Patients with inflammatory bowel disease and post-inflammatory polyps have an increased risk of colorectal neoplasia: A meta-analysis

Table 1 The summarized characteristics of the included studies

Included studies	Study design	IBD phenotypes	Country	Median disease duration(yr)	PSC (n, %)	Family history of CRC (n, %)	Extensive colitis (n, %)	Median follow-up time (yr)	The risk of various grades of colorectal neoplasia (PIPs vs nonPIPs)	Conclusion
Jong MEd 2019[21]	Cohort Study	UC, CD, UNCLASSIFIED IBD	Netherlands	≥ 8.0	27 (5.2%)	74 (14.3%)	345 (66.5%)	21.6 years in PIPs, 22.9 yr in nonPIPs	CRN 36/154 vs 65/365 (aHR = 1.08, 95%CI: 0.66-1.75a); ACRN 9/154 vs 10/365 (aHR = 1.38, 95%CI: 0.52-3.68b); CRC 6/154 vs 7/365	PIPs did not increase the risk of CRN, ACRN or CRC
Mahmoud R 2019[15]	Cohort Study	UC, CD, UNCLASSIFIED IBD	NetherlandsAmerica	≥ 8.0	234 (14.8%)	93 (5.9%)	1275 (80.6%)	5.4 years in PIPs, 4.5 years in nonPIPs	CRN 64/462 vs 124/1120 (aHR = 1.25, 95%CI: 0.88-1.77c); ACRN 17/462 vs 24/1120 (aHR = 1.17, 95%CI: 0.59-2.31d)	PIPs did not increase the risk of CRN or ACRN
Xu W 2020[22]	Cohort Study	UC	China	6.0	10 (4.1%)	NR	116 (47.2%)	13.0	ACRN 11/57 vs 8/189 (aOR = 5.46, 95%CI: 1.69-17.638e)	PIPs increased the risk of ACRN
Choi C-HR 2017[14]	Cohort Study	UC	United Kingdom	≥ 8.0	42 (4.3%)	48 (4.9%)	987 (100%)	13.0	CRN 66/447 vs 31/540 (aHR = 1.20, 95%CI: 0.80-1.80f)	PIPs did not increase the risk of CRC
Jegadeesan R 2016[20]	Case-Control Study	UC	American	12.5	47 (10.1%)	65 (13.1%)	457 (97.9%)	3.0	CRN 32/138 vs 79/329	PIPs did not increase the risk of CRN
Lutgens M 2015[19]	Case-Control Study	UC, CD, UNCLASSIFIED IBD	Netherlands Belgium	NR	30 (5.7%)	33 (6.2%)	349 (65.7%)	NR	CRC 126/260 vs 62/270 (aHR = 2.30, 95%CI: 1.20-4.10g)	PIPs increased the risk of CRC
Baars JE 2011[13]	Case-Control Study	UC, CD, UNCLASSIFIED IBD	Netherlands	9.0	22 (4.3%)	34 (6.6%)	156 (30.4%)	15.5	CRC 71/147 vs 68/366 (aRR = 1.92, 95%CI: 1.28-2.88h)	PIPs increased the risk of CRC
Velayos FS 2006[12]	Case-Control Study	UC	American	17.0	50 (13.3%)	24 (6.4%)	318 (84.6%)	NR	CRC 105/184 vs 83/192 (aOR = 2.50, 95%CI: 1.40-4.60i)	PIPs increased the risk of CRC
Rutter MD 2004[18]	Case-Control Study	UC	United Kingdom	22.0	NR	NR	204 (100%)	NR	CRN 42/95 vs 26/109 (aOR = 2.29, 95%CI: 1.28-4.11j)	PIPs increased the risk of CRN

^aAdjusted factors: IBD type, sex, concomitant PSC, age at IBD diagnosis, maximum disease extent, medication use, family history of CRC, and the mean inflammation score.

^bAdjusted factors: concomitant PSC, and the mean inflammation score.

^cStudy did not report.

^dThirty-eight patients (including 1 ACRN) were excluded due to missing values.

^eAdjusted factors: colorectal stricture, the presence of PIPs, age at IBD diagnosis, disease duration, and concomitant PSC.

^fAdjusted factors: patient’s age, average number of biopsies, surveillance interval, and colonoscopy type (i.e., white-light or chromoendoscopy).

^gAdjusted factors: IBD type, concomitant PSC, microscopic disease extent, and the presence of PIPs.

^hAdjusted factors: age at IBD diagnosis, sex, duration of PSC, disease duration, disease extent at onset, and the presence of PIPs.

ⁱAdjusted factors: age at IBD diagnosis, and disease duration.

^jAdjusted factors: backwash ileitis, shortened colon, tubular colon, scarring, segment of severe inflammation, normal colonic appearance, the presence of PIPs, and colonic stricture. IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis; CRC: Colorectal cancer; PIPs: Post-inflammatory polyps; UC: Ulcerative colitis; CD: Crohn’s disease; UNCLASSIFIED IBD: Unclassified inflammatory bowel disease; CRN: Colorectal neoplasia; ACRN: Advanced colorectal neoplasia; NR: Not reported.

