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Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study
Clinical Gastroenterology and Hepatology 2014;-:-–-
Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study Christine Rungoe,* Jacob Simonsen,* Lene Riis,‡ Morten Frisch,* Ebbe Langholz,§ and Tine Jess*,k *Department of Epidemiology Research, Statens Serum Institut, Copenhagen; ‡Department of Pathology, Herlev University Hospital, Copenhagen; §Department of Internal Medicine, Gentofte University Hospital, Copenhagen; and kDepartment of Clinical Epidemiology, University of Aalborg, Aalborg, Denmark BACKGROUND & AIMS:
We examined the risk of cervical neoplasia (dysplasia or cancer) in women with ulcerative colitis (UC) or Crohn’s disease (CD). We also calculated the reverse, the risk for diagnosis with cervical neoplasia before development of inflammatory bowel disease (IBD).
METHODS:
We established a national cohort of women diagnosed with UC (n [ 18,691) or CD (n [ 8717) between 1979 and 2011 and a control cohort of individually matched women from the general population (controls, n [ 1,508,334). Incidence rate ratios (IRRs) of screening activity and diagnosis of cervical neoplasia in women with IBD were assessed by Cox proportional hazards regression analysis. Odds ratios (ORs) of cervical neoplasia before diagnosis of IBD were calculated by using conditional logistic regression.
RESULTS:
Women with CD underwent cervical cancer screening as often as women in the general population (IRR, 0.99; 95% confidence interval [CI], 0.96–1.02), whereas screening frequency was slightly increased in women with UC (IRR, 1.06; 95% CI, 1.04–1.08). A total of 561 patients with UC were diagnosed with dysplasia during a median follow-up time of 7.8 years, and 28 patients with UC developed cervical cancer, compared with 1918 controls. A total of 407 patients with CD were diagnosed with dysplasia during a median follow-up time of 8.3 years, and 26 patients with CD developed cervical cancer, compared with 940 controls. Patients with UC had increased risk of low-grade (IRR, 1.15; 95% CI, 1.00–1.32) and high-grade (IRR, 1.12; 95% CI, 1.01–1.25) squamous intraepithelial lesions (SILs), whereas patients with CD had increased risks of lowgrade SIL (IRR, 1.26; 95% CI, 1.07–1.48), high-grade SIL (IRR, 1.28; 95% CI, 1.13–1.45), and cervical cancer compared with controls (IRR, 1.53; 95% CI, 1.04–2.27). ORs for cervical cancer were also increased 1–9 years before diagnosis of UC, compared with women without UC (OR, 2.78; 95% CI, 2.12–3.64) or CD (OR, 1.85; 95% CI, 1.08–3.15).
CONCLUSIONS:
In a population-based nationwide cohort study, we found a 2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity.
Keywords: Neoplasia; Thiopurines; Treatment; Cancer Risk Factor.
he risk of cervical neoplasia (ie, dysplasia or cancer) in patients with inflammatory bowel disease (IBD) remains debated. Whereas some studies suggest an increased risk of cervical neoplasia in patients with IBD,1–3 others find risk of cervical neoplasia to be no different from that of non-IBD individuals4–6 unless patients are smokers or have used oral contraceptives for extended time periods. The central etiologic factor for cervical dysplasia or cancer, described as necessary but not sufficient, is persistent infection with high-risk oncogenic types of human papilloma virus (HPV).7 In addition to high-risk HPV, several other cofactors such as high parity, early age at first-time pregnancy,
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long-term hormonal contraception use, and immunosuppressive drug therapy have been associated with progression from chronic infection to cancer.7,8 Most HPV
Abbreviations used in this paper: ATC, Anatomical Therapeutic Chemical; CD, Crohn’s disease; CI, confidence interval; HCD, hormonal contraceptive device; HPV, human papilloma virus; HSIL, high-grade squamous intraepithelial lesion; IBD, inflammatory bowel disease; IRR, incidence rate ratio; LSIL, low-grade squamous intraepithelial lesion; NPR, National Patient Register; OR, odds ratio; TNF, tumor necrosis factor; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.07.036
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infections spontaneously regress during the course of months to a few years, whereas others persist and progress, and it remains unclear why some people clear their infection, and others do not.9 It may be hypothesized that the underlying immunologic changes in IBD or the treatment of IBD with immunosuppressive drugs may lead to increased risk of cervical neoplasia because of impaired ability to clear HPV infections. The aim of the present study was to assess a national cohort of women with ulcerative colitis (UC) or Crohn’s disease (CD) individually matched to a large sample of women from the general population without IBD to examine (1) the risk of cervical dysplasia and cervical cancer in women with a diagnosis of IBD; (2) the effect of IBD medications (mesalamines, corticosteroids, azathioprine, or tumor necrosis factor [TNF]-a antagonists) on the risk of cervical neoplasia; (3) the effect of hormonal contraceptive devices (HCDs) on the risk of cervical neoplasia; and, reversely, (4) the risk of cervical neoplasia before a diagnosis of IBD.
Methods Study Population The source population, which consisted of approximately 4 million women residing in Denmark from 1979 to 2011, was established by use of the Danish Civil Registration system, in which all Danes are registered by a 10-digit identification number.10 The identification number is unique and constant throughout life and serves as an identifier that makes linkage between national registers possible. The Danish Civil Registration system contains continuously updated information on sex, place of birth, address, marital status, and dates of immigration, emigration, and death of all citizens. We identified patients with IBD by use of the Danish National Patient Register (NPR),11 which contains individual-level healthcare information on hospital contacts, diagnoses, and surgical and other procedures performed in Danish hospitals since 1977 and in ambulatory outpatient settings since 1995. To minimize any impact of prevalent cases, we only included patients with a first diagnosis of IBD after January 1, 1979 by using the International Classification of Diseases, 8th and 10th revision, codes for CD (563.00-563.09 and code group K50) and UC (563.19, 569.04, and code group K51). IBD diagnoses in NPR have been found to be accurate and almost complete with validity estimates for registered CD and UC of 97% and 90%, respectively, by using a pathology register as reference.12 To avoid diagnostic ambiguity, patients with a diagnosis of both UC and CD recorded in the NPR were not included. Individuals with a history of total hysterectomy (International Classification of Diseases-8 and -10 codes 61000, 61020, 61040, 61050, or 61100, KLCD, KLDC, KLCE, or KLCC) in the NPR before diagnosis of IBD or the index date were also excluded.
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For each IBD patient we randomly sampled 50 agematched female controls from the general population (born 6 months from the IBD patient) who were alive at the time of the index patient’s first recorded IBD diagnosis in NPR, had no history of IBD or hysterectomy, and lived in the same municipality as the IBD patient at the time of IBD diagnosis.
Medical Treatment of Inflammatory Bowel Disease Detailed individual-level information on medical treatment for IBD and use of HCD was extracted from the National Prescription Registry,13 which contains information on all prescriptions redeemed from all Danish pharmacies since 1995. From the date of first recorded prescription, IBD patients were defined as “ever users” and compared with “never users” of the medication in question. As IBD medications we included azathioprine (the primary thiopurine used in Denmark; Anatomical Therapeutic Chemical [ATC] code L04AX01), mesalamine/sulfasalazine (ATC code A07EC), oral corticosteroids (ATC code H02AB), and topical corticosteroids (ATC codes A07EA01, A07EA02, and A07EA06). Treatment with TNF-a antagonists was identified by combining manually collected data, NPR procedure codes from inpatient and outpatient settings (BOHJ18A), and data from the National Prescription Registry (ATC codes L04AB01, L04B02, and L04AB04). As HCD we included oral contraceptives, vaginal ring, and intrauterine devices (ATC codes G02B, G03AA07–G03AC09).
Covariates Information on age, sex, and municipality at diagnosis of IBD was obtained from the Danish Civil Registration system. Information on comorbidities up to 5 years before entry and during follow-up was obtained from the NPR. Comorbidities were categorized into 32 different disease groups (modified Charlson comorbidity index).
Outcomes The primary outcomes were participation in cervical smear screening and diagnoses of cervical dysplasia and cervical cancer recorded in the Danish Cancer Registry. By use of unique reimbursement codes, which were obtained from the Danish National Health Service Register14 where all specialists are contracted by law, we obtained information on all smear tests performed in IBD patients and controls by date of procedure. In Denmark, these procedures are mainly performed by general practitioners or private specialists in gynecology. Both are contracted with the tax-funded public health care system. Cases of cervical dysplasia were categorized according to recommendations from the Danish Society of Obstetrics
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and Gynaecology and the Danish Society of Pathology and based on data from the Danish Pathology Registry,15 whereas information on cervical cancer (International Classification of Diseases-10 code C53) was obtained from the Danish Cancer Registry.16 Dysplasia was categorized as (1) low-grade squamous intraepithelial lesion (LSIL) including mild cervical intraepithelial neoplasia or (2) high-grade squamous intraepithelial lesion (HSIL) including moderate-to-severe cervical intraepithelial neoplasia; the latter included carcinoma in situ. In addition to dysplasia, we assessed cervical cancers (squamous cell carcinoma and adenocarcinomas) as a separate outcome. When studying a given neoplasia outcome, only patients with no or a former milder degree of neoplasia than the outcome of interest were included.
