Supplementary Table 1A: Risk of microscopic colitis in relation with dose of drugs used, cases compared to community controls
COMMUNITY CONTROLS
1 year risk period†
NSAIDS
PPIs
Statins
SSRIs
ACE-inhibitors
Beta-blockers
2 year risk period‡
Case
Control
Case
Control
N (%)
N (%)
ORadj (95% CI)
P-value
N (%)
N (%)
DDDs*
218 (100)
15,045 (100)
138 (100)
9,160 (100)
0
176 (81)
14,599 (97.0)
1 (ref)
102 (74)
8,877 (96.9)
ORadj (95% CI)
P-value
1 (ref)
1-7
8 (3.7)
160 (1.1)
0.9 (0.4-2.2)
0.851
11 (8.0)
110 (1.2)
3.7 (1.5-9.0)
0.004
8-15
10 (4.6)
124 (0.8)
0.8 (0.3-2.0)
0.674
7 (5.1)
80 (0.9)
3.7 (1.3-10.2)
0.013
>15
24 (11)
162 (1.1)
3.1 (1.7-5.8)
<0.001
18 (13)
93 (1.0)
10.8 (5.0-23.4)
<0.001
0
126 (58)
14,538 (96.6)
1 (ref)
86 (62)
8,853 (96.6)
1 (ref)
1-29
17 (7.8)
129 (0.9)
8.7 (4.2-18.1)
<0.001
12 (8.7)
68 (0.7)
4.0 (1.4-11.4)
0.010
30-90
23 (11)
126 (0.8)
13.9 (7.2-26.9)
<0.001
13 (9.4)
67 (0.7)
12.3 (5.5-27.4)
<0.001
>90
52 (24)
252 (1.7)
13.9 (8.2-23.6)
<0.001
27 (20)
172 (1.9)
5.9 (3.1-11.5)
<0.001
0
176 (81)
14,683 (97.6)
1 (ref)
105 (76)
8,925 (97.4)
1 (ref)
1-29
4 (1.8)
34 (0.2)
1.5 (0.4-6.8)
0.567
0 (0)
18 (0.2)
-
0.981
30-90
6 (2.8)
35 (0.2)
2.4 (0.8-7.0)
0.104
8 (5.8)
28 (0.3)
4.0 (1.3-12.1)
0.014
>90
32 (15)
293 (1.9)
1.0 (0.6-1.9)
0.899
25 (18)
189 (2.1)
1.7 (0.8-3.6)
0.148
0
195 (89)
14,940 (99.3)
1 (ref)
126 (91.3)
9,093 (99.3)
1 (ref)
1-29
1 (0.5)
11 (0.1)
4.6 (0.5-41.4)
0.173
1 (0.7)
7 (0.1)
7.0 (0.7-71.2)
0.101
30-90
6 (2.8)
18 (0.1)
5.1 (1.4-18.0)
0.012
1 (0.7)
12 (0.1)
2.2 (0.3-18.9)
0.487
>90
16 (7.3)
76 (0.5)
4.0 (2.0-8.0)
<0.001
10 (7.2)
48 (0.5)
5.3 (2.2-12.6)
<0.001
0
187 (86)
14,821 (98.5)
1 (ref)
114 (83)
9,012 (98.4)
1 (ref)
1-29
4 (1.8)
47 (0.3)
1.7 (0.5-6.0)
0.378
8 (5.8)
69 (0.8)
3.2 (1.3-8.1)
0.012
30-90
7 (3.2)
31 (0.2)
3.9 (0.9-16.0)
0.060
3 (2.2)
16 (0.2)
6.1 (1.5-24.3)
0.010
>90
20 (9.2)
146 (1.0)
1.7 (0.9-3.5)
0.121
13 (9.4)
63 (0.7)
2.7 (1.1-6.7)
0.038
0
169 (78)
14,671 (98)
1 (ref)
104 (75)
8,908 (97.2)
1 (ref)
1-29
13 (6)
57 (0.4)
8.3 (3.6-19.0)
9 (6.5)
45 (0.5)
6.8 (2.6-18.1)
<0.001
1
<0.001
30-90
10 (4.6)
94 (0.6)
2.7 (1.2-6.2)
0.017
7 (5.1)
51 (0.6)
2.3 (0.8-6.9)
0.123
>90
26 (12)
223 (1.5)
1.6 (0.8-3.0)
0.168
18 (13)
156 (1.7)
1.9 (0.9-4.2)
0.099
*DDDs, defined daily doses. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.
# Adjusted for concomitant use of NSAIDs, PPIs, statins, SSRIs, low-dose aspirin, ACE-inhibitors and beta-blockers.
† 1 year risk period (A): Odds ratios from the analysis with a 1 year risk period assessment available. See Figure 1, risk period (A).
