200-1206.

31. Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces

hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease.

Gastroenterology 2005;128:862-869.

32. van der Valk ME, Mangen M-JJ, Leenders M, et al. Healthcare costs of

inflammatory bowel disease have shifted from hospitalisation and surgery towards

anti-TNFα therapy: results from the COIN study. Gut 2014;63:72-79.

33. Eberhardson M, Söderling JK, Neovius M, et al. Anti-TNF treatment in Crohn’s

disease and risk of bowel resection-a population based cohort study. Aliment

Pharmacol Ther 2017;46:589-598.

34. Inflammatory Bowel Disease Guidance and Guidelines. National Institute for

Health and Care Excellence. National Institute for Health and Care Excellence,

2015. https://www.nice.org.uk/guidance/qs81/resources. Accessed October 25,

2017.

35. Solberg IC, Vatn MH, Høie O, et al. Clinical Course in Crohn’s Disease: Results of

a Norwegian Population-Based Ten-Year Follow-Up Study. Clin Gastroenterol

Hepatol 2007;5:1430-1438.

36. Lewis JD, Brensinger C, Bilker WB, et al. Validity and completeness of the

General Practice Research Database for studies of inflammatory bowel disease.

Pharmacoepidemiol Drug Saf 2002;11:211-218.

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37. Herrett E, Thomas SL, Schoonen WM, et al. Validation and validity of diagnoses

in the General Practice Research Database: a systematic review. Br J Clin

Pharmacol 2010;69:4-14.

38. National Institute for Health and Care Excellence. Infliximab and Adalimumab for

the Treatment of Crohn’s Disease | Guidance and Guidelines., 2010.

39. Bardhan KD, Simmonds N, Royston C, et al. A United Kingdom inflammatory

bowel disease database: Making the effort worthwhile. J Crohn’s Colitis

2010;4:405-412.

40. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of

Crohn’s disease and ulcerative colitis in a commercially insured US population.

Dig Dis Sci 2013;58:519-525.

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Tables and Figures

Table 1 – Demographics and clinical characteristics of those with first or second gastrointestinal res ections.

First resection Second resection

Resection No resection p-value Second

resection

No second

resection

p-value

Total number of subjects, n (%) 611 (20) 2,448 (80) 75 (12) 536 (88)

Female sex, n (%) 320 (52) 1,309 (53) 0.626 37 (49) 283 (53) 0.574

Age at diagnosis, mean years (sd) 41 (19) 44 (19) <0.005 42 (19) 40 (18) 0.296

Deprivation score, median (IQR) 21 (11 – 35) 18 (11 – 34) 0.197 21 (11 – 36) 20 (11 – 35) 0.630

Duration of CD, median years (IQR) 8 (5 – 13) 6 (3 – 10) <0.005 12 (8 – 18) 8 (4 – 12) <0.005

Charlson ≥2, n (%) 113 (18) 438 (18) 0.729 9 (12) 104 (19) 0.122

Ever smoked, n (%) 335 (57) 1202 (52) 0.012 47 (64) 288 (56) 0.195

Ever prescribed an immunomodulator, n (%) 268 (44) 823 (34) <0.005 39 (52) 229 (43) 0.129

Steroids within 90 days of diagnosis, n (%) 122 (20) 476 (19) 0.771 9 (12) 113 (21) 0.065

Prescribed an immunomodulator after the

initial resection

N/A N/A N/A 34 (45) 263 (49) 0.545

Note: Incident cohort diagnosed at least 12 months after joining a ResearchOne GP practice. Those with surgery before a diagnosis of CD

excluded.

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Table 2. Cumulative hazard with 95% confidence inte rvals of first and second gastrointestinal surgerie s in those

with Crohn’s disease.