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include patients diagnosed with UC or CD from 1989 to 2011, which enabled us to identify women with HSIL or cervical cancer up to 9 years before IBD. Specifically, we investigated the odds for being diagnosed with HSIL or cancer <1 year and 1–9 years before IBD diagnosis. All analyses were performed by using SAS v9.3 (SAS Institute, Cary, NC).
Ethics The study was register-based and followed the regulations and instructions set up by the Danish Data Protection Agency (Danish Protection Board approval no. 2008-54-0472).
Results Statistical Analysis All persons were followed from date of IBD diagnosis (index date) until the outcome of interest, date of emigration, death, date of total hysterectomy, or end of study (December 31, 2011). By using Cox proportional hazard regression, we estimated incidence rate ratios (IRRs) of (1) cancer screening (expressed as numbers of smears taken), (2) risk of cervical dysplasia (LSIL or HSIL), and (3) risk of cervical cancer in patients with IBD as compared with matched controls from the background population, where each stratum was defined by 1 IBD patient and up to 50 corresponding control persons. For each IBD patient and matched controls, we defined the index date as the date of diagnosis of IBD. Time since index date was used as underlying time scale. IRRs for dysplasia and cancer were adjusted for calendar period, age, disease duration, number of smear tests taken, and comorbidities. IRRs were further stratified on time since diagnosis (1, 2–4, 5–9, and 10þ years) and age at diagnosis (25, 26–39, 40–59, and 60þ years), and stratified IRRs were compared by Wald test for homogeneity. Second, we investigated the risk of cervical dysplasia or cancer according to use of IBD-related medical treatment (categorized 1) as ever vs never use of a given treatment and (2) according to number of prescriptions and use of HCD (categorized according to number of redeemed prescriptions; 0, 1–20, 21–50, 50þ) during follow-up by using the Cox regression model described above. These analyses were confined to patients diagnosed with IBD after 1994, when nationwide data on medication use became available. Last, in a reverse analysis we investigated the odds of being diagnosed with HSIL or cervical cancer before IBD (or IBD index date for controls) in a matched casecontrol analysis within the same population. We used conditional logistic regression adjusted for calendar period, age, disease duration, number of smear tests taken, and comorbidities and restricted the analysis to
During the study period, 18,691 women were diagnosed with UC and 8717 with CD (Table 1). These were matched to 1,508,334 female controls from the general population.
Participation in Routine Cervical Cancer Screening Patients with UC had a slightly higher participation in smear test than matched female controls (IRR, 1.06; 95% confidence interval [CI], 1.04–1.08), whereas patients with CD had smear tests performed as often as controls (IRR, 0.99; 95% CI, 0.96–1.02).
Risk of Cervical Dysplasia After Inflammatory Bowel Disease Ulcerative colitis. A total of 561 patients with UC were diagnosed with dysplasia (LSIL, n ¼ 199; HSIL, n ¼ 362) during a median follow-up time of 7.8 years, resulting in
Table 1. Characteristics of Women Diagnosed With CD or UC in Denmark From 1979 to 2011
Total patients, n Mean age at diagnosis (y) Age at diagnosis (y) 0–25 26–39 40–59 60þ Ever use of IBD drugsa Mesalamine Topical steroids Oral steroids Azathioprine TNF-a antagonist
a
UC, n (%)
CD, n (%)
18,691 46.4
8717 40.4
3081 5372 4775 5463
(16.5) (28.7) (25.5) (29.2)
2645 2394 1812 1866
(30.3) (27.5) (20.8) (21.4)
4521 3371 3461 1415 774
(31.2) (23.3) (23.9) (9.8) (5.0)
1570 1357 1821 1737 1071
(25.5) (22.0) (29.5) (28.2) (17.0)
Ever users as registered in the National Prescription Registry since 1995.
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Table 2. IRRs of Cervical Dysplasia or Cancer in Patients With UC or CD Diagnosed From 1979 to 2011 as Compared With Individually Matched Women From the General Population Type of No. of cervical lesion events LSILa HSILb Cervical cancer
199 362 28
UC, IRR (95% CI)
No. of events
CD, IRR (95% CI)
1.15 (1.00–1.32) 1.12 (1.01–1.25) 0.78 (0.53–1.13)
145 262 26
1.26 (1.07–1.48) 1.28 (1.13–1.45) 1.53 (1.04–2.27)
a
LSIL including mild cervical intraepithelial neoplasia. HSIL including moderate-to-severe cervical intraepithelial neoplasia; the latter includes in situ. IRRs are adjusted for age, calendar period, disease duration, comorbidities, and number of smear tests taken.
b
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Risk of Cervical Cancer After Inflammatory Bowel Disease Ulcerative colitis. Twenty-eight patients with UC developed cervical cancer compared with 1918 controls, with no significant difference in risk (IRR, 0.78; 95% CI, 0.53–1.13; Table 2 and Figure 1). Crohn’s disease. Twenty-six patients with CD developed cervical cancer compared with 940 controls, resulting in a significantly increased risk of cervical cancer in patients with CD (IRR, 1.53; 95% CI, 1.04–2.27; Table 2). The risk may increase by time since diagnosis of CD (Figure 1), although this did not reach statistical significance.
Risk of Cervical Neoplasia According to Age a slightly increased risk of both LSIL (IRR, 1.15; 95% CI, 1.00–1.32) and HSIL (IRR, 1.12; 95% CI, 1.01–1.25) (Table 2). As it appears from Figure 1, the IRR of HSIL did not increase with time since diagnosis of UC. Crohn’s disease. A total of 407 patients with CD were diagnosed with dysplasia (LSIL, n ¼ 145; HSIL, n ¼ 262) during a median follow-up time of 8.3 years. Patients with CD were at significantly increased risk of both LSIL (IRR, 1.26; 95% CI, 1.07–1.48) and HSIL (IRR, 1.28; 95% CI, 1.13–1.45) (Table 2). The IRR of HSIL may increase by time since diagnosis of CD, although CIs were broad (Figure 1).
When stratifying risk of HSIL and cancer by age at diagnosis of IBD, only patients with UC diagnosed at age 26–39 had significantly increased risk of HSIL (IRR, 1.17; 95% CI, 1.01–1.35) (Table 3). However, Wald test for homogeneity revealed no significant difference in IRR between patients aged 25, 26–39, 40–59, or 60þ years at diagnosis (Table 3). Patients with CD aged 0–25 years (IRR, 1.30; 95% CI, 1.11–1.51) and 26–39 years (IRR, 1.30; 95% CI, 1.06–1.58) at diagnosis were at significantly increased risk of HSIL, and those aged 0–25 at diagnosis of CD were at increased risk of cervical cancer
Figure 1. Risk of cervical HSILs and cancer according to time since diagnosis of UC and CD.
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Table 3. IRRs of Cervical HSILs or Cancer According to Age at Diagnosis of UC and CD HSIL
Cervical cancer IRR (95% CI)
UC Age at diagnosis (y) 0–25 26–39 40–59 60þ Homogeneitya CD Age at diagnosis (y) 0–25 26–39 40–59 60þ Homogeneitya
1.06 1.17 1.24 0.70
(0.90–1.25) (1.01–1.35) (0.92–1.69) (0.22–2.20) .45
0.86 0.96 0.52 0.72
1.30 (1.11–1.51) 1.30 (1.06–1.58) 1.22 (0.72–2.08) 0 .85
2.70 1.54 1.05 0.60
(0.32–2.30) (0.56–1.67) (0.21–1.25) (0.34–1.52) .85
(1.47–4.96) (0.82–2.89) (0.39–2.82) (0.15–2.42) .41
a
Wald test.
(IRR, 2.70; 95% CI, 1.47–4.96) (Table 3). Overall, however, age-stratified IRRs did not differ significantly from one another (Wald test, Table 3).
analyzing the impact of number of redeemed prescriptions on cervical neoplasia risk, an 8% increase in IRR for HSIL per redeemed prescription of azathioprine was observed in patients with CD (IRR, 1.08; 95% CI, 1.04–1.13). Number of redeemed prescriptions of oral corticosteroids (IRR, 1.02; 95% CI, 0.98–1.06) or TNF-a antagonists (IRR, 1.16; 95% CI, 0.87–1.55) had no significant impact on risk. Cumulative exposure to any of these medications did not affect the risk of LSIL or cancer (low power) in CD or of any kind of neoplasia in UC (Table 5).