‡ 2 year risk period (B): Odds ratios from the analysis with 2 year valid data available, but excluding the 1 year prior to index date, thus including
a 1 year lag-time. See Figure 1, risk period (B).
2
Supplementary Table 1B: Risk of microscopic colitis in relation with dose of drugs used, cases compared to colonoscopy controls
COLONOSCOPY CONTROLS
1 year risk period†
NSAIDS
PPIs
Statins
SSRIs
ACE-inhibitors
Beta-blockers
Case
Control
N (%)
DDDs*
ORadj (95% CI)
2 year risk period‡
P-value
Case
Control
ORadj (95% CI)
P-value
N (%)
N (%)
N (%)
148 (100)
475 (100)
95 (100)
296 (100)
0
121 (82)
455 (95.8)
1 (ref)
68 (72)
282 (95.3)
1 (ref)
1-7
5 (3.4)
7 (1.5)
1.9 (0.4-9.6)
0.464
8 (8.4)
6 (2.0)
2.7 (0.5-13.4)
0.229
8-15
6 (4.1)
8 (1.7)
0.6 (0.1-3.8)
0.578
6 (6.3)
2 (0.7)
-
0.989
>15
16 (11)
5 (1.1)
3.6 (0.7-19.2)
0.131
13 (14)
6 (2.0)
5.7 (1.3-25.4)
0.024
0
83 (56)
441 (92.8)
1 (ref)
57 (60)
285 (96.3)
1 (ref)
1-29
12 (8.1)
5 (1.1)
1.9 (0.4-9.3)
0.454
11 (12)
5 (1.7)
6.9 (1.1-42.9)
0.040
30-90
20 (14)
11 (2.3)
10.9 (3.0-40.1)
<0.001
8 (8.4)
1 (0.3)
-
0.991
>90
33 (22)
18 (3.8)
11.7 (3.4-41.1)
<0.001
19 (20)
5 (1.7)
4.3 (1.0-17.7)
0.045
0
120 (81)
455 (95.8)
1 (ref)
74 (78)
284 (95.9)
1 (ref)
1-29
4 (2.7)
0 (0)
-
0.985
0 (0)
0 (0)
-
30-90
3 (2)
4 (0.8)
2.1 (0.2-20.6)
0.511
3 (3.2)
0 (0)
-
>90
21 (14)
16 (3.4)
0.5 (0.1-2.7)
0.396
18 (19)
12 (4.1)
1.4 (0.26-6.95)
0
131 (89)
475 (100)
1 (ref)
86 (91)
296 (100)
1 (ref)
1-29
1 (0.7)
0 (0)
-
1 (1.1)
0 (0)
-
30-90
4 (2.7)
0 (0)
-
0 (0)
0 (0)
-
>90
12 (8.1)
0 (0)
-
8 (8.4)
0 (0)
-
0
126 (85)
457 (96.2)
1 (ref)
78 (82)
286 (96.6)
1 (ref)
0.722
1-29
4 (2.7)
14 (2.9)
-
4 (4.2)
1 (0.3)
-
30-90
7 (4.7)
0 (0)
-
2 (2.1)
0 (0)
-
>90
11 (7.4)
4 (0.8)
15.6 (1.8-132.7)
11 (12)
9 (3)
1.6 (0.2-12.9)
0
117 (79)
467 (98.3)
1 (ref)
72 (76)
290 (98.0)
1 (ref)
1-29
7 (4.7)
2 (0.4)
5.9 (0.7-51.9)
0.111
5 (5.3)
2 (0.7)
8.5 (0.9-84.1)
0.068
30-90
7 (4.7)
3 (0.6)
5.9 (0.4-87.7)
0.198
5 (5.3)
3 (1)
0.5 (0.03-6.9)
0.565
0.012
3
0.640
>90
17 (11)
3 (0.6)
1.8 (0.3-11.4)
0.531
13 (14)
1 (0.3)
4.3 (0.4-49.1)
0.243
*DDDs, defined daily doses. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.
# Adjusted for concomitant use of NSAIDs, PPIs, statins, SSRIs, low-dose aspirin, ACE-inhibitors and beta-blockers.
† 1 year risk period (A): Odds ratios from the analysis with a 1 year risk period assessment available. See Figure 1, risk period (A).
‡ 2 year risk period (B): Odds ratios from the analysis with 2 year valid data available, but excluding the 1 year prior to index date, thus including
a 1 year lag-time. See Figure 1, risk period (B).
4
A
Supplementary Figure 1A and 1B: Risk of
microscopic colitis compared to community
and colonoscopy controls in risk period 1
year prior to index date (risk period A).
# Adjusted for concomitant use of NSAIDs,
PPIs, statins, SSRIs, low-dose aspirin, ACEinhibitors, beta-blockers; celiac disease;
inflammatory bowel disease; hypothyroid
disease; polyarthritis; rheumatoid arthritis
and type 2 diabetes mellitus.
