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Background: The aetiology of inflammatory bowel disease remains largely unknown.
Aim: We performed a comprehensive assessment of potential risk factors associated with the occurrence of inflammatory bowel disease.
Methods: We identified a cohort of patients 20–84 years old between 1995 and 1997 registered in the General Practitioner Research Database in the UK. A total of 444 incident cases of IBD were ascertained and validated with the general practitioner. We performed a nested case–control analysis using all cases and a random sample of 10 000 frequency-matched controls.
Results: Incidence rates for ulcerative colitis, Crohn's disease, and indeterminate colitis were 11, 8, and 2 cases per 100 000 person-years, respectively. Among women, we found that long-term users of oral contraceptives were at increased risk of developing UC (OR: 2.35; 95% CI: 0.89–6.22) and CD (OR: 3.15; 95% CI: 1.24–7.99). Similarly, long-term users of HRT had an increased risk of CD (OR: 2.60; 95% CI: 1.04–6.49) but not UC. Current smokers experienced a reduced risk of UC along with an increased risk of CD. Prior appendectomy was associated with a decreased the risk of UC (OR: 0.37; 95% CI: 0.14–1.00).
Conclusions: Our results support the hypothesis of an increased risk of inflammatory bowel disease associated with oral contraceptives use and suggest a similar effect of hormone replacement therapy on CD. We also confirmed the effects of smoking and appendectomy on inflammatory bowel disease.
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The incidence of inflammatory bowel disease (IBD) tends to plateau in those regions with the greatest incidence rates but is still growing in low-incidence areas such as southern Europe, Asia, and much of the developing world.1 Nevertheless the aetiology of the disease remains largely unknown. While some risk factors such as smoking have been studied in more detail, the impact of most other factors on the two main entities that constitute IBD, ulcerative colitis (UC) and Crohn's disease (CD) has not been established yet.
We conducted a prospective cohort study with a nested case–control analysis using data from the General Practice Research Database (GPRD) to identify risk factors associated with the occurrence of UC and CD in this population.
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The resulting overall incidence of IBD was 21 per 100 000 py in our 20–84 year old source population. The corresponding incidences for UC, CD, and indeterminate colitis were 11, 8, and 2 cases per 100 000 py, respectively. Figure 1 shows incidence rates of UC, and CD stratified by age groups. Incidence of CD was highest in the youngest age group. Incidence of UC varied with age and showed several peaks in patients in the third, and fifth decade of life as well as among those over 70 years of age. Incidence rate of CD was similar between sexes whereas incidence rate of UC was higher in males (12 per 100 000 py) than in females (8 per 100 000 py).
Table 1 shows the estimates of the association between selected prior comorbidity and the estimates of OR for UC and CD. Diabetes was associated with an increased OR of UC (2.09, 95% CI:1.20–3.66) but not CD. On the other hand, rheumatoid arthritis was more markedly associated with CD (OR:4.38, 95% CI:2.01–9.51). Patients diagnosed with IBS more than 1 year before the index date experienced an increased risk of both UC and CD.