Hormonal Contraceptive Devices and Risk of Cervical Neoplasia In UC, treatment with HCD did not influence risk of cervical neoplasia (Supplementary Table 1). However, patients with CD with >20 redeemed prescriptions were at significantly increased risk of HSIL, reflecting 2% increase in the risk of HSIL per redeemed HCD prescription (IRR, 1.02; 95% CI, 1.01–1.04) (Supplementary Table 1). No statistically significant impact on cancer risk was observed (Supplementary Table 1).
Cervical Neoplasia Before Inflammatory Bowel Disease
Inflammatory Bowel Disease Medications and Risk of Cervical Neoplasia In crude analyses of ever use, mesalamine, azathioprine, and corticosteroids had no impact on cervical neoplasia risk in CD or UC (Table 4). CD patients who had ever used TNF-a antagonists were at significantly increased risk of HSIL (IRR, 1.85, 95% CI, 1.12–3.04) compared with non-users, whereas this was not the case in UC (IRR, 1.12; 95% CI, 0.45–2.79). No cervical cancer cases had received TNF-a antagonists (Table 4). When
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Ulcerative colitis. Overall, 34 UC patients and 1626 control women were diagnosed with HSIL <1 year before UC diagnosis/index date (odds ratio [OR]<1y, 1.10; 95% CI, 0.75–1.48), whereas 279 patients with UC and 11,908 control women were diagnosed with HSIL 1–9 years before index date, resulting in significantly increased OR1–9y of 1.18 (95% CI, 1.04–1.30). Also, the OR of cancer before diagnosis of UC was significantly increased both <1 year before UC diagnosis/index date
Table 4. IRRs of Cervical Neoplasia in Patients With UC or CD According to Ever Use of Medications During Follow-up LSILa Type of medication UC Mesalamine Topical corticosteroids Oral corticosteroids Azathioprine TNF-a antagonist CD Mesalamine Topical corticosteroids Oral corticosteroids Azathioprine TNF-a antagonist
HSILb
Cervical cancerc
Nd
IRR (95% CI)
Nd
IRR (95% CI)
Nd
IRR (95% CI)
44 33 32 11 1
0.88 1.05 1.13 0.84 0.56
(0.60–1.28) (0.70–1.58) (0.74–1.70) (0.45–1.58) (0.08–4.12)
80 48 59 23 5
0.81 0.71 0.97 0.87 1.12
(0.62–1.07) (0.52–0.99) (0.72–1.32) (0.56–1.36) (0.45–2.79)
4 4 3 0 0
0.93 (0.27–3.21) 1.66 (0.48–5.77) 1.05 (0.26–4.24) NA NA
33 19 21 24 8
1.09 0.88 0.63 0.97 1.08
(0.68–1.73) (0.52–1.50) (0.38–1.06) (0.59–1.60) (0.50–2.31)
53 37 48 49 21
1.25 1.14 1.12 1.43 1.85
(0.85–1.84) (0.76–1.71) (0.77–1.64) (0.98–2.09) (1.12–3.04)
1 1 0 1 0
0.67 (0.06–7.40) 1.33 (0.13–13.56) NA 0.98 (0.10–9.90) NA
NOTE. Table concerns all patients diagnosed from 1995 to 2010. a LSIL including mild cervical intraepithelial neoplasm. b HSIL including moderate-to-severe cervical intraepithelial neoplasia. The latter includes carcinoma in situ. c Primary cancer with origin in cervix uteri. d Number of exposed.
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Table 5. Change in IRRs of Cervical Neoplasia in Patients With UC or CD per Redeemed Prescription/Administration of Oral Corticosteroids, Azathioprine, or TNF-a Antagonists Type of medication UC Oral corticosteroids Azathioprine TNF-a antagonist CD Oral corticosteroids Azathioprine TNF-a antagonist
LSILa (IRRchange, 95% CI)
HSILb (IRRchange, 95% CI)
Cervical cancerc (IRRchange, 95% CI)
1.03 (1.00–1.06) 0.96 (0.85–1.08) 0.79 (0.38–1.63)
0.99 (0.95–1.04) 0.99 (0.97–1.02) 1.04 (0.95–1.15)
1.01 (0.98–1.04) NA NA
0.91 (0.83–1.00) 0.99 (0.97–1.02) 1.01 (0.96–1.07)
1.02 (0.98–1.06) 1.08 (1.04–1.13) 1.16 (0.87–1.55)
NA 0.99 (0.95–1.04) NA
NOTE. Table concerns all patients diagnosed from 1995 to 2010. a LSIL including mild cervical intraepithelial neoplasm. b HSIL including moderate-to-severe cervical intraepithelial neoplasia. The latter includes carcinoma in situ. c Primary cancer with origin in cervix uteri.
(UC, n ¼ 10; controls, n ¼ 162; OR<1y, 3.10; 95% CI, 1.63–5.86) and 1–9 years before index date (UC, n ¼ 56; controls, n ¼ 1007; OR1–9y, 2.78; 95% CI, 2.12–3.64). Crohn’s disease. Overall, 15 women with CD and 735 control women were diagnosed with HSIL <1 year before IBD diagnosis/index date (OR<1y, 1.03; 95% CI, 0.62–1.72), whereas 131 women with CD and 4799 control women were diagnosed with HSIL 1–9 years before index date, resulting in a significantly increased OR1–9y of 1.38 (95% CI, 1.16–1.65). Also, the OR of cervical cancer <1 year before IBD (OR<1y, 5.13; 95% CI, 2.05–12.9) and 1–9 years before IBD (OR1–9y, 1.85; 95% CI, 1.08–3.15) was significantly increased.
Discussion In this population-based cohort study of 27,408 IBD women, we observed an increased risk of LSIL and HSIL in both UC and CD and an increased risk of cervical cancer in patients with CD, despite normal screening frequency in CD patients and only a slightly elevated screening frequency in UC patients. Use of common IBD medications did not influence neoplasia risk in UC, whereas patients with CD who had ever used TNF-a antagonists had significantly increased risk of HSIL compared with non-users. Also, 2% increase in risk of HSIL per redeemed prescription of HCD was observed in patients with CD. In reverse analyses, we observed a significant excess in cervical neoplasia occurrence up to 10 years before UC and CD diagnoses. The primary strength of the present study was the population-based design combining information from several nationwide registers, thereby creating a historical cohort with prospectively collected individual level information. Hence, information on numbers of smear tests taken and use of medication through follow-up were not affected by recall bias. The IBD diagnoses have been found to be of high completeness and validity in the Danish NPR,12 and the Danish Cancer Register is of highest international standard.16 We were further able to
match IBD women with a broad random selection of the general population matched on sex, age, and place of living. This is of importance because the prevalence of HPV is highly dependent on age and because smear test screening was not introduced simultaneously in all parts of the country. As a potential limitation, information on smoking was not available. Smoking is suggested to have an effect on the progression of chronic HPV infection to HSIL or invasive cancer,17 and this might to some extent explain the increased risk of cervical neoplasia observed in our patients with CD. Also, disease severity may potentially confound results. However, considering medication use as a proxy for disease severity, it is noteworthy that only azathioprine but not corticosteroids or TNF inhibitors (at least not in cumulative analyses) was associated with increased risk of cervical neoplasia. This suggests limited confounding by disease severity. Last, vaccination policies may potentially influence risk estimates. However, HPV vaccines (mainly Gardasil) were first introduced as part of the national childhood vaccination program in 2009. We believe that an effect of a vaccine introduced to young girls in 2009 would not be observable in the present study. Likewise, it was not the aim of the present study to assess the incidence of high-risk oncogenic HPV infections in patients with IBD. We found women with UC, but not CD, to have slightly higher participation in smear testing than their controls. It is of importance to acknowledge that incidence and mortality of cervical neoplasia are highly dependent on screening and treatment of precursor lesions.18 However, only few studies have taken participation in screening into consideration when analyzing risk of cervical neoplasia in IBD, and results are conflicting.4,19,20 Singh et al20 found slightly lower participation in cervical cancer screening in Canadian patients with IBD than in controls and even lower participation in screening in patients on immunosuppressive treatment compared with IBD patients without such treatment.20 In contrast, Hutfless et al4 found the prevalence of smear testing in a 3-year period to be higher in IBD patients (93%) than in non-IBD patients (79%). In the present
