Comorbidity Before and After a Diagnosis of Inflammatory Bowel Disease

Charles N. Bernstein; Zoann Nugent; Seth Shaffer; Harminder Singh; Ruth Ann Marrie

Aliment Pharmacol Ther. 2021;54(5):637-651.

Results

We included 9247 IBD cases (4253 CD, 4994 UC) and 85 691 controls in the analyses. The median (interquartile range [IQR]) age at diagnosis of IBD was 36 (25, 52) and was significantly younger in persons with CD (33 years [23,49]) than in UC (39 years [27,54] P < 0.0001). Forty-seven per cent of all IBD cases were male. IBD cases and controls had similar Socioeconomic Factor Index scores (Table 1).

Overall the RRs and HRs were highly correlated (r = +0.69, P = 0.013). Similar patterns were evident in CD (r = +0.69, P = 0.013) and UC (+0.71, P = 0.0094). When data were compared between disease types RR (P = 0.012) and HR (P = 0.0015) are higher in CD than UC. RR and HR for males and females did not differ significantly overall.

Pre-IBD Diagnosis Comorbidities

All comorbidities were increased pre diagnosis except for diabetes and dementia (Table 2). Peptic ulcer disease had the highest RR pre-diagnosis of all the comorbidities [RR = 2.01, CI 1.82, 2.23]. For all of Cardiac, connective tissue disease/rheumatic disease, peptic ulcer disease, and renal disease the RR was greater in CD than in UC. For peripheral vascular disease, chronic pulmonary disease, liver disease, and cancer the increase was similar in CD and UC. In the case of cerebrovascular disease, paraplegia/hemiplegia, diabetes and dementia there was no increase in either CD or UC. The increased RR was greater in females compared to males for cerebrovascular disease, while for all other comorbidities there was no difference in RR by sex.

Post-IBD Diagnosis Comorbidities

All comorbidities were increased post-IBD diagnosis (Table 3, Figure 1, Figures S1-S12). There was a significantly increased HR in CD for cerebrovascular disease [1.49 (1.26–1.75)], paraplegia/hemiplegia [1.66 CI (1.19–2.30)] diabetes [1.14 (CI 1.03–1.27)], and dementia [1.44 (CI 1.16–1.78)], but no increase was evident for any of these conditions in UC. For chronic pulmonary disease, the increase in UC was significant [1.12 (1.003–1.26)] but the increase for CD was not significant. For all other comorbidities the increased HR was evident in both CD and UC, however, was increased to a greater extent in CD for peptic ulcer disease and renal disease. The greatest increased HR post-diagnosis was seen in connective tissue disease/rheumatic disease [HR = 2.49 (CI 2.21–2.79)] and especially for connective tissue disease/rheumatic disease in CD [HR = 2.88 (CI 2.43–3.39)]. There was a greater increase in HR for females in peripheral vascular disease [1.83 (1.57, 2.13)] vs males [1.25 (CI 1.11, 1.42)] and for connective tissue disease/rheumatic disease the HR was increased in males [2.93 (CI 2.41–3.57)] compared to females [2.28 (CI 1.97–2.64)]. For all other comorbidities with an increased HR post-IBD diagnosis, the HR was similar by sex. Compared to other age groups persons under age 25 had the greatest increased HR for peripheral vascular disease, connective tissue disease/rheumatic disease, peptic ulcer disease, and liver disease, and did not have an increased HR for chronic pulmonary disease, or paraplegia/hemiplegia. The largest HR for a comorbidity post-IBD diagnosis was for connective tissue disease/rheumatic disease in persons under age 25 [5.70 (CI 3.43–9.49)]. There was an increase in all comorbidities in adults over age 25 however for diabetes an increased HR was evident only for those over age 50 and for dementia there was an increase in HR for persons 25–50 years for all IBD and 25–65 years for CD.

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Figure 1.

Hazard ratios of comorbid diseases in IBD and Crohn's disease and ulcerative colitis compared to matched controls

The number of persons with IBD needed to present with a specific comorbidity was lowest for peptic ulcer disease by 10 years at 21 and was lowest for connective tissue disease/rheumatic disease by 20 years at 11 (Table 4). For all comorbidities except diabetes, the median age at diagnosis was lower in IBD compared to the age of first diagnosis in controls (Table 5).

As an association with paraplegia/hemiplegia was unexpected, we explored whether persons with these health system contacts had prior contacts for cerebrovascular disease, muscular dystrophy, cerebral palsy and motor vehicle accident. For each of the latter three diagnoses the incidence was less than six and hence, cannot be reported. However, of 184 persons with IBD without cerebrovascular disease or paraplegia/hemiplegia prior to diagnosis of IBD, 56% were subsequently diagnosed with paraplegia/hemiplegia alone, 15% with paraplegia/hemiplegia followed by cerebrovascular disease and 29% with cerebrovascular disease followed by paraplegia/hemiplegia, compared to 1155 matched controls with 43%, 25% and 32% in those categories (P = 0.0018). There was no difference between IBD and controls for age at diagnosis of paraplegia/hemiplegia. If persons with prior cerebrovascular disease are excluded from an analysis for paraplegia/hemiplegia the HR for IBD was 1.48 (CI 1.22, 1.79), for CD was 1.58 (CI 1.19, 2.10) and for UC was 1.41 (CI 1.09, 1.82) (Figure 1).