Year of diagnosis

Number at risk

Primary resection. Cumulative hazard

(95% CI) Year of diagnosis

Number at risk

Second resection. Cumulative hazard (95%

CI)

1990 to 1995 1990 to 1995 Resection within 1 year 46 0.30 (0.18 - 0.49) Second resection within 2 years* 30 NA Resection within 5 years 39 0.45 (0.29 - 0.68) Second resection within 5 years 25 0.19 (0.08 - 0.45) Resection within 10 years 32 0.58 (0.40 - 0.86)

Second resection within 10 years 17 0.48 (0.27 - 0.88) 1996 to 2001

1996 to 2001

Resection within 1 year 435 0.09 (0.07 - 0.12) Second resection within 2 years* 110 0.03 (0.01 - 0.09) Resection within 5 years 379 0.18 (0.14 - 0.22) Second resection within 5 years 90 0.08 (0.04 - 0.16) Resection within 10 years 340 0.23 (0.19 - 0.29) Second resection within 10 years 63 0.18 (0.11 - 0.30)

2002 to 2007

2002 to 2007 Resection within 1 year 909 0.13 (0.11 - 0.16) Second resection within 2 years* 197 0.06 (0.03 - 0.10)

Resection within 5 years 799 0.21 (0.18 - 0.24) Second resection within 5 years 158 0.12 (0.08 - 0.18) Resection within 10 years 308 0.25 (0.22 - 0.29) Second resection within 10 years 48 0.16 (0.11 - 0.24)

2008 to 2013

2008 to 2013 Resection within 1 year 1165 0.13 (0.11 - 0.15) Second resection within 2 years* 147 0.05 (0.02 - 0.09)

Resection within 5 years 250 0.22 (0.19 - 0.25) Second resection within 5 years 38 0.11 (0.06 - 0.20) Resection within 10 years 1 NA Second resection within 10 years 1 NA

Note: Incident cohort diagnosed at least 12 months after joining a ResearchOne GP practice. Those with surgery before a diagnosis of CD

excluded.

* Resection within 2 years used as second surgery defined as at least 1 year after the primary resection.

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Figure legends

Figure 1. 1, 5, and 10 year primary gastrointestinal surgery risk in persons with Crohn’s

disease, 1994 - 2013.

Figure 2. Kaplan-Meier failure curve showing time to first gastrointestinal resection.

Four equal cohorts. CD incident 12 months cohort. Excluded those with surgery before

a diagnosis of CD.

Figure 3. Second gastrointestinal surgery risk 2, 5, and 10 years after a primary

resection, 1994 - 2013.

Figure 4. Kaplan-Meier failure curve showing time to second gastrointestinal resection.

Four equal cohorts. CD incident 12 months cohort. Excluded those with surgery before

a diagnosis of CD.

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Online supplemental materials.

Table 1. Read code definitions for Crohn’s disease cohort

(Crohn's colitis) or (Crohn'++ Crohn's duodenitis

[X]Other Crohn's disease Crohn's gastritis

CC - Crohn's colitis Crohn's ileitis

CD - Crohn's disease Crohn's jejunitis

Crohn's - small intestine Crohn's oesophagitis

Crohn's - terminal ileum Crohn's proctitis

Crohn's colitis Crohn's regional enteritis

Crohn's dis. large bowel NOS Enteritis: [regional-Crohn's++

Crohn's dis. small bowel NOS Exac Crohn's dis large intest

CROHNS DISEASE Exac Crohn's dis small intest

Crohn's disease Perianal Crohn's disease

Crohn's disease (& [regional++ Regional enterit small bowel

Crohn's disease NOS Regional enteritis - Crohn

Crohn's disease of colon Regional enteritis - Crohn's

Crohn's disease of duodenum Regional enteritis NOS

Crohn's disease of ileum Regional enteritis-colon

Crohn's disease of jejunum Regional enteritis-duodenum

Crohn's disease of oesophagus Regional enteritis-jejunum

Crohn's disease of rectum Regional enteritis-large bowel

Crohn's disease of stomach Regional enteritis-rectum

Crohn's disease-ileum NOS Regional enteritis-small bowel

Crohn's disease-ileum unspecif Regional ileocolitis

Crohn's disease-terminal ileum

Table 2. Read code definitions for gastrointestinal surgery

Abdominoperineal excn rectum & end colostomy (& named vars) Other excision of right hemicolon

Anterior resection of rectum and anastomosis NEC Other exteriorisation of colon

Anterior resection of rectum and exteriorisation of bowel Other exteriorisation of colon NOS

Anterior resection rectum + staple anastomosis colon-rectum Other operation on colon NOS