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study, not only were we able to demonstrate a slightly increased screening activity in patients with UC (but not CD), we also implemented this information into all subsequent analyses of risk of cervical neoplasia. In our study, women with UC and CD had increased risk of both LSIL and HSIL. LSIL is known to have a high rate of spontaneous regression, whereas HSIL is more aggressive and requires intervention. A slightly increased risk of HSIL was found in patients with UC, and the increased risk in CD patients is in line with findings by others. Singh et al6 found a significantly increased risk of cervical abnormalities in a subgroup of CD patients (patients using 10þ prescriptions of oral contraceptives and patients on combined immunosuppressive treatment). Two other relatively small studies have suggested an increased risk of abnormal smear in IBD patients compared with controls, with no clear differences between patients with UC or CD.1,4 Of notice, although both UC and CD patients had higher odds of being diagnosed with cervical cancer before IBD, only patients with CD were at an increased risk of developing cervical cancer after the IBD diagnosis. This is in accordance with a detailed IBD cohort study from Northern Jutland, Denmark, which suggested an increased risk of carcinoma in situ and cervical cancer among patients with CD but not UC.21 Likewise, Goldacre et al22 found an increased risk of cervical cancer in patients with CD but not UC. The reason for the difference in risk of cervical cancer in patients with CD and UC is unclear but could partly be related to smoking, which we were not able to control for. In the study from North Jutland, risk factors were smoking (standardized incidence ratio, 2.15; 95% CI, 1.27–3.40), ever use of mesalamine (standardized incidence ratio, 1.69; 95% CI, 1.08–2.51) or thiopurines (standardized incidence ratio, 2.47; 95% CI, 1.54–3.73), and young age (<20 years) at CD diagnosis (standardized incidence ratio, 2.52; 95% CI, 1.26–4.51).21 In the present study, we also found a significantly higher risk of cervical neoplasia in patients diagnosed with CD at young age and in CD patients treated with azathioprine. On the other hand, we did not find that use of mesalamine or corticosteroids influenced risk of cervical dysplasia among IBD patients, in accordance with the majority of other studies investigating impact of IBD medication on risk of cervical neoplasia.1–6 A single study has suggested that combined use of corticosteroids and immunosuppressive drugs (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and infliximab) is associated with risk of cervical neoplasia in patients with CD.6 Somewhat in line with these findings, we observed ever use of TNF-a antagonists in CD patients to associate with increased risk of HSIL. However, this was not confirmed in analyses of cumulative number of administrations of these drugs. Accordingly, current Danish guidelines do not recommend HPV screening before initiation of treatment with TNF-a antagonists.23 Use of HCD has also been associated with increased risk of cervical neoplasia.24 We found an increased risk of HSIL in CD patients with long-term use of HCD. To what
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extent use of HCD is also associated with different sexual behavior (ie, not using barrier method as prevention) or alters the composition of the cervical mucus is unknown and to our knowledge unexplored in the IBD population. Finally, we observed markedly increased odds of HSIL and cervical cancer up to 10 years before diagnosis of UC or CD. This is a novel finding that may suggest a yet unexplored common susceptibility to IBD and cervical neoplasia rather than an etiologic role of IBD or its treatment in development of cervical neoplasia. This finding needs to be confirmed and further investigated in future studies.
Conclusion In this nationwide study of patients with IBD followed during a 35-year period, women with a diagnosis of CD had increased risk of cervical dysplasia and cancer despite similar screening intensity as in the general population. Treatment with TNF-a antagonists and HCD may influence risk of cervical neoplasia in CD. Patients with UC only had increased risk of dysplasia along with a slightly increased screening frequency compared with controls. Interestingly, reverse analyses showed markedly elevated odds of cervical neoplasia up to 10 years before IBD diagnosis, which may indicate a common susceptibility to cervical neoplasia and IBD. This observation needs further investigation. Patients with IBD should be encouraged to follow the screening program for cervical neoplasia, and clinicians should be aware of the slightly increased risk of HPV-related cervical lesions in IBD patients.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.07.036.
References 1. Bhatia J, Bratcher J, Korelitz B, et al. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol 2006;12:6167–6171. 2. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008;103:631–636. 3. Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderate-to-severe Crohn’s disease. Am J Gastroenterol 2009;104:2524–2533. 4. Hutfless S, Fireman B, Kane S, et al. Screening differences and risk of cervical cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:598–605. 5. Lees CW, Critchley J, Chee N, et al. Lack of association between cervical dysplasia and IBD: a large case-control study. Inflamm Bowel Dis 2009;15:1621–1629. 6. Singh H, Demers AA, Nugent Z, et al. Risk of cervical abnormalities in women with inflammatory bowel disease: a
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Rungoe et al population-based nested case-control study. Gastroenterology 2009;136:451–458. 7. Ibeanu OA. Molecular pathogenesis of cervical cancer. Cancer Biol Ther 2011;11:295–306. 8. Moore EE, Wark JD, Hopper JL, et al. The roles of genetic and environmental factors on risk of cervical cancer: a review of classical twin studies. Twin Res Hum Genet 2012;15:79–86. 9. Einstein MH, Schiller JT, Viscidi RP, et al. Clinician’s guide to human papillomavirus immunology: knowns and unknowns. Lancet Infect Dis 2009;9:347–356.
10. Pedersen CB, Gotzsche H, Moller JO, et al. The Danish Civil Registration System: a cohort of eight million persons. Dan Med Bull 2006;53:441–449. 11. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39:30–33. 12. Fonager K, Sorensen HT, Rasmussen SN, et al. Assessment of the diagnoses of Crohn’s disease and ulcerative colitis in a Danish hospital information system. Scand J Gastroenterol 1996;31:154–159. 13. Kildemoes HW, Sorensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health 2011;39:38–41.
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19. Long MD, Porter CQ, Sandler RS, et al. Suboptimal rates of cervical testing among women with inflammatory bowel disease. Clin Gastroenterol Hepatol 2009;7:549–553. 20. Singh H, Nugent Z, Demers AA, et al. Screening for cervical and breast cancer among women with inflammatory bowel disease: a population-based study. Inflamm Bowel Dis 2011;17: 1741–1750. 21. Jess T, Horvath-Puho E, Fallingborg J, et al. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. Am J Gastroenterol 2013;108:1869–1876. 22. Goldacre MJ, Wotton CJ, Yeates D, et al. Cancer in patients with ulcerative colitis, Crohn’s disease and coeliac disease: record linkage study. Eur J Gastroenterol Hepatol 2008;20:297–304. 23. Nordgaard-Lassen I, Dahlerup JF, Belard E, et al. Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J 2012;59:C4480. 24. Moreno V, Bosch FX, Munoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:1085–1092.
14. Andersen JS, Olivarius NF, Krasnik A. The Danish National Health Service Register. Scand J Public Health 2011;39:34–37. 15. Bjerregaard B, Larsen OB. The Danish Pathology Register. Scand J Public Health 2011;39:72–74. 16. Gjerstorff ML. The Danish Cancer Registry. Scand J Public Health 2011;39:42–45.
Reprint requests Address requests for reprints to: Tine Jess, MD, DMSc, Department of Epidemiologic Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark. e-mail: [email protected]; fax: þ4532683868.
17. Fonseca-Moutinho JA. Smoking and cervical cancer. ISRN Obstet Gynecol 2011;2011:847684.
Conflicts of interest The authors disclose no conflicts.
18. Wacholder S. Chapter 18: statistical issues in the design and analysis of studies of human papillomavirus and cervical neoplasia. J Natl Cancer Inst Monogr 2003;(31):125–130.
Funding Dr Tine Jess was supported by a Female Research Leader grant (no. 09-066323) from the Danish Council of Independent Research.
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Supplementary Table 1. IRRs of Cervical Neoplasia Among Patients With CD or UC Comparing Users and Non-users of HCDs LSIL No. of prescriptions of HCDa UC 0 1–20 21–50 50þ Change in IRR per redeemed HCD prescriptionc CD 0 1–20 21–50 50þ Change in IRR per redeemed HCD prescriptionc
a
Cervical cancer
Nb
IRR (95% CI)
Nb
IRR (95% CI)
Nb
IRR (95% CI)
53 27 36 5
(Reference) 0.95 (0.56–1.62) 1.02 (0.61–1.70) 1.25 (0.47–3.29) 1.01 (0.99–1.02)
87 56 79 10
(Reference) 1.19 (0.82–1.75) 1.07 (0.75–1.54) 1.30 (0.65–2.59) 1.01 (1.00–1.01)
8 2 2 0
(Reference) 1.86 (0.29–11.96) 1.76 (0.27–11.65) NA 1.01 (0.96–1.05)
26 20 28 4
(Reference) 0.84 (0.44–1.61) 0.94 (0.50–1.74) 1.32 (0.42–4.09) 1.00 (0.99–1.02)
28 23 63 7
(Reference) 1.26 (0.68–2.34) 2.46 (1.45–4.17) 2.67 (1.09–6.52) 1.02 (1.01–1.04)
2 1 0 1
(Reference) 2.62 (0.14–48.23) NA 33.50 (0.99–1129) 1.03 (0.97–1.10)
Defined by cumulative use of ATC codes G02B, G03AA07–G03AC09 within the study period. Number of events. c Trend per prescription of HCD. b
HSIL
Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study Christine Rungoe,* Jacob Simonsen,* Lene Riis,‡ Morten Frisch,* Ebbe Langholz,§ and Tine Jess*,k *Department of Epidemiology Research, Statens Serum Institut, Copenhagen; ‡Department of Pathology, Herlev University Hospital, Copenhagen; §Department of Internal Medicine, Gentofte University Hospital, Copenhagen; and kDepartment of Clinical Epidemiology, University of Aalborg, Aalborg, Denmark BACKGROUND & AIMS:
We examined the risk of cervical neoplasia (dysplasia or cancer) in women with ulcerative colitis (UC) or Crohn’s disease (CD). We also calculated the reverse, the risk for diagnosis with cervical neoplasia before development of inflammatory bowel disease (IBD).