Table 1. Risk of UC and CD associated with selected comorbidity and prior smoking status
| ||UC cases (%) (n = 222)||CD cases (%) (n = 171)||Controls (%) (n = 10 000)||UC OR* (95% CI)||CD OR* (95% CI)|
|OA||36 (16.2)||35 (20.5)||1545 (15.5)||0.92 (0.62–1.38)||1.43 (0.92–2.23)|
|RA||5 (2.3)||8 (4.7)||112 (1.1)||2.16 (1.31–3.54)||4.38 (2.01–9.51)|
|Depression||44 (19.8)||28 (16.3)||1478 (14.8)||1.38 (0.95–2.00)||0.94 (0.59–1.48)|
|Anxiety||36 (16.2)||22 (12.9)||1200 (12)||1.33 (0.89–1.98)||0.96 (0.58–1.59)|
|Stress||8 (3.6)||8 (4.7)||368 (3.7)||0.80 (0.39–1.67)||1.17 (0.56–2.45)|
|Asthma||28 (12.6)||16 (9.4)||881 (8.8)||1.41 (0.93–2.15)||0.97 (0.57–1.67)|
|COPD||6 (2.7)||4 (2.3)||258 (2.6)||0.81 (0.34–1.94)||0.84 (0.29–2.41)|
|Diabetes||15 (6.8)||5 (2.9)||299 (3.0)||2.09 (1.20–3.66)||1.10 (0.44–2.75)|
|IBS†||19 (8.6)||22 (13.0)||407 (4.1)||2.16 (1.31–3.54)||3.40 (2.11–5.47)|
| non-smoker||130 (58.6)||74 (43.3)||5307 (53.1)||1||1|
| smoker||37 (16.7)||60 (35.1)||2379 (23.8)||0.61 (0.42–0.89)||1.74 (1.22–2.48)|
| ex-smoker||27 (12.2)||19 (11.1)||700 (7.0)||1.45 (0.94–2.23)||1.75 (1.01–3.00)|
| unknown||28 (12.6)||18 (10.5)||1614 (16.1)||0.71 (0.46–1.08)||0.80 (0.47–1.36)|
|Appendectomy||4 (1.8)||8 (4.7)||469 (4.7)||0.37 (0.14–1.00)||0.92 (0.45–1.91)|
We found that patients with a recorded diagnosis of depression for the first time in the 2 years prior to the index date presented a small increased risk of UC (OR:1.39, 95% CI: 0.71–2.71) no different from the one when the diagnosis had been made two or more years prior (OR:1.37, 95% CI: 0.90–2.08). Patients diagnosed with anxiety in the 2 years prior to the index date and two or more years before the index date presented ORs for UC of 0.79 (95% CI:0.31–1.98) and 1.50 (95% CI:0.97–2.30), respectively.
Current smokers had a reduced risk of UC (OR:0.61, 95% CI:0.42–0.89) and an increased risk of CD (OR:1.74, 95% CI:1.22–2.48). The reduced risk of UC among smokers transformed into a slightly elevated risk of UC after smoking cessation. Interestingly, this increased risk of UC among ex-smokers was seen only in the first year after smoking cessation (OR:2.51, 95% CI:1.24–5.09) and thereafter (more than 1 year) returned close to the background risk (OR:1.19, 95% CI:0.72–1.99). The corresponding estimates of CD among former smokers were 2.01 (95% CI:0.71–5.66) and 1.68 (95% CI:0.92–3.07), respectively.
Patients who underwent appendectomy presented a decreased risk of developing UC (OR:0.37, 95% CI:0.14–1.00). The association was very similar when appendectomy 5 years or more before index date was considered (OR:0.42, 95% CI:0.16–1.15). Appendectomy was not associated with the subsequent occurrence of CD.
As shown in Table 2, neither aspirin (OR:0.76, 95% CI:0.44–1.29) nor NA-NSAIDs (OR:1.38, 95% CI:0.96–2.00) were significantly associated with the risk of IBD. Current use of paracetamol was associated with a twofold increased risk of IBD (2.02, 95% CI:1.43–2.85). When we examined the effect of paracetamol according to treatment duration, we observed that the increased risk was concentrated during the first month after starting paracetamol (OR:3.32, 95% CI:2.15–5.14) and then decreased gradually over time. Chronic users of paracetamol for longer than 1 year experienced no increased risk of IBD (OR:0.90, 95% CI:0.45–1.79). Results were similar when analysing separately UC and CD.