Closure of anastomosis of ileum Other operation on ileum NOS

Closure of perforation of ileum Other operations on colon

Colectomy Other operations on rectum

Colectomy and anastomosis NEC Other specified creation of ileostomy

Colectomy and exteriorisation of bowel NEC Other specified excision of ileum

Colectomy and ileostomy NEC Other specified other excision of colon

Colectomy NEC Other specified subtotal excision of colon

Colectomy: [other NOS] or [NEC] or [hemi- NEC] or [Rankin] Other specified total excision of colon

Colon and caecum operations Other specified total excision of colon and rectum

Colostomy NEC Panproc/colec

Colostomy operation Panproctocolectomy and anastomosis of ileum to anus NEC

Construction of sigmoid colostomy Panproctocolectomy and ileostomy

Construction of temporary colostomy Parks panproctocolectomy

Creation defunctioning ileostomy (& [Brooke] or [split]) Partial colectomy

Creation of continent ileostomy Partial colectomy NEC

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Creation of defunctioning ileostomy Proctectomy and anastomosis of colon to anus

Creation of ileostomy Proctocolectomy

Creation of ileostomy NOS Proctocolectomy NEC

Creation of loop ileostomy Resection of ileum

Creation of permanent ileostomy Resection of jejunum

Creation of temporary ileostomy Resection of terminal ileum

Excision large intestine (& colectomy) Revision of anastomosis of ileum

Excision of anus Right hemicolectomy

Excision of lesion of colon NEC Right hemicolectomy and anastomosis NEC

Excision of rectum (& NEC) Right hemicolectomy and ileostomy however further qualified

Excision of rectum (& NEC) Right hemicolectomy+end to end anastomosis of ileum to colon

Excision small intestine Segmental excision of small intestine

Excision small intestine NOS Sigmoid colectomy

Extended excision of right hemicolon NOS Sigmoid colectomy

Extended right hemicolectomy Sigmoid colectomy and anastomosis NEC

Extended right hemicolectomy and ileostomy Sigmoid colectomy and anastomosis of colon to rectum

Extended right hemicolectomy and ileostomy HFQ Sigmoid colectomy and colostomy

Hartmann's procedure Sigmoid colectomy and ileostomy

Hemicolectomy NEC Sigmoid colectomy and ileostomy however further qualified

Ileectomy and ileostomy Sigmoid colectomy with stoma

Ileectomy NEC Subtotal colectomy

Ileostomy operation Subtotal colectomy with anastomosis

Ileum operations Subtotal colectomy with ileorectal anastomosis

Jejunum operations Subtotal excision of colon NOS

Laparoscopic sigmoid colectomy Total colectomy

Laparoscopic transverse colectomy Total colectomy

Laparoscopically assisted right hemicolectomy Total colectomy

Laparoscopic-assist right hemicolectomy (?AND/OR[colectomy]) Total colectomy

Left hemicolectomy Total colectomy & ileo-rectal anastomosis (& Hampton)

Left hemicolectomy Total colectomy and anastomosis of ileum to rectum

Left hemicolectomy & end-to-end anastomosis colon to colon Total colectomy and ileostomy

Left hemicolectomy and exteriorisation of bowel NEC Total colectomy and ileostomy NEC

Left hemicolectomy with anastomosis Total excision of colon NOS

Other excision of colon Transverse colectomy

Other excision of colon NOS Transverse colectomy with anastomosis

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Validation of inflammatory bowel disease diagnoses within the UK primary care

database, SystmOne.

Introduction

Electronic health records from primary care databases are an important resource for

biomedical research. They allow the analysis of large cohorts, long-term trends and

investigation into rare outcomes. The SystmOne primary care databases is one of the

largest in the United Kingdom (UK) and includes clinical records from ~ 2700 UK general

practices.1 ResearchOne is a novel, ethically approved dataset that comprises a subset of

~6 million individual clinical records from SystmOne.2

Despite the growing use of electronic datasets there are uncertainties around data

quality and completeness. Data are sparse on the validity of chronic disease diagnoses

within primary care databases and the SystmOne database has not been externally

validated to our knowledge, to date.

Aim

Here we explore the validity of inflammatory bowel disease (IBD) diagnoses within

the SystmOne primary care database.

Methods

Consecutive patients were recruited and consented from IBD out-patient clinic

attendances at Leeds Teaching Hospital NHS Trust, UK. Data were collected from hospital

clinic letters, endoscopy reports, histopathology results and primary care electronic records.