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Table 1. Descriptive characteristics of the cases and controls
	IBD	Control	P	CD	UC	P
N	9247	85 691		4253	4994
Age at IBD diagnosis (median, IQR)	36			33	39	<0.0001
Age at IBD diagnosis (median, IQR)	25–52			23–49	27–54
SEFI median	−0.33	−0.33	0.82	−0.31	−0.35	0.073
(IQR)	−1.02 to +0.58	−1.01 to 0.58		−0.97 to +0.62	−1.03 to +0.55
% Male	47			43	50	<0.0001

Abbreviations: IQR, interquartile range; SEFI, Socioeconomic Factor Index.

Table 2. Relative rates of comorbidities in IBD compared to controls prior to IBD diagnosis
Group	All				Male				Female
	Events	Rate per 1000 PY		Relative rate (CI)	Events	Rate per 1000 PY		Relative rate (CI)	Events	Rate per 1000 PY		Relative rate (CI)
	Events	IBD	Control	Relative rate (CI)	Events	IBD	Control	Relative rate (CI)	Events	IBD	Control	Relative rate (CI)
Cardiac
IBD	3153	2.90	2.58	1.12 (0.97–1.30)	1604	3.03	2.73	1.11 (0.90–1.36)	1549	2.78	2.44	1.14 (0.93–1.40)
CD	1223	2.66	2.21	1.20 (0.96–1.52)	547	2.53	2.30	1.10 (0.76–1.60)	676	2.76	2.14	1.29 (0.95–1.74)
UC	1930	3.08	2.89	1.07 (0.88–1.29)	1057	3.36	3.03	1.11 (0.85–1.44)	873	2.80	2.73	1.02 (0.77–1.36)
Cerebro-vascular disease
IBD	2872	2.67	2.33	1.14 (0.98–1.33)	1252	2.31	2.10	1.10 (0.87–1.39)	1620	2.99	2.55	1.17 (0.96–1.43)
CD	1169	2.46	2.12	1.16 (0.92–1.47)	440	1.97	1.84	1.07 (0.71–1.63)	729	2.84	2.34	1.21 (0.90–1.63)
UC	1703	2.84	2.51	1.13 (0.93–1.38)	812	2.55	2.28	1.12 (0.83–1.50)	891	3.13	2.76	1.14 (0.86–1.50)
Peripheral vascular disease
IBD	2586	3.06^a	2.01^a	1.52 (1.29–1.79)^a	1123	2.72^a	1.80^a	1.51 (1.18–1.93)^a	1463	3.37^a	2.22^a	1.52 (1.23–1.88)^a
CD	1081	2.79^a	1.89^a	1.48 (1.15–1.90)^a	388	2.09	1.57	1.33 (0.88–2.01)	693	3.34^a	2.15^a	1.55 (1.14–2.12)^a
UC	1505	3.27^a	2.11^a	1.55 (1.26–1.91)^a	735	3.15^a	1.96^a	1.61 (1.19–2.17)^a	770	3.40^a	2.28^a	1.49 (1.11–2.00)^a
Chronic pulmonary disease
IBD	39 174	173^a	105^a	1.65 (1.54–1.77)^a	17 477	141^a	88^a	1.60 (1.44–1.77)^a	21 697	207^a	122^a	1.70 (1.54–1.87)^a
CD	18 080	182^a	109^a	1.67 (1.51–1.86)^a	7366	150^a	94^a	1.60 (1.36–1.87)^a	10 714	210^a	121^a	1.73 (1.51–2.00)^a
UC	21 094	165^a	101^a	1.63 (1.48–1.80)^a	10 111	134^a	84^a	1.60 (1.39–1.83)^a	10 983	205^a	123^a	1.66 (1.45–1.91)^a
Connective/rheumatic
IBD	2575	3.46^a	1.96^a	1.76 (1.51–2.06)^a	731	2.25^a	1.10^a	2.05 (1.56–2.70)^a	1844	4.60^a	2.81^a	1.64 (1.35–1.97)^a
CD	1151	3.73^a	1.94^a	1.92 (1.53–2.41)^a	294	2.45^a	1.08^a	2.27 (1.48–3.46)^a	857	4.75^a	2.64^a	1.80 (1.37–2.36)^a
UC	1424	3.25^a	1.98^a	1.64 (1.33–2.03)^a	437	2.12^a	1.11^a	1.91 (1.33–2.75)^a	987	4.47^a	2.98^a	1.50 (1.15–1.95)^a
Peptic ulcer
IBD	6200	10.18^a	5.06^a	2.01 (1.82–2.23)^a	2946	10.01^a	4.97^a	2.01 (1.73–2.34)^a	3254	10.33^a	5.13^a	2.01 (1.75–2.32)^a
CD	2767	13.04^a	4.79^a	2.72 (2.35–3.15)^a	1151	12.72^a	4.53^a	2.81 (2.25–3.51)^a	1616	13.28^a	5.00^a	2.66 (2.20–3.22)^a
UC	3433	8.11^a	5.27^a	1.54 (1.33–1.78)^a	1795	8.31^a	5.28^a	1.57 (1.28–1.93)^a	1638	7.90^a	5.26^a	1.50 (1.22–1.85)^a
Liver
IBD	2719	3.37^a	2.11^a	1.60 (1.37–1.86)^a	1487	3.70^a	2.43^a	1.52 (1.23–1.89)^a	1232	3.08^a	1.82^a	1.69 (1.35–2.12)^a
CD	1188	3.29^a	2.07^a	1.59 (1.26–2.02)^a	584	3.40^a	2.39^a	1.42 (1.01–1.99)^a	604	3.21^a	1.82^a	1.77 (1.28–2.43)^a
UC	1531	3.42^a	2.14^a	1.60 (1.30–1.96)^a	903	3.90^a	2.45^a	1.59 (1.21–2.10)^a	628	2.96^a	1.81^a	1.63 (1.19–2.23)^a
Renal
IBD	956	1.13^a	0.72^a	1.58 (1.22–2.04)^a	474	1.10^a	0.74^a	1.48 (1.02–2.16)^a	482	1.15^a	0.69^a	1.67 (1.17–2.37)^a
CD	413	1.24^a	0.68^a	1.83 (1.26–2.67)^a	185	1.16	0.71	1.64 (0.95–2.83)	228	1.30^a	0.65^a	2.00 (1.23–3.26)^a
UC	543	1.04^a	0.75^a	1.39 (1.01–1.93)^a	289	1.06	0.76	1.39 (0.88–2.18)	254	1.02	0.73	1.40 (0.88–2.23)
Para/hemiplegia
IBD	887	0.85	0.69	1.24 (0.96–1.61)	435	0.86	0.70	1.23 (0.84–1.79)	452	0.85	0.68	1.26 (0.88–1.80)
CD	385	0.87	0.66	1.32 (0.89–1.94)	158	0.76	0.63	1.19 (0.62–2.31)	227	0.96	0.69	1.40 (0.85–2.29)
UC	502	0.84	0.70	1.19 (0.84–1.68)	277	0.92	0.74	1.25 (0.77–2.02)	225	0.75	0.66	1.13 (0.66–1.92)
Cancer
IBD	5494	6.81^a	4.56^a	1.49 (1.33–1.68)^a	2232	6.14^a	3.71^a	1.66 (1.39–1.98)^a	3262	7.43^a	5.39^a	1.38 (1.18–1.61)^a
CD	2285	6.56^a	4.19^a	1.57 (1.31–1.87)^a	778	5.37^a	3.16^a	1.70 (1.27–2.28)^a	1507	7.51^a	5.02^a	1.50 (1.20–1.87)^a
UC	3209	7.01^a	4.87^a	1.44 (1.24–1.68)^a	1454	6.67^a	4.08^a	1.63 (1.31–2.04)^a	1755	7.36^a	5.76^a	1.28 (1.03–1.58)^a
Diabetes
IBD	6498	5.67	5.82	0.97 (0.87–1.09)	3082	5.78	5.67	1.02 (0.87–1.20)	3416	5.58	5.97	0.94 (0.80–1.09)
CD	2625	5.04	5.20	0.97 (0.81–1.15)	1062	4.58	4.79	0.96 (0.72–1.27)	1563	5.39	5.52	0.98 (0.78–1.22)
UC	3873	6.18	6.34	0.98 (0.85–1.12)	2020	6.62	6.28	1.05 (0.86–1.29)	1853	5.75	6.40	0.90 (0.73–1.11)
Dementia
IBD	825	0.61	0.66	0.92 (0.68–1.25)	326	0.52	0.53	0.97 (0.60–1.56)	499	0.69	0.78	0.89 (0.60–1.31)
CD	319	0.59	0.56	1.06 (0.67–1.68)	115	0.47	0.47	1.01 (0.45–2.30)	204	0.69	0.64	1.08 (0.61–1.91)
UC	506	0.62	0.73	0.84 (0.57–1.25)	211	0.55	0.58	0.95 (0.51–1.74)	295	0.69	0.91	0.76 (0.44–1.31)