Table 2 The methodological quality of each included study was assessed by using the Risk of Bias in Nonrandomized Studies - of Interventions (ROBINS-I) assessment tool

Included study	Bias due to confounding	Bias in selection of participants into the study	Bias in classification of interventions	Bias due to deviations from intended interventions	Bias due to missing data	Bias in measurement of outcomes	Bias in selection of the reported result	Overall bias
Jong et al[21], 2019	Moderate	Moderate	Low	Low	Low	Low	Low	Moderate
Mahmoud et al[15], 2019	Moderate	Moderate	Low	Low	Low	Low	Low	Moderate
Xu et al[22], 2020	Moderate	Moderate	Moderate	Low	Low	Low	Moderate	Moderate
Choi et al[14], 2017	Serious	Moderate	Moderate	Low	Low	Low	Moderate	Serious
Jegadeesan et al[20], 2016	Serious	Moderate	Moderate	Low	Low	Low	Moderate	Serious
Lutgens et al[19], 2015	Serious	Moderate	Moderate	Low	Low	Low	Low	Serious
Baars et al[13], 2011	Moderate	Moderate	Moderate	Low	Low	Low	Low	Moderate
Velayos et al[12], 2006	Moderate	Moderate	Moderate	Low	Low	Low	Moderate	Moderate
Rutter et al[18], 2004	Moderate	Moderate	Moderate	Low	No information	Low	Moderate	No information

Table 3 The results of subgroup analysis in colorectal neoplasia and advanced colorectal neoplasia

Subgroup	Study	Pooled RR (95%CI)	P value	I2 value，%
Colorectal neoplasia
Study design
Cohort study	4	1.88 (1.18-3.00)	0.008	80.0
Case-control study	5	1.68 (1.20-2.35)	0.002	85.6
Methodological quality
Serious/Critical risk of bias	3	1.74 (1.00-3.01)	0.049	87.5
Low/Moderate/Unclear risk of bias	6	1.74 (1.28-2.36)	0.000	80.7
IBD phenotypes
UC	5	1.76 (1.18-2.63)	0.006	81.6
CD	NA	NA	NA	NA
UNCLASSIFIED IBD	NA	NA	NA	NA
Geographic regions
Europe	5	2.05 (1.62-2.59)	0.000	60.7
America	2	1.17 (0.86,1.59)	0.314	56.1
Asia	1	4.56 (1.93,10.79)	0.000	NA
Advanced colorectal neoplasia (ACRN)
Study design
Cohort study	3	2.42 (1.36-4.32)	0.003	40.1
Case-control study	3	1.92 (1.27-2.90)	0.002	88.6
Methodological quality
Serious/Critical risk of bias	1	2.11 (1.64-2.71)	0.000	NA
Low/Moderate/Unclear risk of bias	5	2.1 (1.35-3.27)	0.001	80.6

RR: Risk ratio; CRN: Colorectal neoplasia; IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn’s disease; UNCLASSIFIED IBD: Unclassified inflammatory bowel disease; ACRN: Advanced colorectal neoplasia; NA: Not available.

Table 4 Assessing the overall quality of evidence supporting each outcome using Grading of Recommendations, Assessment, Development and Evaluation

Outcomes	Illustrative comparative risksa (95%CI)		Relative effect (95%CI)	No of Participants (studies)	Quality of the evidence(GRADE)
	Assumed risk	Corresponding risk
	NonPIPs	PIPs
Association of PIPs with colorectal neoplasia; Follow-up: 3.0-22.9 yr	Study populationb
	157 per 1000	273 per 1000(212 to 351)	RR 1.74 (1.35 to 2.24)	5424 (9 studies)	Low
Association of PIPs with advanced colorectal neoplasia; Follow-up: 3.0-22.9 yr	Study populationb
	102 per 1000	211 per 1000(151 to 293)	RR 2.07 (1.48 to 2.87)	3766 (6 studies)	Moderate due to large effect
Association of PIPs with colorectal cancer; Follow-up: 3.0-22.9 yr	Study populationb
	184 per 1000	356 per 1000(243 to 520)	RR 1.93 (1.32 to 2.82)	1938 (4 studies)	Low

^aThe basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI).

^bLabel: Moderate. GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect; Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality: We are very uncertain about the estimate. CI: Confidence interval; RR: Risk ratio.

Table 5 Societal recommendations for colorectal cancer surveillance in inflammatory bowel disease patients with post-inflammatory polyps

Society	Surveillance intervals	Surveillance techniques
AGA 2010	More frequent surveillance (No specific interval recommended)	Chromoendoscopy with targeted biopsies OR Standard or high-definition colonoscopy along with random biopsies
ASGE 2015	Every year	Chromoendoscopy with targeted biopsies OR Random biopsies (2-4 biopsies every from 10 cm) and targeted biopsies if chromoendoscopy is not available or the yield of chromoendoscopy is reduced
Cancer Council Australian 2019	Every year	Chromoendoscopy with targeted biopsies
BSG/ACPGBI 2010	Every 3 yr	Chromoendoscopy with targeted biopsies OR Random biopsies (2-4 biopsies every from 10 cm) and targeted biopsies if chromoendoscopy is not available
NICE 2011	Every 3 yr	Chromoendoscopy with targeted biopsies
ECCO 2013/2017	Every 2-3 yr	Chromoendoscopy with targeted biopsies OR White light endoscopy with random biopsies (4 biopsies every from 10 cm) and targeted biopsies
JSGE 2018/2020	Not mention the definite interval (Every 1-2 yr for patients with left-sided colitis or extensive colitis)	Chromoendoscopy with targeted biopsies OR Available endoscopic technology with targeted biopsies to increase the neoplasia detection rate
Chinese Society of Gastroenterology 2018/2020	Not mention the definite interval (Every 1-2 yr for patients with left-sided colitis or extensive colitis)	Chromoendoscopy/magnifying endoscopy with targeted biopsies

IBD: Inflammatory bowel disease; PIPs: Post-inflammatory polyps; AGA: American Gastroenterology Association; ASGE: American Society of Gastrointestinal Endoscopy; BSG: The British Society of Gastroenterology; ACPGBI: The Association of Coloproctology for Great Britain and Ireland; NICE: National Institute for Clinical Excellence; ECCO: The European Crohn’s and Colitis Organization; JSGE: The Japanese Society of Gastroenterology.