We recorded the IBD diagnosis; Crohn’s disease (CD), ulcerative colitis (UC), or IBD-

unclassified (IBD-U), the date of first diagnosis, first gastrointestinal (GI) resectional surgery

after an IBD diagnosis and the type of surgery performed. Operations were classified as

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hospital records were taken as the reference standard for the study.

Primary care recorded entries were taken as the first recorded Read code entry for IBD and

the number, type and date of the first recorded, IBD-related surgery. Where there were

multiple different Read code entries for IBD we classified the IBD diagnoses as follows;

• CD – CD Read codes only or IBD-U followed by CD Read code.

• UC – UC Read codes only or IBD-U followed by UC Read code.

• IBD-U – IBD-U Read codes only or a combination of CD & UC Read codes.

We planned to recruit 100 patients with IBD and data held on the SystmOne primary care

database. This is in line with previous validation studies from different datasets 3, 4 and would

give enough patients to draw a meaningful conclusion about the accuracy of the database.

Continuous variables were presented as medians with interquartile range (IQR) for non-

parametric and means with standard deviations (SD) for parametric variables.

We considered p values of <0.05 to be statistically significant. We used STATA 14

(StataCorp LP, College Station, TX, USA) for all of our analyses.

The study was approved by the North West - Liverpool Central Research Ethics Committee

and the NHS health research authority (REF: 16/NW0076).

Results

We recruited, and consented 100 patients with IBD from outpatient clinics at Leeds Teaching

Hospitals NHS Trust (table 1) who were registered with a SystmOne practice. From the

hospital histological diagnoses there were 62 patients with CD, 35 With UC and 3 with

indeterminate colitis. There were 23 individuals who had undergone a GI surgical resection

for IBD, 61%) of these were ileo-colonic resections (table 1).

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ACCEPTED MANUSCRIPTThe results of the validation are shown in table 2. IBD diagnoses were recorded in 98 (98%)

individuals’ SystmOne GP records. The type of IBD was correct in 93% of individuals, and

date of diagnosis was within 6 months for 76% and within 12 months for 85%. Individuals

who had undergone surgery was recorded in 91% of patient’s primary care records. The

surgery type was correct in 81% of cases. The surgery date was accurate within 6 months in

18 (90%) of cases and within 12 months in 19 (95%) of cases.

Discussion

Discussion

There is increasing use of primary care databases for epidemiological research studies into

population health. There is a need to validate these databases for the accuracy of clinical

data within them to justify their continued use. Here we have shown that the SystmOne

database has good accuracy for IBD diagnoses and associated GI resectional surgery for

use in healthcare research.

There have been previous studies examining the validity of UK primary care databases. 4-6

Our results are in concordance with a study by Lewis et al who compared GPRD primary

care data with data from GP questionnaires. 7 Here, IBD diagnoses to be accurate in 92% of

cases. A systematic review and meta-analysis of diagnostic coding in UK primary care

computerized datasets found an overall median accuracy of 89%, which is also in line with

our results. 4

We have also shown that the dates of diagnoses are accurate to within 12 months. This is

an important finding as epidemiological investigations using primary care dataset will often

seek to investigate long-term outcomes in longitudinal, observational studies. It is important

therefore to have an accurate start point to investigate the clinical disease course.

Strengths

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to general practitioners to confirm cases, often without additional information from hospital

records. This introduces a potential bias as primary care practitioners are validating their

own clinical entries. Our study uses hospital data as the reference standard. Inflammatory

bowel disease is typically diagnosed and managed in secondary care after endoscopy and

histology 8 so we believe that this is the most robust way of confirming such a diagnosis.

We randomly selected consecutive patients from out-patient clinics and expect the results of

this study to be generalizable to the remainder of the SystmOne database and other UK

databases as SystmOne GPs are not pre-selected and should be representative of primary

care practitioners.