Note: Confidence intervals conform to Bonferroni corrections.
^aRelative rates significantly different from 1 following Bonferroni's correction.

Table 3. Hazard ratios of comorbid diseases overall and by age group and sex after IBD diagnosis
Age	All	<25	25–50	50–65	65+
Sex	Male & female
Cardiac
IBD	1.27 (1.14–1.42)^a	2.35 (0.75–7.29)	1.22 (0.95–1.56)	1.39 (1.15–1.68)^a	1.24 (1.07–1.43)^a
CD	1.32 (1.12–1.56)^a	1.57 (0.28–8.85)	1.27 (0.88–1.84)	1.51 (1.14–2.01)^a	1.23 (0.99–1.53)
UC	1.24 (1.08–1.43)^a	3.70 (0.76–18.1)	1.17 (0.82–1.67)	1.29 (1.02–1.65)^a	1.24 (1.03–1.50)^a
Cerebro-vascular disease
IBD	1.25 (1.12–1.40)^a	1.69 (0.68–4.19)	1.24 (0.99–1.55)	1.41 (1.15–1.73)^a	1.19 (1.01–1.40)^a
CD	1.49 (1.26–1.75)^a	2.06 (0.70–6.05)	1.40 (1.01–1.93)^a	1.72 (1.29–2.30)^a	1.39 (1.09–1.78)^a
UC	1.10 (0.96–1.25)	0.98 (0.14–6.95)	1.11 (0.79–1.55)	1.20 (0.92–1.55)	1.07 (0.88–1.29)
Peripheral vascular disease
IBD	1.68 (1.50–1.88)^a	3.78 (2.03–7.05)^a	2.24 (1.78–2.83)^a	1.77 (1.45–2.17)^a	1.36 (1.14–1.62)^a
CD	1.70 (1.43–2.01)^a	3.90 (1.74–8.74)^a	2.03 (1.44–2.85)^a	1.95 (1.46–2.62)^a	1.28 (0.99–1.67)
UC	1.67 (1.44–1.93)^a	3.61 (1.36–9.55)^a	2.46 (1.79–3.37)^a	1.63 (1.23–2.16)^a	1.41 (1.13–1.76)^a
Chronic pulmonary disease
IBD	1.11 (1.02–1.20)^a	1.06 (0.83–1.36)	1.31 (1.17–1.47)^a	1.29 (1.07–1.55)^a	1.38 (1.12–1.70)^a
CD	1.09 (0.995–1.20)	1.15 (0.82–1.60)	1.25 (1.06–1.49)^a	1.34 (1.02–1.75)^a	1.41 (1.02–1.95)^a
UC	1.12 (1.003–1.26)^a	0.96 (0.65–1.41)	1.37 (1.16–1.60)^a	1.25 (0.996–1.57)	1.36 (1.04–1.78)^a
Connective/rheumatic
IBD	2.49 (2.21–2.79)^a	5.70 (3.43–9.49)^a	2.72 (2.26–3.28)^a	2.64 (2.13–3.26)^a	1.77 (1.38–2.26)^a
CD	2.88 (2.43–3.39)^a	5.17 (2.69–9.96)^a	2.99 (2.33–3.85)^a	3.01 (2.21–4.10)^a	2.17 (1.49–3.15)^a
UC	2.17 (1.83–2.56)^a	6.65 (2.96–14.9)^a	2.43 (1.84–3.21)^a	2.35 (1.75–3.16)^a	1.53 (1.11–2.12)^a
Peptic ulcer
IBD	1.81 (1.60–2.06)^a	3.46 (2.34–5.12)^a	1.79 (1.48–2.16)^a	1.61 (1.24–2.07)^a	1.74 (1.33–2.27)^a
CD	2.30 (1.93–2.74)^a	4.74 (2.99–7.51)^a	2.11 (1.63–2.73)^a	1.81 (1.23–2.65)^a	2.47 (1.62–3.77)^a
UC	1.45 (1.21–1.73)^a	1.66 (0.79–3.50)	1.49 (1.11–1.98)^a	1.47 (1.04–2.07)^a	1.41 (1.01–1.96)^a
Liver
IBD	1.79 (1.60–1.99)^a	3.52 (2.42–5.14)^a	1.77 (1.49–2.09)^a	1.62 (1.32–2.00)^a	1.72 (1.32–2.23)^a
CD	1.93 (1.64–2.26)^a	3.02 (1.80–5.09)^a	2.02 (1.59–2.55)^a	1.66 (1.21–2.26)^a	1.79 (1.18–2.74)^a
UC	1.67 (1.43–1.95)^a	4.22 (2.44–7.29)^a	1.56 (1.22–1.98)^a	1.59 (1.20–2.11)^a	1.68 (1.20–2.34)^a
Renal
IBD	1.63 (1.42–1.88)^a	3.91 (1.55–9.83)^a	2.91 (2.14–3.95)^a	1.62 (1.21–2.16)^a	1.33 (1.09–1.61)^a
CD	2.01 (1.63–2.47)^a	3.13 (0.85–11.4)	4.12 (2.71–6.24)^a	1.88 (1.24–2.84)^a	1.48 (1.08–2.02)^a
UC	1.39 (1.14–1.68)^a	4.83 (1.36–17.1)^a	2.01 (1.26–3.19)^a	1.41 (0.96–2.06)	1.24 (0.98–1.55)