Risk period (A): Odds ratios from the analysis
1 year prior to index date. See Figure 1, risk
period (A).
Mo, months; SSRIs, selective serotonin reuptake inhibitors.
Current use (<3 mo)
Statins
Community controls
Colonoscopy controls
Current use (<3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (<3 mo)
PPIs
Current use (<3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (<3 mo)
Current use (<3 mo)
NSAIDs
Past use (3-12 mo)
Past use (3-12 mo)
0
10
20
30 90 92 94 96 98 100
Adjusted Odds Ratio (95% CIs)
B
Current use (< 3 mo)
Beta- Current use (< 3 mo)
blockers Past use (3-12 mo)
Community controls
Colonoscopy controls
Past use (3-12 mo)
Current use (< 3 mo)
ACECurrent use (< 3 mo)
inhibitors
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
Low-dose Current use (< 3 mo)
Aspirin
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
SSRIs
Current use (< 3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
0
10
20
Adjusted Odds Ratio (95% CIs)
5
30 160 162 164 166 168 170
A
Supplementary Figure 2A and 2B: Risk of
microscopic colitis compared to community and
colonoscopy controls in risk period within 2
years before index date, while excluding the 1
year prior to index date (risk period B).
Community controls
Colonoscopy controls
Current use (< 3 mo)
Statins
Current use (< 3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
# Adjusted for concomitant use of NSAIDs, PPIs,
statins, SSRIs, low-dose aspirin, ACE-inhibitors,
beta-blockers; celiac disease; inflammatory bowel
disease; hypothyroid disease; polyarthritis;
rheumatoid arthritis and type 2 diabetes mellitus.
Risk period (B): Odds ratios from the analysis
within 2 years before index date while excluding
the year prior to index date. See Figure 1, risk
period (B).
Mo, months; SSRIs, selective serotonin re-uptake
inhibitors.
PPIs
Current use (< 3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
Current use (< 3 mo)
NSAIDs
Past use (3-12 mo)
Past use (3-12 mo)
0
B
10
20
30
120 122 124 126 128 130
Adjusted Odds Ratio (95% CIs)
Current use (< 3 mo)
Betablockers
Current use (< 3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
ACEinhibitors
Current use (< 3 mo)
Past use (3-12 mo)
Past use (3-12 mo)
Current use (< 3 mo)
Community controls
Colonoscopy controls
Current use (< 3 mo)
SSRIs
Past use (3-12 mo)
Past use (3-12 mo)
0
10
20
Adjusted Odds Ratio (95% CIs)
6
30
70 72 74 76 78 80
A)
Risk Period A) 1 year exposure period
Supplementary Figure 3A and 3B: Risk of
Microscopic colitis for individual types of NSAIDs,
cases compared to community and colonoscopy
controls.
Community controls
Colonoscopy controls
Celecoxib
Celecoxib
Diclofenac
Diclofenac
Etoricoxib
Etoricoxib
Ibuprofen
Ibuprofen
Naproxen
Naproxen
Combination of NSAIDs
Combination of NSAIDs
0
5
10
15
Adjusted Odds Ratio (95% CIs)
Test for heterogeneity p=0.1179
B)
Risk Period B) 2 year exposure period excluding the year prior to index date
Celecoxib
Celecoxib
Diclofenac
Diclofenac
Etoricoxib
Etoricoxib
Ibuprofen
Ibuprofen
Naproxen
Naproxen
Combination of NSAIDs
Combination of NSAIDs
7
0
Test for heterogeneity p=0.3113
5
10
15
Adjusted Odds Ratio (95% CIs)
20 70 71 72 73 74 75
Community controls
Colonoscopy controls
A)
Risk Period A) 1 year exposure period
Community controls
Colonoscopy controls
Esomeprazole
Supplementary Figure 4A and 4B: Risk of
Microscopic colitis for individual types of PPIs, cases
compared to community and colonoscopy controls.
Esomeprazole
Omeprazole
Omeprazole
Pantoprazole
Pantoprazole
Rabeprazole
Rabeprazole
Combination of PPIs
Combination of PPIs
0
20
40
B)
60
90 100 110 120 130
Adjusted Odds Ratio (95% CIs)
Test for heterogeneity p=0.9819
Test for heterogeneity p=0.0622
Risk Period B) 2 year exposure period excluding the year prior to index date
Esomeprazole
Esomeprazole
Omeprazole
Omeprazole
Pantoprazole
Pantoprazole
Combination of PPIs
Combination of PPIs
0
10
Test for heterogeneity p=0.9597
Test for heterogeneity p=0.022
8
20
Adjusted Odds Ratio (95% CIs)
30 300 302 304 306 308 310
Community controls
Colonoscopy controls