Table 2. Risk of IBD associated with NSAID use
| ||IBD cases (%) (n = 444)||Controls (%) (n = 10000)||IBD OR* (95% CI)|
|Non-use||412 (92.8)||9294 (92.9)||1|
|Current use||16 (3.6)||400 (4.0)||0.76 (0.44–1.29)|
| <1 month||1 (0.2)||28 (0.3)||0.86 (0.11–6.40)|
| 1–12 months||8 (1.8)||144 (1.4)||1.02 (0.46–2.23)|
| >1 year||7 (1.6)||228 (2.3)||0.60 (0.27–1.33)|
|Past use||16 (3.6)||306 (3.1)||1.05 (0.62–1.77)|
|Non-use||209 (47.1)||5057 (50.6)||1|
|Current use||47 (10.6)||625 (6.3)||1.38 (0.96–2.00)|
| <1 month||19 (4.3)||219 (2.2)||1.53 (0.92–2.55)|
| 1–12 months||11 (2.5)||197 (2.0)||1.06 (0.55–2.05)|
| >1 year||17 (3.8)||209 (2.1)||1.45 (0.80–2.61)|
|Past use||188 (42.3)||4318 (43.2)||0.93 (0.75–1.15)|
|Non-use||229 (51.6)||6022 (60.2)||1|
|Current use||58 (13.1)||699 (7.0)||2.02 (1.43–2.85)|
| <1 month||30 (6.8)||210 (2.1)||3.32 (2.15–5.14)|
| 1–12 months||17 (3.8)||232 (2.3)||1.53 (0.87–2.68)|
| >1 year||11 (2.5)||257 (2.6)||0.90 (0.45–1.79)|
|Past use||157 (35.4)||3279 (32.8)||1.22 (0.98–1.53)|
Women who were currently using OCs were at increased risk of developing both UC (OR:1.58, 95% CI:0.71–3.52) and CD (OR:1.94, 95% CI:0.85–4.45). These risks were especially elevated with long-term use of OCs (Table 3). While current users of HRT had a twofold increased OR of developing CD (OR:2.08, 95% CI:1.10–4.38), their risk of UC was similar to those women who never used HRT (OR:0.96, 95% CI:0.41–2.25). Increasing duration of HRT use was associated with a greater risk of CD (Table 3).
Table 3. Risk of UC and CD associated with OC and HRT use
| ||UC cases (%) (n = 96)||CD cases (%) (n = 92)||Controls (%) (n = 5162)||UC OR* (95% CI)||CD OR* (95% CI)|
|Non-use||72 (75.0)||58 (63.0)||3669 (71.1)||1||1|
|Current use||11 (11.5)||14 (15.2)||410 (7.9)||1.58 (0.71–3.52)||1.94 (0.85–4.45)|
| <1 month||1 (1.0)||3 (3.3)||68 (1.3)||0.79 (0.10–6.09)||2.49 (0.66–9.36)|
| 1–12 months||4 (4.2)||2 (2.2)||181 (3.5)||1.31 (0.42–4.11)||0.61 (0.13–2.87)|
| >1 year||6 (6.3)||9 (9.8)||161 (3.1)||2.35 (0.89–6.22)||3.15 (1.24–7.99)|
|Past use||13 (13.5)||20 (21.7)||1083 (21.0)||0.67 (0.32–1.39)||1.04 (0.50–2.17)|
|Non-use||84 (87.5)||71 (77.2)||4454 (86.3)||1||1|
|Current use||7 (7.3)||12 (13.0)||368 (7.1)||0.96 (0.41–2.25)||2.08 (1.00–4.38)|
| <1 month||1 (1.0)||1 (1.1)||51 (1.0)||0.99 (0.13–7.51)||1.13 (0.15–8.80)|
| 1–12 months||2 (2.1)||4 (4.4)||133 (2.6)||0.76 (0.18–3.26)||1.97 (0.65–5.94)|
| >1 year||4 (4.2)||7 (7.6)||184 (3.6)||1.11 (0.38–3.26)||2.60 (1.04–6.49)|
|Past use||5 (5.2)||9 (9.8)||340 (6.6)||0.75 (0.29–1.98)||1.66 (0.71–3.86)|
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We report an incidence rate of UC and CD similar to recent reports from the UK.3–4 We only considered as valid incident cases those patients whose IBD diagnosis was confirmed by the GP. However, we did not receive information on 13% of all potential cases, and therefore the incidence rates reported could slightly underestimate the true incidence rates. We performed a sensitivity analysis considering an extreme hypothetical scenario where all potential cases for whom we did not receive information were truly incident cases. The overall incidence rate of IBD would be 24 per 100 000 py under this scenario instead of 21 per 100 000 py, giving an idea of the maximum amount of underestimation. An advantage of our study is that all cases were confirmed directly by the GP, who ascertained the exact diagnosis (UC, CD, or indeterminate colitis) together with date of first diagnosis based on all information available to her/him rather than classifying cases solely using the codes recorded in the database, frequently unspecific with respect to the type of IBD and incorrect timing of first diagnosis.