Para/hemiplegia
IBD	1.44 (1.15–1.80)^a	0.93 (0.23–3.74)	1.93 (1.24–3.00)^a	1.54 (1.07–2.22)^a	1.28 (0.99–1.66)
CD	1.66 (1.19–2.30)^a	1.89 (0.42–8.53)	1.59 (0.94–2.68)	1.95 (1.05–3.63)^a	1.57 (0.97–2.54)
UC	1.29 (0.99–1.68)	-	2.41 (1.29–4.52)^a	1.26 (0.71–2.22)	1.14 (0.77–1.67)
Cancer
IBD	1.51 (1.39–1.63)^a	2.09 (1.32–3.30)^a	1.83 (1.59–2.11)^a	1.52 (1.33–1.74)^a	1.21 (1.04–1.40)^a
CD	1.62 (1.44–1.82)^a	1.77 (0.99–3.16)	2.01 (1.66–2.45)^a	1.65 (1.35–2.01)^a	1.24 (0.99–1.54)
UC	1.42 (1.27–1.58)^a	2.68 (1.34–5.37)^a	1.67 (1.37–2.04)^a	1.42 (1.18–1.71)^a	1.20 (1.001–1.43)^a
Diabetes
IBD	1.10 (1.01–1.21)^a	1.30 (0.72–2.34)	1.05 (0.91–1.20)	1.13 (1.01–1.27)^a	1.17 (1.01–1.35)^a
CD	1.14 (1.03–1.27)^a	1.52 (0.69–3.36)	1.08 (0.89–1.31)	1.21 (1.01–1.44)^a	1.16 (0.90–1.49)
UC	1.07 (0.97–1.19)	1.06 (0.42–2.68)	1.02 (0.84–1.23)	1.08 (0.90–1.30)	1.17 (0.96–1.43)
Dementia
IBD	1.18 (1.02–1.36)^a	1.41 (0.40–5.03)	1.58 (1.02–2.46)^a	1.19 (0.87–1.62)	1.14 (0.999–1.3)
CD	1.44 (1.16–1.78)^a	1.89 (0.42–8.48)	2.36 (1.37–4.04)^a	1.62 (1.05–2.49)^a	1.26 (0.99–1.61)
UC	1.01 (0.85–1.19)	0.70 (0.05–10.8)	0.84 (0.41–1.69)	0.89 (0.52–1.53)	1.07 (0.88–1.30)
Sex	Male
Cardiac
IBD	1.18 (1.01–1.37)^a	2.04 (0.45–9.16)	1.13 (0.80–1.59)	1.33 (1.04–1.70)^a	1.12 (0.91–1.38)
CD	1.03 (0.83–1.28)	1.57 (0.2–12.59)	1.11 (0.62–1.99)	1.25 (0.86–1.82)	0.86 (0.58–1.29)
UC	1.27 (1.05–1.53)^a	2.88 (0.32–25.8)	1.15 (0.71–1.84)	1.38 (1.01–1.88)^a	1.26 (0.99–1.62)
Cerebro-vascular disease
IBD	1.26 (1.06–1.48)^a	2.59 (0.74–9.03)	1.38 (0.98–1.95)	1.38 (1.04–1.84)^a	1.16 (0.92–1.47)
CD	1.45 (1.12–1.87)^a	1.79 (0.41–7.86)	1.80 (1.04–3.10)^a	1.59 (1.01–2.50)^a	1.28 (0.87–1.87)
UC	1.14 (0.95–1.38)	18.6 (0.70–497)	1.11 (0.65–1.88)	1.27 (0.90–1.80)	1.10 (0.81–1.48)
Peripheral vascular disease
IBD	1.53 (1.30–1.80)^a	4.92 (1.89–12.8)^a	2.26 (1.57–3.26)^a	1.56 (1.17–2.09)^a	1.26 (0.99–1.60)
CD	1.40 (1.09–1.80)^a	3.80 (1.05–13.7)^a	1.70 (0.99–2.91)	1.65 (1.05–2.61)^a	1.06 (0.68–1.65)
UC	1.61 (1.31–1.98)^a	6.93 (1.66–28.9)^a	2.74 (1.72–4.37)^a	1.50 (1.03–2.19)^a	1.37 (1.01–1.85)^a
Chronic pulmonary disease
IBD	1.25 (1.11–1.42)^a	0.95 (0.65–1.41)	1.30 (1.09–1.55)^a	1.31 (1.02–1.69)^a	1.28 (0.97–1.70)
CD	1.17 (0.996–1.37)	0.88 (0.52–1.50)	1.20 (0.94–1.53)	1.40 (0.96–2.03)	1.04 (0.63–1.72)
UC	1.32 (1.12–1.54)^a	1.05 (0.60–1.85)	1.38 (1.10–1.73)^a	1.26 (0.93–1.71)	1.43 (1.004–2.04)^a
Connective/rheumatic
IBD	2.93 (2.41–3.57)^a	12.1 (5.12–28.6)^a	3.64 (2.64–5.03)^a	2.82 (1.96–4.06)^a	1.82 (1.22–2.73)^a
CD	3.31 (2.45–4.47)^a	10.3 (3.53–29.9)^a	4.55 (2.85–7.27)^a	2.95 (1.71–5.07)^a	1.44 (0.67–3.08)
UC	2.68 (2.06–3.49)^a	16.0 (3.80–67.7)^a	3.00 (1.91–4.71)^a	2.73 (1.67–4.45)^a	2.02 (1.25–3.24)^a
Peptic ulcer