METHODS:
We established a national cohort of women diagnosed with UC (n [ 18,691) or CD (n [ 8717) between 1979 and 2011 and a control cohort of individually matched women from the general population (controls, n [ 1,508,334). Incidence rate ratios (IRRs) of screening activity and diagnosis of cervical neoplasia in women with IBD were assessed by Cox proportional hazards regression analysis. Odds ratios (ORs) of cervical neoplasia before diagnosis of IBD were calculated by using conditional logistic regression.
RESULTS:
Women with CD underwent cervical cancer screening as often as women in the general population (IRR, 0.99; 95% confidence interval [CI], 0.96–1.02), whereas screening frequency was slightly increased in women with UC (IRR, 1.06; 95% CI, 1.04–1.08). A total of 561 patients with UC were diagnosed with dysplasia during a median follow-up time of 7.8 years, and 28 patients with UC developed cervical cancer, compared with 1918 controls. A total of 407 patients with CD were diagnosed with dysplasia during a median follow-up time of 8.3 years, and 26 patients with CD developed cervical cancer, compared with 940 controls. Patients with UC had increased risk of low-grade (IRR, 1.15; 95% CI, 1.00–1.32) and high-grade (IRR, 1.12; 95% CI, 1.01–1.25) squamous intraepithelial lesions (SILs), whereas patients with CD had increased risks of lowgrade SIL (IRR, 1.26; 95% CI, 1.07–1.48), high-grade SIL (IRR, 1.28; 95% CI, 1.13–1.45), and cervical cancer compared with controls (IRR, 1.53; 95% CI, 1.04–2.27). ORs for cervical cancer were also increased 1–9 years before diagnosis of UC, compared with women without UC (OR, 2.78; 95% CI, 2.12–3.64) or CD (OR, 1.85; 95% CI, 1.08–3.15).
CONCLUSIONS:
In a population-based nationwide cohort study, we found a 2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity.
Keywords: Neoplasia; Thiopurines; Treatment; Cancer Risk Factor.
he risk of cervical neoplasia (ie, dysplasia or cancer) in patients with inflammatory bowel disease (IBD) remains debated. Whereas some studies suggest an increased risk of cervical neoplasia in patients with IBD,1–3 others find risk of cervical neoplasia to be no different from that of non-IBD individuals4–6 unless patients are smokers or have used oral contraceptives for extended time periods. The central etiologic factor for cervical dysplasia or cancer, described as necessary but not sufficient, is persistent infection with high-risk oncogenic types of human papilloma virus (HPV).7 In addition to high-risk HPV, several other cofactors such as high parity, early age at first-time pregnancy,
T
long-term hormonal contraception use, and immunosuppressive drug therapy have been associated with progression from chronic infection to cancer.7,8 Most HPV
Abbreviations used in this paper: ATC, Anatomical Therapeutic Chemical; CD, Crohn’s disease; CI, confidence interval; HCD, hormonal contraceptive device; HPV, human papilloma virus; HSIL, high-grade squamous intraepithelial lesion; IBD, inflammatory bowel disease; IRR, incidence rate ratio; LSIL, low-grade squamous intraepithelial lesion; NPR, National Patient Register; OR, odds ratio; TNF, tumor necrosis factor; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.07.036
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infections spontaneously regress during the course of months to a few years, whereas others persist and progress, and it remains unclear why some people clear their infection, and others do not.9 It may be hypothesized that the underlying immunologic changes in IBD or the treatment of IBD with immunosuppressive drugs may lead to increased risk of cervical neoplasia because of impaired ability to clear HPV infections. The aim of the present study was to assess a national cohort of women with ulcerative colitis (UC) or Crohn’s disease (CD) individually matched to a large sample of women from the general population without IBD to examine (1) the risk of cervical dysplasia and cervical cancer in women with a diagnosis of IBD; (2) the effect of IBD medications (mesalamines, corticosteroids, azathioprine, or tumor necrosis factor [TNF]-a antagonists) on the risk of cervical neoplasia; (3) the effect of hormonal contraceptive devices (HCDs) on the risk of cervical neoplasia; and, reversely, (4) the risk of cervical neoplasia before a diagnosis of IBD.
Methods Study Population The source population, which consisted of approximately 4 million women residing in Denmark from 1979 to 2011, was established by use of the Danish Civil Registration system, in which all Danes are registered by a 10-digit identification number.10 The identification number is unique and constant throughout life and serves as an identifier that makes linkage between national registers possible. The Danish Civil Registration system contains continuously updated information on sex, place of birth, address, marital status, and dates of immigration, emigration, and death of all citizens. We identified patients with IBD by use of the Danish National Patient Register (NPR),11 which contains individual-level healthcare information on hospital contacts, diagnoses, and surgical and other procedures performed in Danish hospitals since 1977 and in ambulatory outpatient settings since 1995. To minimize any impact of prevalent cases, we only included patients with a first diagnosis of IBD after January 1, 1979 by using the International Classification of Diseases, 8th and 10th revision, codes for CD (563.00-563.09 and code group K50) and UC (563.19, 569.04, and code group K51). IBD diagnoses in NPR have been found to be accurate and almost complete with validity estimates for registered CD and UC of 97% and 90%, respectively, by using a pathology register as reference.12 To avoid diagnostic ambiguity, patients with a diagnosis of both UC and CD recorded in the NPR were not included. Individuals with a history of total hysterectomy (International Classification of Diseases-8 and -10 codes 61000, 61020, 61040, 61050, or 61100, KLCD, KLDC, KLCE, or KLCC) in the NPR before diagnosis of IBD or the index date were also excluded.
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For each IBD patient we randomly sampled 50 agematched female controls from the general population (born 6 months from the IBD patient) who were alive at the time of the index patient’s first recorded IBD diagnosis in NPR, had no history of IBD or hysterectomy, and lived in the same municipality as the IBD patient at the time of IBD diagnosis.
Medical Treatment of Inflammatory Bowel Disease Detailed individual-level information on medical treatment for IBD and use of HCD was extracted from the National Prescription Registry,13 which contains information on all prescriptions redeemed from all Danish pharmacies since 1995. From the date of first recorded prescription, IBD patients were defined as “ever users” and compared with “never users” of the medication in question. As IBD medications we included azathioprine (the primary thiopurine used in Denmark; Anatomical Therapeutic Chemical [ATC] code L04AX01), mesalamine/sulfasalazine (ATC code A07EC), oral corticosteroids (ATC code H02AB), and topical corticosteroids (ATC codes A07EA01, A07EA02, and A07EA06). Treatment with TNF-a antagonists was identified by combining manually collected data, NPR procedure codes from inpatient and outpatient settings (BOHJ18A), and data from the National Prescription Registry (ATC codes L04AB01, L04B02, and L04AB04). As HCD we included oral contraceptives, vaginal ring, and intrauterine devices (ATC codes G02B, G03AA07–G03AC09).
Covariates Information on age, sex, and municipality at diagnosis of IBD was obtained from the Danish Civil Registration system. Information on comorbidities up to 5 years before entry and during follow-up was obtained from the NPR. Comorbidities were categorized into 32 different disease groups (modified Charlson comorbidity index).
Outcomes The primary outcomes were participation in cervical smear screening and diagnoses of cervical dysplasia and cervical cancer recorded in the Danish Cancer Registry. By use of unique reimbursement codes, which were obtained from the Danish National Health Service Register14 where all specialists are contracted by law, we obtained information on all smear tests performed in IBD patients and controls by date of procedure. In Denmark, these procedures are mainly performed by general practitioners or private specialists in gynecology. Both are contracted with the tax-funded public health care system. Cases of cervical dysplasia were categorized according to recommendations from the Danish Society of Obstetrics
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and Gynaecology and the Danish Society of Pathology and based on data from the Danish Pathology Registry,15 whereas information on cervical cancer (International Classification of Diseases-10 code C53) was obtained from the Danish Cancer Registry.16 Dysplasia was categorized as (1) low-grade squamous intraepithelial lesion (LSIL) including mild cervical intraepithelial neoplasia or (2) high-grade squamous intraepithelial lesion (HSIL) including moderate-to-severe cervical intraepithelial neoplasia; the latter included carcinoma in situ. In addition to dysplasia, we assessed cervical cancers (squamous cell carcinoma and adenocarcinomas) as a separate outcome. When studying a given neoplasia outcome, only patients with no or a former milder degree of neoplasia than the outcome of interest were included.