Limitations

We included a relatively small sample size of 100 patients from the SystmOne database,

and only 23 of these had undergone a GI surgical resection for IBD which may limit the

accuracy of the final estimates for our secondary outcome. A systematic review of validation

studies of a similar dataset, the General Practice Research Datalink (now called the Clinical

Practice Research Datalink) in 2010 included 347 studies. 4 Here, the median number of

cases reviewed was 104, which is consistent with our study. A further limitation is that we

could not verify diagnoses made in primary care, where subsequent care is managed solely

by the GP, as we approached the validation from the secondary care records. We expect

this scenario to be unlikely for conditions such as inflammatory bowel disease that are

typically diagnosed after colonoscopy, performed in secondary care centres with subsequent

management being co-ordinated through dedicated hospital clinics. Studies have shown that

over a third of patients are solely managed in secondary care services in the UK. 9 The latest

estimates, albeit from the 1990’s, showed that there were only 26 consultations per 100,000

population per year for inflammatory bowel disease related symptoms. 10 CD can occur at

any location in the GI tract and UC at different colonic locations. This level of detail is not

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in this study.

Conclusions

There is increasing use of large-scale population datasets for epidemiological research. A

concern with using these datasets is the accuracy of information held in them. Here we have

shown that inflammatory bowel disease diagnoses are correct for 93% of patients on the

SystmOne database, giving validity to research studies using this data source.

ResearchOne is a novel, ethically approved dataset that comprises a subset of ~6million

individual clinical records from SystmOne. This information is de-identified and so cannot be

externally validated but we expect our results to be generalizable to this dataset as the

records are not pre-selected for inclusion. IBD is typically diagnosed and managed from

secondary care facilities in the UK. It is reasonable to assume that other chronic diseases

will have similar coding accuracy to the estimates we have made for IBD.

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Table 1 – Inflammatory bowel disease patients and g astrointestinal surgery resections

included in the validation study.

Frequency

Inflammatory bowel disease 100

Crohn's disease 62 (62)

Ulcerative colitis 35 (35)

Indeterminate colitis 3 (3)

Surgery 23

Small bowel resection 2 (9)

Ileo-colonic resection 14 (61)

Colonic resection 0 (0)

Total colectomy 7 (30)

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Table 2 – Validation of inflammatory bowel disease diagnoses held within the primary

care databases SystmOne compared to the reference s tandard of hospital medical

records.

Inflammatory bowel disease diagnoses Frequency

Diagnosis recorded in primary care record 98 (98)

Diagnosis correct, n (%) 92 (93)

Difference in diagnosis date, median days (IQR) 38 (4 - 188)

Diagnosis date correct within 6 months, n (%) 75 (76)

Diagnosis date correct within 12 months, n (%) 84 (85)

Gastrointestinal surgery diagnoses

First surgery recorded on primary care record, n (%) 21 (91)

First surgery type correct, n (%) 17 (81)

Difference in surgery date, median days (range) 0 (0 - 2922)

First surgery date correct within 6 months, n (%) 18 (90)

First surgery date correct within 12 months, n (%) 19 (95)

IQR – inter-quartile range.

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References

1. SystmOne primary care database. [01/06/2017]; Available from: https://www.tpp-

uk.com/products/systmone.

2. ResearchOne health and care research database. [13.04.2017]; Available from:

http://www.researchone.org/.

3. Aberra FN, Brensinger CM, Bilker WB, et al. Antibiotic use and the risk of flare of

inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice

journal of the American Gastroenterological Association. 2005;3:459-65.

4. Herrett E, Thomas SL, Schoonen WM, et al. Validation and validity of diagnoses in the

General Practice Research Database: a systematic review. Br J Clin Pharmacol. 2010;69(1):4-14.

5. Soriano JB, Maier WC, Visick G, et al. Validation of general practitioner-diagnosed COPD in

the UK General Practice Research Database. Eur J Epidemiol. 2001;17(12):1075-80.

6. Lewis JD, Schinnar R, Bilker WB, et al. Validation studies of the health improvement network

(THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf. 2007;16(4):393-

401.

7. Lewis JD, Brensinger C, Bilker WB, et al. Validity and completeness of the General Practice

Research Database for studies of inflammatory bowel disease. Pharmacoepidemiol Drug Saf.

2002;11(3):211-8.

8. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel

disease in adults. Gut. 2011;60(5):571-607.

9. Stone MA, Mayberry JF, Baker R. Prevalence and management of inflammatory bowel

disease: a cross-sectional study from central England. European journal of gastroenterology &

hepatology. 2003;15:1275-80.

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decreasing risk of first and subsequent surgeries in

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