IBD	1.68 (1.39–2.02)^a	3.41 (1.96–5.95)^a	1.56 (1.16–2.09)^a	1.52 (1.04–2.23)^a	1.64 (1.11–2.44)^a
CD	2.40 (1.84–3.13)^a	4.73 (2.45–9.12)^a	2.07 (1.37–3.12)^a	1.93 (1.09–3.42)^a	2.67 (1.42–5.01)^a
UC	1.25 (0.99–1.57)	1.69 (0.60–4.79)	1.20 (0.82–1.77)	1.30 (0.80–2.08)	1.26 (0.77–2.06)
Liver
IBD	1.81 (1.55–2.11)^a	3.08 (1.81–5.22)^a	1.71 (1.35–2.15)^a	1.87 (1.40–2.49)^a	1.69 (1.15–2.48)^a
CD	1.99 (1.57–2.52)^a	2.10 (1.02–4.32)^a	2.06 (1.47–2.87)^a	2.02 (1.28–3.19)^a	1.71 (0.87–3.36)
UC	1.69 (1.37–2.07)^a	4.92 (2.31–10.5)^a	1.46 (1.06–2.01)^a	1.78 (1.22–2.58)^a	1.69 (1.06–2.68)^a
Renal
IBD	1.53 (1.25–1.87)^a	2.94 (0.81–10.6)	2.76 (1.79–4.25)^a	1.57 (1.04–2.36)^a	1.23 (0.93–1.61)
CD	1.77 (1.29–2.43)^a	2.23 (0.27–18.7)	3.53 (1.87–6.65)^a	1.77 (0.99–3.18)	1.29 (0.81–2.05)
UC	1.40 (1.08–1.81)^a	3.53 (0.69–18.0)	2.26 (1.25–4.10)^a	1.45 (0.87–2.39)	1.19 (0.85–1.67)
Para/hemiplegia
IBD	1.52 (1.13–2.06)^a	1.33 (0.17–10.2)	2.29 (1.22–4.30)^a	1.52 (0.93–2.49)	1.34 (0.88–2.05)
CD	1.62 (1.04–2.53)^a	2.91 (0.32–26.1)	1.61 (0.68–3.84)	1.91 (0.82–4.48)	1.47 (0.71–3.07)
UC	1.46 (1.03–2.07)^a	-	3.15 (1.36–7.28)^a	1.31 (0.63–2.72)	1.28 (0.76–2.15)
Cancer
IBD	1.56 (1.38–1.75)^a	2.41 (1.21–4.79)^a	2.37 (1.89–2.96)^a	1.51 (1.24–1.84)^a	1.17 (0.95–1.43)
CD	1.66 (1.38–2.00)^a	2.19 (0.91–5.22)	2.67 (1.91–3.72)^a	1.56 (1.14–2.14)^a	1.14 (0.80–1.63)
UC	1.49 (1.28–1.74)^a	2.73 (1.02–7.31)^a	2.16 (1.59–2.92)^a	1.48 (1.16–1.90)^a	1.18 (0.92–1.51)
Diabetes
IBD	1.02 (0.92–1.13)	1.01 (0.39–2.60)	0.92 (0.75–1.13)	1.14 (0.96–1.35)	1.02 (0.79–1.31)
CD	0.97 (0.81–1.17)	1.51 (0.50–4.53)	0.86 (0.60–1.23)	1.14 (0.83–1.55)	0.91 (0.58–1.43)
UC	1.04 (0.90–1.21)	0.47 (0.07–3.29)	0.97 (0.73–1.28)	1.13 (0.89–1.44)	1.08 (0.80–1.45)
Dementia
IBD	1.13 (0.94–1.35)	0.53 (0.03–8.32)	1.97 (1.03–3.75)^a	0.90 (0.53–1.53)	1.10 (0.85–1.42)
CD	1.41 (1.02–1.96)^a	-	4.04 (1.77–9.19)^a	0.95 (0.35–2.57)	1.22 (0.79–1.89)
UC	0.98 (0.76–1.27)	1.40 (0.08–25.5)	0.74 (0.25–2.24)	0.88 (0.42–1.83)	1.04 (0.76–1.43)
Sex	Female
Cardiac
IBD	1.39 (1.19–1.61)^a	2.94 (0.49–17.7)	1.33 (0.90–1.96)	1.48 (1.10–1.99)^a	1.35 (1.11–1.65)^a
CD	1.62 (1.30–2.01)^a	1.57 (0.08–31.4)	1.44 (0.84–2.47)	1.85 (1.25–2.75)^a	1.55 (1.15–2.08)^a
UC	1.21 (0.998–1.47)	5.26 (0.49–56.1)	1.22 (0.68–2.18)	1.14 (0.74–1.77)	1.22 (0.94–1.59)
Cerebro-vascular disease
IBD	1.25 (1.07–1.46)^a	1.11 (0.27–4.49)	1.16 (0.84–1.59)	1.44 (1.08–1.92)^a	1.21 (1.01–1.45)^a
CD	1.52 (1.22–1.88)^a	2.43 (0.52–11.4)	1.20 (0.78–1.86)	1.83 (1.25–2.68)^a	1.49 (1.08–2.05)^a
UC	1.05 (0.86–1.28)	-	1.11 (0.69–1.77)	1.10 (0.73–1.67)	1.04 (0.78–1.39)
Peripheral vascular disease
IBD	1.83 (1.57–2.13)^a	3.14 (1.37–7.21)^a	2.23 (1.66–3.01)^a	2.02 (1.52–2.67)^a	1.47 (1.16–1.87)^a
CD	1.94 (1.56–2.41)^a	3.97 (1.41–11.1)^a	2.22 (1.46–3.35)^a	2.22 (1.51–3.25)^a	1.48 (1.02–2.14)^a