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include patients diagnosed with UC or CD from 1989 to 2011, which enabled us to identify women with HSIL or cervical cancer up to 9 years before IBD. Specifically, we investigated the odds for being diagnosed with HSIL or cancer <1 year and 1–9 years before IBD diagnosis. All analyses were performed by using SAS v9.3 (SAS Institute, Cary, NC).
Ethics The study was register-based and followed the regulations and instructions set up by the Danish Data Protection Agency (Danish Protection Board approval no. 2008-54-0472).
Results Statistical Analysis All persons were followed from date of IBD diagnosis (index date) until the outcome of interest, date of emigration, death, date of total hysterectomy, or end of study (December 31, 2011). By using Cox proportional hazard regression, we estimated incidence rate ratios (IRRs) of (1) cancer screening (expressed as numbers of smears taken), (2) risk of cervical dysplasia (LSIL or HSIL), and (3) risk of cervical cancer in patients with IBD as compared with matched controls from the background population, where each stratum was defined by 1 IBD patient and up to 50 corresponding control persons. For each IBD patient and matched controls, we defined the index date as the date of diagnosis of IBD. Time since index date was used as underlying time scale. IRRs for dysplasia and cancer were adjusted for calendar period, age, disease duration, number of smear tests taken, and comorbidities. IRRs were further stratified on time since diagnosis (1, 2–4, 5–9, and 10þ years) and age at diagnosis (25, 26–39, 40–59, and 60þ years), and stratified IRRs were compared by Wald test for homogeneity. Second, we investigated the risk of cervical dysplasia or cancer according to use of IBD-related medical treatment (categorized 1) as ever vs never use of a given treatment and (2) according to number of prescriptions and use of HCD (categorized according to number of redeemed prescriptions; 0, 1–20, 21–50, 50þ) during follow-up by using the Cox regression model described above. These analyses were confined to patients diagnosed with IBD after 1994, when nationwide data on medication use became available. Last, in a reverse analysis we investigated the odds of being diagnosed with HSIL or cervical cancer before IBD (or IBD index date for controls) in a matched casecontrol analysis within the same population. We used conditional logistic regression adjusted for calendar period, age, disease duration, number of smear tests taken, and comorbidities and restricted the analysis to
During the study period, 18,691 women were diagnosed with UC and 8717 with CD (Table 1). These were matched to 1,508,334 female controls from the general population.
Participation in Routine Cervical Cancer Screening Patients with UC had a slightly higher participation in smear test than matched female controls (IRR, 1.06; 95% confidence interval [CI], 1.04–1.08), whereas patients with CD had smear tests performed as often as controls (IRR, 0.99; 95% CI, 0.96–1.02).
Risk of Cervical Dysplasia After Inflammatory Bowel Disease Ulcerative colitis. A total of 561 patients with UC were diagnosed with dysplasia (LSIL, n ¼ 199; HSIL, n ¼ 362) during a median follow-up time of 7.8 years, resulting in
Table 1. Characteristics of Women Diagnosed With CD or UC in Denmark From 1979 to 2011
Total patients, n Mean age at diagnosis (y) Age at diagnosis (y) 0–25 26–39 40–59 60þ Ever use of IBD drugsa Mesalamine Topical steroids Oral steroids Azathioprine TNF-a antagonist
a
UC, n (%)
CD, n (%)
18,691 46.4
8717 40.4
3081 5372 4775 5463
(16.5) (28.7) (25.5) (29.2)
2645 2394 1812 1866
(30.3) (27.5) (20.8) (21.4)
4521 3371 3461 1415 774
(31.2) (23.3) (23.9) (9.8) (5.0)
1570 1357 1821 1737 1071
(25.5) (22.0) (29.5) (28.2) (17.0)
Ever users as registered in the National Prescription Registry since 1995.
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Table 2. IRRs of Cervical Dysplasia or Cancer in Patients With UC or CD Diagnosed From 1979 to 2011 as Compared With Individually Matched Women From the General Population Type of No. of cervical lesion events LSILa HSILb Cervical cancer
199 362 28
UC, IRR (95% CI)
No. of events
CD, IRR (95% CI)
1.15 (1.00–1.32) 1.12 (1.01–1.25) 0.78 (0.53–1.13)
145 262 26
1.26 (1.07–1.48) 1.28 (1.13–1.45) 1.53 (1.04–2.27)
a
LSIL including mild cervical intraepithelial neoplasia. HSIL including moderate-to-severe cervical intraepithelial neoplasia; the latter includes in situ. IRRs are adjusted for age, calendar period, disease duration, comorbidities, and number of smear tests taken.
b
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Risk of Cervical Cancer After Inflammatory Bowel Disease Ulcerative colitis. Twenty-eight patients with UC developed cervical cancer compared with 1918 controls, with no significant difference in risk (IRR, 0.78; 95% CI, 0.53–1.13; Table 2 and Figure 1). Crohn’s disease. Twenty-six patients with CD developed cervical cancer compared with 940 controls, resulting in a significantly increased risk of cervical cancer in patients with CD (IRR, 1.53; 95% CI, 1.04–2.27; Table 2). The risk may increase by time since diagnosis of CD (Figure 1), although this did not reach statistical significance.
Risk of Cervical Neoplasia According to Age a slightly increased risk of both LSIL (IRR, 1.15; 95% CI, 1.00–1.32) and HSIL (IRR, 1.12; 95% CI, 1.01–1.25) (Table 2). As it appears from Figure 1, the IRR of HSIL did not increase with time since diagnosis of UC. Crohn’s disease. A total of 407 patients with CD were diagnosed with dysplasia (LSIL, n ¼ 145; HSIL, n ¼ 262) during a median follow-up time of 8.3 years. Patients with CD were at significantly increased risk of both LSIL (IRR, 1.26; 95% CI, 1.07–1.48) and HSIL (IRR, 1.28; 95% CI, 1.13–1.45) (Table 2). The IRR of HSIL may increase by time since diagnosis of CD, although CIs were broad (Figure 1).
When stratifying risk of HSIL and cancer by age at diagnosis of IBD, only patients with UC diagnosed at age 26–39 had significantly increased risk of HSIL (IRR, 1.17; 95% CI, 1.01–1.35) (Table 3). However, Wald test for homogeneity revealed no significant difference in IRR between patients aged 25, 26–39, 40–59, or 60þ years at diagnosis (Table 3). Patients with CD aged 0–25 years (IRR, 1.30; 95% CI, 1.11–1.51) and 26–39 years (IRR, 1.30; 95% CI, 1.06–1.58) at diagnosis were at significantly increased risk of HSIL, and those aged 0–25 at diagnosis of CD were at increased risk of cervical cancer
Figure 1. Risk of cervical HSILs and cancer according to time since diagnosis of UC and CD.
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Table 3. IRRs of Cervical HSILs or Cancer According to Age at Diagnosis of UC and CD HSIL
Cervical cancer IRR (95% CI)
UC Age at diagnosis (y) 0–25 26–39 40–59 60þ Homogeneitya CD Age at diagnosis (y) 0–25 26–39 40–59 60þ Homogeneitya
1.06 1.17 1.24 0.70
(0.90–1.25) (1.01–1.35) (0.92–1.69) (0.22–2.20) .45
0.86 0.96 0.52 0.72
1.30 (1.11–1.51) 1.30 (1.06–1.58) 1.22 (0.72–2.08) 0 .85
2.70 1.54 1.05 0.60
(0.32–2.30) (0.56–1.67) (0.21–1.25) (0.34–1.52) .85
(1.47–4.96) (0.82–2.89) (0.39–2.82) (0.15–2.42) .41
a
Wald test.
(IRR, 2.70; 95% CI, 1.47–4.96) (Table 3). Overall, however, age-stratified IRRs did not differ significantly from one another (Wald test, Table 3).
analyzing the impact of number of redeemed prescriptions on cervical neoplasia risk, an 8% increase in IRR for HSIL per redeemed prescription of azathioprine was observed in patients with CD (IRR, 1.08; 95% CI, 1.04–1.13). Number of redeemed prescriptions of oral corticosteroids (IRR, 1.02; 95% CI, 0.98–1.06) or TNF-a antagonists (IRR, 1.16; 95% CI, 0.87–1.55) had no significant impact on risk. Cumulative exposure to any of these medications did not affect the risk of LSIL or cancer (low power) in CD or of any kind of neoplasia in UC (Table 5).