Our results suggest that diabetes and rheumatoid arthritis are independent risk factors of UC and CD, respectively. While the underlying mechanism of this association is unknown, some degree of immunologic component in the aetiology of these two conditions as well as IBD could explain in part these findings. Unfortunately, we could not study the effect according to type of diabetes, as this information is often missing in the database. Yet, the vast majority of diabetes in western societies is type II.5 Our definition of RA did not include the specific codes for IBD-associated inflammatory polyarthritis. However, we cannot exclude the possibility that some unspecific RA diagnosis were used by the GPs to code IBD-associated inflammatory polyarthritis before the IBD diagnosis was first made. If this were the case, the observed association could be somewhat overestimated.
We found that prior IBS was associated with both UC and CD. In our analysis, we excluded IBS diagnosed in the year prior to the index date as the recording of IBS could actually be a differential diagnosis at that time. We have previously reported this association in another study using the same database.6
Prior studies have associated both depression and anxiety with UC.7–8 However the temporal sequence of these associations (i.e. whether depression/anxiety precedes UC or is rather a consequence of UC) remains unclear. We found that depression and anxiety were associated with a small increased risk of UC. Interestingly, we observed that this association was also present among patients with a long-standing (two or more years before index date) history of these conditions, which supports a hypothetical role of psychological factors in the occurrence of UC.
Our results for smoking are fully consistent with the available literature, namely a decreased risk of UC and increased risk of CD among current smokers compared with non-smokers.1 The elevated risk of UC and CD among former smokers has also been previously described in detail.9–10 Furthermore, we showed that the deleterious effect of smoking cessation on the occurrence of UC was restricted to the first year after quitting. A similar time relationship has been previously reported.11 In contrast, increased risks of CD of similar magnitude were observed among both current smokers and former smokers irrespective of the time as they quitted smoking.
The inverse association between UC and appendectomy has also been observed in a number of epidemiological studies. A meta-analysis of 17 published studies reported a pooled estimate of 0.31, in lime with our estimate.12 A prior study evidenced that underascertainment of appendectomy existed in the GPRD.13 The same study found that the impact of this under-recording would only introduce a minor bias on the estimate of risk.
The impact of NA-NSAID use on IBD remains controversial. Some studies have found an association between NA-NSAID use and relapse of IBD.14 In our study, we studied the association between NA-NSAID use and first occurrence of IBD rather than relapse of IBD. Our data suggest that neither aspirin nor NA-NSAIDs current use are associated to a significant extent with the occurrence of IBD. Only patients at the beginning of NA-NSAIDs therapy experienced a small increased risk (although non-significant). On the other hand, use of paracetamol was associated with an elevated risk of developing IBD, especially during the first month of treatment. Whether paracetamol was used to treat early ill-defined prodromal symptoms of IBD (confounding by indication), or is truly a triggering risk factor is unclear.
Finally, our results are suggestive of an increased risk of CD and to a lesser extent of UC among women using OCs, especially among those taking it over extended periods of time. Although several prior studies also reported increased risks of IBD associated with OC use, others failed to replicate this finding.1 To the best of our knowledge, the association between HRT use and IBD has not been previously explored. We found that women exposed to HRT had an elevated risk of CD but not UC. As seen for OCs, the risk of CD increased substantially with longer duration of HRT exposure suggesting a causal pathway for this association.
Unfortunately, we could not assess the role of some potential risk factors of IBD not readily available in the database such as family history of IBD, diet, and breastfeeding.
In summary, our data provide support to the hypothesis of increased risk of IBD associated to OCs use and suggest a similar effect of HRT use on CD. We also confirmed the effects of smoking and appendectomy on IBD. The time relationship observed between smoking cessation and UC warrants further investigation as this could provide some insight into a better understanding of the mechanistic effects of smoking. Finally, our results do not support a major effect of NSAIDs or paracetamol on the occurrence of IBD.