UC	1.73 (1.39–2.14)^a	2.15 (0.59–7.79)	2.25 (1.46–3.46)^a	1.81 (1.20–2.75)^a	1.46 (1.06–2.01)^a
Chronic pulmonary disease
IBD	1.32 (1.17–1.48)^a	1.15 (0.83–1.59)	1.32 (1.13–1.55)^a	1.26 (1.004–1.59)^a	1.50 (1.11–2.01)^a
CD	1.36 (1.16–1.59)^a	1.38 (0.90–2.12)	1.29 (1.04–1.60)^a	1.29 (0.94–1.77)	1.78 (1.17–2.70)^a
UC	1.27 (1.07–1.49)^a	0.88 (0.53–1.48)	1.36 (1.08–1.70)^a	1.23 (0.86–1.77)	1.27 (0.84–1.91)
Connective/rheumatic
IBD	2.28 (1.97–2.64)^a	3.70 (1.89–7.24)^a	2.37 (1.89–2.99)^a	2.55 (1.95–3.32)^a	1.74 (1.28–2.36)^a
CD	2.71 (2.22–3.31)	3.42 (1.43–8.19)^a	2.55 (1.89–3.45)^a	3.04 (2.08–4.44)^a	2.52 (1.64–3.88)^a
UC	1.90 (1.53–2.36)^a	4.16 (1.49–11.6)^a	2.16 (1.51–3.07)^a	2.17 (1.50–3.15)^a	1.24 (0.80–1.93)
Peptic ulcer
IBD	1.94 (1.64–2.29)^a	3.52 (2.03–6.10)^a	1.99 (1.55–2.56)^a	1.68 (1.19–2.38)^a	1.82 (1.27–2.62)^a
CD	2.24 (1.77–2.81)^a	4.76 (2.51–9.02)^a	2.14 (1.54–2.98)^a	1.72 (1.03–2.88)^a	2.33 (1.32–4.11)^a
UC	1.66 (1.30–2.13)^a	1.63 (0.56–4.72)	1.81 (1.23–2.68)^a	1.65 (1.03–2.65)^a	1.56 (0.98–2.49)
Liver
IBD	1.76 (1.50–2.06)^a	4.10 (2.38–7.04)^a	1.85 (1.44–2.36)^a	1.41 (1.04–1.90)^a	1.74 (1.22–2.50)^a
CD	1.87 (1.50–2.33)^a	4.60 (2.19–9.65)^a	1.98 (1.42–2.76)^a	1.42 (0.98–2.05)	1.85 (1.08–3.17)^a
UC	1.65 (1.31–2.08)^a	3.60 (1.66–7.80)^a	1.70 (1.18–2.46)^a	1.40 (0.94–2.10)	1.66 (1.02–2.70)^a
Renal
IBD	1.73 (1.42–2.11)^a	5.12 (1.44–18.2)^a	3.08 (1.99–4.75)^a	1.67 (1.10–2.53)^a	1.43 (1.09–1.88)^a
CD	2.21 (1.68–2.91)^a	3.92 (0.76–20.2)	4.65 (2.68–8.09)^a	1.97 (1.14–3.38)^a	1.66 (1.10–2.51)^a
UC	1.37 (1.03–1.82)^a	7.34 (1.15–47.0)^a	1.70 (0.86–3.36)	1.35 (0.72–2.52)	1.29 (0.90–1.83)
Para/hemiplegia
IBD	1.35 (1.08–1.69)^a	0.72 (0.10–5.01)	1.65 (0.94–2.90)	1.57 (0.92–2.69)	1.21 (0.82–1.79)
CD	1.69 (1.08–2.65)^a	1.39 (0.17–11.2)	1.57 (0.75–3.28)	1.99 (0.96–4.11)	1.68 (0.92–3.08)
UC	1.07 (0.69–1.66)	-	1.78 (0.73–4.32)	1.16 (0.44–3.10)	0.95 (0.48–1.87)
Cancer
IBD	1.47 (1.32–1.63)^a	1.88 (1.02–3.47)^a	1.58 (1.32–1.90)^a	1.52 (1.26–1.84)^a	1.26 (1.02–1.54)^a
CD	1.60 (1.37–1.86)^a	1.53 (0.71–3.31)	1.76 (1.38–2.25)^a	1.71 (1.32–2.22)^a	1.32 (1.003–1.73)^a
UC	1.34 (1.15–1.57)^a	2.64 (1.05–6.64)^a	1.40 (1.07–1.83)^a	1.35 (1.03–1.77)^a	1.21 (0.93–1.59)
Diabetes
IBD	1.19 (1.05–1.35)^a	1.59 (0.74–3.41)	1.16 (0.96–1.41)	1.13 (0.94–1.35)	1.31 (1.04–1.65)^a
CD	1.28 (1.07–1.53)^a	1.54 (0.50–4.70)	1.25 (0.96–1.63)	1.27 (0.97–1.66)	1.35 (1.001–1.83)^a
UC	1.11 (0.95–1.30)	1.64 (0.57–4.73)	1.08 (0.81–1.43)	1.01 (0.75–1.36)	1.28 (0.95–1.74)
Dementia
IBD	1.21 (1.01–1.47)^a	2.42 (0.55–10.7)	1.33 (0.76–2.30)	1.48 (0.96–2.27)	1.17 (0.98–1.38)
CD	1.45 (1.11–1.90)^a	4.19 (0.81–21.6)	1.64 (0.84–3.20)	2.08 (1.09–3.96)^a	1.28 (0.98–1.68)
UC	1.03 (0.81–1.31)	-	0.92 (0.34–2.49)	0.91 (0.39–2.11)	1.09 (0.82–1.45)