Hormonal Contraceptive Devices and Risk of Cervical Neoplasia In UC, treatment with HCD did not influence risk of cervical neoplasia (Supplementary Table 1). However, patients with CD with >20 redeemed prescriptions were at significantly increased risk of HSIL, reflecting 2% increase in the risk of HSIL per redeemed HCD prescription (IRR, 1.02; 95% CI, 1.01–1.04) (Supplementary Table 1). No statistically significant impact on cancer risk was observed (Supplementary Table 1).
Cervical Neoplasia Before Inflammatory Bowel Disease
Inflammatory Bowel Disease Medications and Risk of Cervical Neoplasia In crude analyses of ever use, mesalamine, azathioprine, and corticosteroids had no impact on cervical neoplasia risk in CD or UC (Table 4). CD patients who had ever used TNF-a antagonists were at significantly increased risk of HSIL (IRR, 1.85, 95% CI, 1.12–3.04) compared with non-users, whereas this was not the case in UC (IRR, 1.12; 95% CI, 0.45–2.79). No cervical cancer cases had received TNF-a antagonists (Table 4). When
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Ulcerative colitis. Overall, 34 UC patients and 1626 control women were diagnosed with HSIL <1 year before UC diagnosis/index date (odds ratio [OR]<1y, 1.10; 95% CI, 0.75–1.48), whereas 279 patients with UC and 11,908 control women were diagnosed with HSIL 1–9 years before index date, resulting in significantly increased OR1–9y of 1.18 (95% CI, 1.04–1.30). Also, the OR of cancer before diagnosis of UC was significantly increased both <1 year before UC diagnosis/index date
Table 4. IRRs of Cervical Neoplasia in Patients With UC or CD According to Ever Use of Medications During Follow-up LSILa Type of medication UC Mesalamine Topical corticosteroids Oral corticosteroids Azathioprine TNF-a antagonist CD Mesalamine Topical corticosteroids Oral corticosteroids Azathioprine TNF-a antagonist
HSILb
Cervical cancerc
Nd
IRR (95% CI)
Nd
IRR (95% CI)
Nd
IRR (95% CI)
44 33 32 11 1
0.88 1.05 1.13 0.84 0.56
(0.60–1.28) (0.70–1.58) (0.74–1.70) (0.45–1.58) (0.08–4.12)
80 48 59 23 5
0.81 0.71 0.97 0.87 1.12
(0.62–1.07) (0.52–0.99) (0.72–1.32) (0.56–1.36) (0.45–2.79)
4 4 3 0 0
0.93 (0.27–3.21) 1.66 (0.48–5.77) 1.05 (0.26–4.24) NA NA
33 19 21 24 8
1.09 0.88 0.63 0.97 1.08
(0.68–1.73) (0.52–1.50) (0.38–1.06) (0.59–1.60) (0.50–2.31)
53 37 48 49 21
1.25 1.14 1.12 1.43 1.85
(0.85–1.84) (0.76–1.71) (0.77–1.64) (0.98–2.09) (1.12–3.04)
1 1 0 1 0
0.67 (0.06–7.40) 1.33 (0.13–13.56) NA 0.98 (0.10–9.90) NA
NOTE. Table concerns all patients diagnosed from 1995 to 2010. a LSIL including mild cervical intraepithelial neoplasm. b HSIL including moderate-to-severe cervical intraepithelial neoplasia. The latter includes carcinoma in situ. c Primary cancer with origin in cervix uteri. d Number of exposed.
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Table 5. Change in IRRs of Cervical Neoplasia in Patients With UC or CD per Redeemed Prescription/Administration of Oral Corticosteroids, Azathioprine, or TNF-a Antagonists Type of medication UC Oral corticosteroids Azathioprine TNF-a antagonist CD Oral corticosteroids Azathioprine TNF-a antagonist
LSILa (IRRchange, 95% CI)
HSILb (IRRchange, 95% CI)
Cervical cancerc (IRRchange, 95% CI)
1.03 (1.00–1.06) 0.96 (0.85–1.08) 0.79 (0.38–1.63)
0.99 (0.95–1.04) 0.99 (0.97–1.02) 1.04 (0.95–1.15)
1.01 (0.98–1.04) NA NA
0.91 (0.83–1.00) 0.99 (0.97–1.02) 1.01 (0.96–1.07)
1.02 (0.98–1.06) 1.08 (1.04–1.13) 1.16 (0.87–1.55)
NA 0.99 (0.95–1.04) NA
NOTE. Table concerns all patients diagnosed from 1995 to 2010. a LSIL including mild cervical intraepithelial neoplasm. b HSIL including moderate-to-severe cervical intraepithelial neoplasia. The latter includes carcinoma in situ. c Primary cancer with origin in cervix uteri.
(UC, n ¼ 10; controls, n ¼ 162; OR<1y, 3.10; 95% CI, 1.63–5.86) and 1–9 years before index date (UC, n ¼ 56; controls, n ¼ 1007; OR1–9y, 2.78; 95% CI, 2.12–3.64). Crohn’s disease. Overall, 15 women with CD and 735 control women were diagnosed with HSIL <1 year before IBD diagnosis/index date (OR<1y, 1.03; 95% CI, 0.62–1.72), whereas 131 women with CD and 4799 control women were diagnosed with HSIL 1–9 years before index date, resulting in a significantly increased OR1–9y of 1.38 (95% CI, 1.16–1.65). Also, the OR of cervical cancer <1 year before IBD (OR<1y, 5.13; 95% CI, 2.05–12.9) and 1–9 years before IBD (OR1–9y, 1.85; 95% CI, 1.08–3.15) was significantly increased.
Discussion In this population-based cohort study of 27,408 IBD women, we observed an increased risk of LSIL and HSIL in both UC and CD and an increased risk of cervical cancer in patients with CD, despite normal screening frequency in CD patients and only a slightly elevated screening frequency in UC patients. Use of common IBD medications did not influence neoplasia risk in UC, whereas patients with CD who had ever used TNF-a antagonists had significantly increased risk of HSIL compared with non-users. Also, 2% increase in risk of HSIL per redeemed prescription of HCD was observed in patients with CD. In reverse analyses, we observed a significant excess in cervical neoplasia occurrence up to 10 years before UC and CD diagnoses. The primary strength of the present study was the population-based design combining information from several nationwide registers, thereby creating a historical cohort with prospectively collected individual level information. Hence, information on numbers of smear tests taken and use of medication through follow-up were not affected by recall bias. The IBD diagnoses have been found to be of high completeness and validity in the Danish NPR,12 and the Danish Cancer Register is of highest international standard.16 We were further able to
match IBD women with a broad random selection of the general population matched on sex, age, and place of living. This is of importance because the prevalence of HPV is highly dependent on age and because smear test screening was not introduced simultaneously in all parts of the country. As a potential limitation, information on smoking was not available. Smoking is suggested to have an effect on the progression of chronic HPV infection to HSIL or invasive cancer,17 and this might to some extent explain the increased risk of cervical neoplasia observed in our patients with CD. Also, disease severity may potentially confound results. However, considering medication use as a proxy for disease severity, it is noteworthy that only azathioprine but not corticosteroids or TNF inhibitors (at least not in cumulative analyses) was associated with increased risk of cervical neoplasia. This suggests limited confounding by disease severity. Last, vaccination policies may potentially influence risk estimates. However, HPV vaccines (mainly Gardasil) were first introduced as part of the national childhood vaccination program in 2009. We believe that an effect of a vaccine introduced to young girls in 2009 would not be observable in the present study. Likewise, it was not the aim of the present study to assess the incidence of high-risk oncogenic HPV infections in patients with IBD. We found women with UC, but not CD, to have slightly higher participation in smear testing than their controls. It is of importance to acknowledge that incidence and mortality of cervical neoplasia are highly dependent on screening and treatment of precursor lesions.18 However, only few studies have taken participation in screening into consideration when analyzing risk of cervical neoplasia in IBD, and results are conflicting.4,19,20 Singh et al20 found slightly lower participation in cervical cancer screening in Canadian patients with IBD than in controls and even lower participation in screening in patients on immunosuppressive treatment compared with IBD patients without such treatment.20 In contrast, Hutfless et al4 found the prevalence of smear testing in a 3-year period to be higher in IBD patients (93%) than in non-IBD patients (79%). In the present