Note: Confidence intervals conform to Bonferroni corrections.
^aHazard ratios significantly different from 1 following Bonferroni's correction.

Table 4. Number of persons with IBD needed to be followed for 10 years or 20 years to identify one extra person (above the number predicted by the control rate) among the IBD group. Data are presented for each condition
	At 10 years post-diagnosis	At 20 years post-diagnosis
Cardiac	66	61
Cerebrovascular disease	74	32
Peripheral vascular disease	39	22
Chronic pulmonary disease	47	30
Connective tissue disease/rheumatic disease	27	11
Peptic ulcer disease	21	16
Liver disease	30	20
Renal	61	27
Paraplegia/hemiplegia	549	78
Cancer	27	15
Diabetes	70	81
Dementia	169	72

Table 5. Median age (yrs) (interquartile range) at diagnosis of diseases for either cases or controls
	Median age (IQR) IBD cases	Median age (IQR) controls	P value
Cardiac	64 (55, 75)	65 (56, 75)	P = 0.092
Cerebrovascular disease	63 (50.5, 73)	65 (52, 75)	P = 0.0006
Peripheral vascular disease	58 (44, 70)	63 (49, 73)	P < 0.0001
Chronic pulmonary disease	32 (17, 48)	33 (18, 49)	P = 0.0013
Connective tissue disease/rheumatic disease	49 (37, 61)	52 (39, 65)	P < 0.0001
Peptic ulcer disease	40 (28, 56)	44 (31, 59)	P < 0.0001
Liver disease	44 (32, 57)	46 (33, 59)	P = 0.023
Renal	62 (43.5, 76)	67 (52, 79)	P < 0.0001
Paraplegia/hemiplegia	55 (40,71)	59 (40,73)	P = 0.087
Cancer	55 (42, 66)	58 (45, 69)	P < 0.0001
Diabetes	54 (43–64)	54 (43–65)	P = 0.85
Dementia	76 (63, 83)	77 (66, 84)	P < 0.0001

Authors and Disclosures

Charles N. Bernstein^1,2, Zoann Nugent^2,3, Seth Shaffer^1,2, Harminder Singh^1,2,4 and Ruth Ann Marrie^1,2,4

¹Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
²University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
³Cancercare Manitoba, Winnipeg, MB, Canada
⁴Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada

Correspondence
Charles N. Bernstein, 804F-715 McDermot Avenue, Winnipeg, MB R3E3P4, Canada. Email: Charles.Bernstein@umanitoba.ca

Author contributions
CNB: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; technical, or material support; study supervision. ZN; study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; technical, or material support. SS: study concept and design; critical revision of the manuscript for important intellectual content. HA: study concept and design; critical revision of the manuscript for important intellectual content. RAM; study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis.