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study, not only were we able to demonstrate a slightly increased screening activity in patients with UC (but not CD), we also implemented this information into all subsequent analyses of risk of cervical neoplasia. In our study, women with UC and CD had increased risk of both LSIL and HSIL. LSIL is known to have a high rate of spontaneous regression, whereas HSIL is more aggressive and requires intervention. A slightly increased risk of HSIL was found in patients with UC, and the increased risk in CD patients is in line with findings by others. Singh et al6 found a significantly increased risk of cervical abnormalities in a subgroup of CD patients (patients using 10þ prescriptions of oral contraceptives and patients on combined immunosuppressive treatment). Two other relatively small studies have suggested an increased risk of abnormal smear in IBD patients compared with controls, with no clear differences between patients with UC or CD.1,4 Of notice, although both UC and CD patients had higher odds of being diagnosed with cervical cancer before IBD, only patients with CD were at an increased risk of developing cervical cancer after the IBD diagnosis. This is in accordance with a detailed IBD cohort study from Northern Jutland, Denmark, which suggested an increased risk of carcinoma in situ and cervical cancer among patients with CD but not UC.21 Likewise, Goldacre et al22 found an increased risk of cervical cancer in patients with CD but not UC. The reason for the difference in risk of cervical cancer in patients with CD and UC is unclear but could partly be related to smoking, which we were not able to control for. In the study from North Jutland, risk factors were smoking (standardized incidence ratio, 2.15; 95% CI, 1.27–3.40), ever use of mesalamine (standardized incidence ratio, 1.69; 95% CI, 1.08–2.51) or thiopurines (standardized incidence ratio, 2.47; 95% CI, 1.54–3.73), and young age (<20 years) at CD diagnosis (standardized incidence ratio, 2.52; 95% CI, 1.26–4.51).21 In the present study, we also found a significantly higher risk of cervical neoplasia in patients diagnosed with CD at young age and in CD patients treated with azathioprine. On the other hand, we did not find that use of mesalamine or corticosteroids influenced risk of cervical dysplasia among IBD patients, in accordance with the majority of other studies investigating impact of IBD medication on risk of cervical neoplasia.1–6 A single study has suggested that combined use of corticosteroids and immunosuppressive drugs (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and infliximab) is associated with risk of cervical neoplasia in patients with CD.6 Somewhat in line with these findings, we observed ever use of TNF-a antagonists in CD patients to associate with increased risk of HSIL. However, this was not confirmed in analyses of cumulative number of administrations of these drugs. Accordingly, current Danish guidelines do not recommend HPV screening before initiation of treatment with TNF-a antagonists.23 Use of HCD has also been associated with increased risk of cervical neoplasia.24 We found an increased risk of HSIL in CD patients with long-term use of HCD. To what
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extent use of HCD is also associated with different sexual behavior (ie, not using barrier method as prevention) or alters the composition of the cervical mucus is unknown and to our knowledge unexplored in the IBD population. Finally, we observed markedly increased odds of HSIL and cervical cancer up to 10 years before diagnosis of UC or CD. This is a novel finding that may suggest a yet unexplored common susceptibility to IBD and cervical neoplasia rather than an etiologic role of IBD or its treatment in development of cervical neoplasia. This finding needs to be confirmed and further investigated in future studies.
Conclusion In this nationwide study of patients with IBD followed during a 35-year period, women with a diagnosis of CD had increased risk of cervical dysplasia and cancer despite similar screening intensity as in the general population. Treatment with TNF-a antagonists and HCD may influence risk of cervical neoplasia in CD. Patients with UC only had increased risk of dysplasia along with a slightly increased screening frequency compared with controls. Interestingly, reverse analyses showed markedly elevated odds of cervical neoplasia up to 10 years before IBD diagnosis, which may indicate a common susceptibility to cervical neoplasia and IBD. This observation needs further investigation. Patients with IBD should be encouraged to follow the screening program for cervical neoplasia, and clinicians should be aware of the slightly increased risk of HPV-related cervical lesions in IBD patients.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2014.07.036.
References 1. Bhatia J, Bratcher J, Korelitz B, et al. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol 2006;12:6167–6171. 2. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008;103:631–636. 3. Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderate-to-severe Crohn’s disease. Am J Gastroenterol 2009;104:2524–2533. 4. Hutfless S, Fireman B, Kane S, et al. Screening differences and risk of cervical cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2008;28:598–605. 5. Lees CW, Critchley J, Chee N, et al. Lack of association between cervical dysplasia and IBD: a large case-control study. Inflamm Bowel Dis 2009;15:1621–1629. 6. Singh H, Demers AA, Nugent Z, et al. Risk of cervical abnormalities in women with inflammatory bowel disease: a
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Rungoe et al population-based nested case-control study. Gastroenterology 2009;136:451–458. 7. Ibeanu OA. Molecular pathogenesis of cervical cancer. Cancer Biol Ther 2011;11:295–306. 8. Moore EE, Wark JD, Hopper JL, et al. The roles of genetic and environmental factors on risk of cervical cancer: a review of classical twin studies. Twin Res Hum Genet 2012;15:79–86. 9. Einstein MH, Schiller JT, Viscidi RP, et al. Clinician’s guide to human papillomavirus immunology: knowns and unknowns. Lancet Infect Dis 2009;9:347–356.
10. Pedersen CB, Gotzsche H, Moller JO, et al. The Danish Civil Registration System: a cohort of eight million persons. Dan Med Bull 2006;53:441–449. 11. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39:30–33. 12. Fonager K, Sorensen HT, Rasmussen SN, et al. Assessment of the diagnoses of Crohn’s disease and ulcerative colitis in a Danish hospital information system. Scand J Gastroenterol 1996;31:154–159. 13. Kildemoes HW, Sorensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health 2011;39:38–41.
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19. Long MD, Porter CQ, Sandler RS, et al. Suboptimal rates of cervical testing among women with inflammatory bowel disease. Clin Gastroenterol Hepatol 2009;7:549–553. 20. Singh H, Nugent Z, Demers AA, et al. Screening for cervical and breast cancer among women with inflammatory bowel disease: a population-based study. Inflamm Bowel Dis 2011;17: 1741–1750. 21. Jess T, Horvath-Puho E, Fallingborg J, et al. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. Am J Gastroenterol 2013;108:1869–1876. 22. Goldacre MJ, Wotton CJ, Yeates D, et al. Cancer in patients with ulcerative colitis, Crohn’s disease and coeliac disease: record linkage study. Eur J Gastroenterol Hepatol 2008;20:297–304. 23. Nordgaard-Lassen I, Dahlerup JF, Belard E, et al. Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J 2012;59:C4480. 24. Moreno V, Bosch FX, Munoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002;359:1085–1092.
14. Andersen JS, Olivarius NF, Krasnik A. The Danish National Health Service Register. Scand J Public Health 2011;39:34–37. 15. Bjerregaard B, Larsen OB. The Danish Pathology Register. Scand J Public Health 2011;39:72–74. 16. Gjerstorff ML. The Danish Cancer Registry. Scand J Public Health 2011;39:42–45.
Reprint requests Address requests for reprints to: Tine Jess, MD, DMSc, Department of Epidemiologic Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark. e-mail: [email protected]; fax: þ4532683868.
17. Fonseca-Moutinho JA. Smoking and cervical cancer. ISRN Obstet Gynecol 2011;2011:847684.
Conflicts of interest The authors disclose no conflicts.
18. Wacholder S. Chapter 18: statistical issues in the design and analysis of studies of human papillomavirus and cervical neoplasia. J Natl Cancer Inst Monogr 2003;(31):125–130.
Funding Dr Tine Jess was supported by a Female Research Leader grant (no. 09-066323) from the Danish Council of Independent Research.
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Supplementary Table 1. IRRs of Cervical Neoplasia Among Patients With CD or UC Comparing Users and Non-users of HCDs LSIL No. of prescriptions of HCDa UC 0 1–20 21–50 50þ Change in IRR per redeemed HCD prescriptionc CD 0 1–20 21–50 50þ Change in IRR per redeemed HCD prescriptionc
a
Cervical cancer
Nb
IRR (95% CI)
Nb
IRR (95% CI)
Nb
IRR (95% CI)
53 27 36 5
(Reference) 0.95 (0.56–1.62) 1.02 (0.61–1.70) 1.25 (0.47–3.29) 1.01 (0.99–1.02)
87 56 79 10
(Reference) 1.19 (0.82–1.75) 1.07 (0.75–1.54) 1.30 (0.65–2.59) 1.01 (1.00–1.01)
8 2 2 0
(Reference) 1.86 (0.29–11.96) 1.76 (0.27–11.65) NA 1.01 (0.96–1.05)
26 20 28 4
(Reference) 0.84 (0.44–1.61) 0.94 (0.50–1.74) 1.32 (0.42–4.09) 1.00 (0.99–1.02)
28 23 63 7
(Reference) 1.26 (0.68–2.34) 2.46 (1.45–4.17) 2.67 (1.09–6.52) 1.02 (1.01–1.04)
2 1 0 1
(Reference) 2.62 (0.14–48.23) NA 33.50 (0.99–1129) 1.03 (0.97–1.10)
Defined by cumulative use of ATC codes G02B, G03AA07–G03AC09 within the study period. Number of events. c Trend per prescription of HCD. b
HSIL