Declaration of personal interests: Dr Bernstein is supported by the Bingham Chair in Gastroenterology. Dr Bernstein has served on Advisory Boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Roche Canada, Janssen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada; Consultant for Mylan Pharmaceuticals and Takeda; Educational grants from Abbvie Canada, Pfizer Canada, Takeda Canada, and Janssen Canada. Speaker's panel for Abbvie Canada, Janssen Canada, Medtronic Canada, and Takeda Canada. Received research funding from Abbvie Canada and Pfizer Canada. Dr Nugent has no conflicts to report. Dr Shaffer has served as consultant for Takeda Canada. Dr Singh has served as consultant for Amgen Canada, Bristol-Myers Squibb Canada, Sandoz Canada, Roche Canada, Takeda Canada and Guardant Health. Dr Marrie receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Research Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, and US Department of Defense. She is supported by the Waugh Family Chair in Multiple Sclerosis. She has no conflicts of interest to report. The results and conclusions presented are those of the authors and no official endorsement by Manitoba Health, or other data providers is intended or should be inferred. The study was approved as part of the Lifetime Cost of IBD program of research by the University of Manitoba Health Research Ethics Board.

Appendix 1

Codes used to assign components of the Charlson Index. Manitoba Health stores these data as a left-justified character without decimal places. The HIV/AIDS coding was not used in this study

Disease group	ICD9		ICD10
Disease group	3Code	5Code	ICD10
Myocardial infarction	410, 412	410, 412	I21, I22, I252
Congestive heart failure	398, 402, 425, 428	39891, 40201, 40211, 40291, 40401, 40403, 40411, 40413, 40491, 40493, 4254, 4255, 4257, 4258, 4259, 428	I43, I50, I099, I110, I130, I132, I255, I420, I425, I426, I427, I428, I429, P290
Peripheral vascular disease	440, 441, 443, 447, 557	0930, 4373, 440, 441, 4431, 4432, 4438, 4439, 4471, 5571, 5579, V434	I70, I71, I731, I738, I739, I771, I790, I792, K551, K558, K559, Z958, Z959
Cerebrovascular disease	430–438	36234, 430–438	G45, G46, I60-I69, H340
Dementia	290, 294, 331	290, 2941, 3312	F00, F01, F02, F03, G30, F051, G311
Chronic pulmonary disease	416, 490–496,500–505	4168, 4169, 490–496, 500–505, 5064, 5081, 5088	J40-J47, J60-J67, I278, I279, J684, J701, J703
Connective tissue disease-rheumatic disease	446, 710, 714, 725	4465, 7100–7104, 7140, 7141, 7142, 7148, 725	M05, M32, M33, M34, M06, M315, M351, M353, M360
Peptic ulcer disease	531–534	531–534	K25-K28
Mild liver disease	070, 570, 571, 573	07022, 07023, 07032, 07033, 07044, 07054, 0706, 0709, 570, 571, 5733, 5734, 5738, 5739, V427	B18, K73, K74, K700, K701, K702, K703, K709, K717, K713, K714, K715, K760, K762, K763, K764, K768, K769, Z944
Diabetes without complications	250	2500, 2501, 2502, 2503, 2508, 2509	E100, E101, E106, E108, E109, E110, E111, E116, E118, E119, E120, E121, E126, E128, E129, E130, E131, E136, E138, E139, E140, E141, E146, E148, E149
Diabetes with complications		2504, 2505, 2506, 2507	E102-E105, E107, E112-E115, E117, E122-E125, E127, E132-E135, E137, E142-E145, E147
Paraplegia and hemiplegia	334, 342, 343, 344	3341, 342, 343, 3440–3446, 3449	G81, G82, G041, G114, G801, G802, G830, G831, G832, G833, G834, G839
Renal disease	403, 582, 583, 585, 586, 588, V56	40301, 40311, 40391, 40402, 40403, 40412, 40413, 40492, 40493, 582, 5830, 5831, 5832, 5834, 5836, 5837, 585, 586, 5880, V420, V451, V56	N18, N19, N052-N057, N250, I120, I131, N032-N037, Z490, Z491, Z492, Z940, Z992
Cancer	140–165, 170–172, 174–176, 179–182, 183–195, 200–208, 238	140–165, 170–172, 174–176, 179–182, 183–195, 200–208, 2386	C00-C26, C30-C34, C37-C41, C43, C45-C58, C60-C76, C81-C85, C88, C90-C97
Moderate or severe liver disease	456, 572	4560, 4561, 4562, 5722, 5723, 5724, 5728	K704, K711, K721, K729, K765, K766, K767, I850, I859, I864, I982
Metastatic carcinoma	196, 197, 198, 199	196, 197, 198, 199	C77-C80
AIDS/HIV	042, 043, 044	042, 043, 044	B20, B21, B22, B24