Small bowel capsule endoscopy and treat-to-target in Crohn's disease: A systematic review

Table 1 Studies showing the impact of small bowel capsule endoscopy on disease reclassification and subsequent patient management during follow-up of patients suspected or diagnosed with inflammatory bowel disease

Ref.	Study design	Sample size	Patient population	Compared modality	CE lesions considered diagnostic for CD	Positive SB findings	Impact in patient management1
Reclassification of Crohn’s disease location
Chong et al[28], 2005	Prospective, blinded	43	Group 1: Known CD (n = 22) Group 2: Suspected CD2 (n = 21)	Push enteroscopy and enteroclysis	≥ 1 erosion/ ulcer	Group 1: 17/22 (jejunum, n = 7) vs 3/22 at push enteroscopy, P < 0.001 and 4/21 at enteroclysis, P < 0.001 Group 2: 4/21 (jejunum, n = 2), no statistically significant difference vs other modalities	30/43 (70%) Group 1: 16 (73%) Group 2: 14 (67%)
De Bona et al[38], 2006	Prospective	38	Suspected CD2 Group 1: Ongoing symptoms (n = 12) Group 2: Ongoing symptoms and inflammatory biomarkers3 (n = 26)	NA	Diagnostic if > 3 erosions/ ulcerations Suspicious if ≤ 3 and/or nodular pattern	Diagnostic: 13/38 (34.2%) (jejunum, n = 5) Suspicious: 2/38 (5.3%) Group 1: 1/12 (8.3%) Group 2: 14/26 (46.2%) P = 0.022	15/38 (39.5%) i.e., 100% of patients with positive CE findings
Efthymiou et al[29], 2009	Prospective, blinded	55	Group 1: Known CD (n = 29) Group 2: Suspected CD2 (n = 26)	Enteroclysis	Diffuse erythema, erosions, > 3 aphthoid ulcers, ulcers of different shape and strictures	Group 1: 20/29 (jejunum, n = 8) vs 11/27 at enteroclysis4, incremental diagnostic yield= 33.4% (P = 0.035) Group 2: 16/26 (jejunum, n = 6), vs 6/20 at enteroclysis5, incremental diagnostic yield = 35.0% (P = 0.039)	-
Tukey et al[78], 2009	Retrospective	105	Suspected CD2	NA	Any ulcers	39/105 (37%) Prevalence rate of CD diagnosis after a 12-mo follow-up = 13% Se 77%, Sp 89%, PPV 50%, NPV 96%	-
Mehdizadeh et al[39], 2010	Retrospective	134	Known CD	NA	Diagnostic if > 3 ulcerations Suspicious if ≤ 3 ulcerations	Diagnostic: 52/134 (38.8%) Suspicious: 17/134 (12.7%) Jejunum lesions 53%, proximal ileum lesions 67%	52/134 (38.8%) i.e., 100% of patients with positive CE findings
Lorenzo-Zúñiga et al[40], 2010	Retrospective	14	Known CD	NA	≥ 7 mucosal breaks or ulcerations	12/14 (86%) According to indications of CE: Abdominal pain = 3/3 Anemia = 5/5 Disease extent re-evaluation = 4/6	9/14 (64%) i.e., 100% of patients in whom CE was performed because of abdominal pain, 80% for anemia, 33% for disease extent re-evaluation
Petruzziello et al[31], 2010	Prospective	64	Known CD of the distal ileum (n = 32) Control group (n = 32)	SICUS	> 3 aphthoid ulcers, deep ulcers, stricture(s)	CD group: 16/32 (50%) with upper SB lesions vs 3/32 (9%) at SICUS, 30/32 (93%) with distal SB lesions vs 30/32 (93%) at SICUS Control group: 0/32 (0%)	-
Dussault et al[79], 2013	Retrospective	71	Known CD	NA	Moderate: erythema and few aphthoid ulcers Severe: multiple and/or deep ulcers and/or stenosis	Moderate: 32/71 (45.1%) Severe: 12 (16.9%) According to indications of CE: Anemia = 4/6 Symptoms = 11/25 Disease re-evaluation = 28/37	38/71 (53.5%) i.e., 75% of patients with severe lesions and 53% with moderate lesions
Kalla et al[80], 2013	Retrospective	315	Known (n = 50) or suspected2 (n = 265) CD	NA	> 3 ulcers with erythema or edema	Known CD: 33/50 (66%) (jejunum, n = 1 / diffuse, n = 16) Suspected CD: 45/265 (17%) (jejunum, n = 5 / diffuse, n = 7)	Known CD: 73% Suspected CD: 90% of patients with positive CE findings
Flamant et al[81], 2013	Retrospective	108	Known CD (32 L1, 25 L2, 51 L3)	NA	Diffuse erythema and edema, linear/ circumferential ulcerations, ≥ 3 aphthous ulcers, or stenosis	68/108 (63%) (jejunum, n = 60 of whom n = 18 i.e., 17% only in the jejunum) Restricted colonic location of the disease associated with a significantly decreased risk of jejunal lesions by 80% (OR = 0.21, P = 0.002)	- Jejunal lesions=sole independent factor associated with increased risk of clinical relapse (HR = 1.99, P = 0.02)
Cotter et al[82], 2014	Retrospective	50	Known CD	NA	Moderate: Lewis score ≥ 135 Severe: Lewis score > 790	Moderate: 33/50 (66%) Severe: 11/50 (22%)	Proportion of patients on thiopurines and/or biologics increasing from 2/50 (4%) to 15/50 (30%) after CE, P = 0.023
Urgesi et al[41], 2015	Retrospective	492	Suspected CD on obscure gastrointestinal bleeding	NA	Mucosal fissure, ulcers of different shape, cobblestoning mucosa, aphthous ulcers, stricture(s), erythema/edema, loss of villi	94/492 (19.1%) (jejunum, n = 31)	64/94 -68%) i.e., 100% of confirmed CD
Greener et al[10], 2016	Prospective	79	Known CD	MRE	Lewis score ≥ 135	Proximal disease location detected by CE in 51% of patients vs 26% by MRE (P < 0.01) (isolated proximal lesions, n = 9)	-
Chao et al[83], 2018	Retrospective	197	Suspected CD in elderly patients2	NA	Lewis score > 790	8/197 (4.1%)	4/197 (2.0%) i.e., 50% of patients with positive CD findings
Carter et al[30], 2018	Prospective, blinded	50	Suspected CD2	Intestinal ultrasound	Lewis score ≥ 135	Similar diagnostic yield: 19/50 (38%) for SBCE and intestinal ultrasound, correlation r = 0.532, P < 0.001	-
Sorrentino and Nguyen[32], 2018	Retrospective	43	Known CD (20 never had surgery, 23 in the post-operative setting)	Ileocolono-scopy and MRE/CTE and CRP/FL	Any ulcerations or multiple erosions	Surgery-naïve group: 13/20 (65%) vs 8/20 (40%) at ileocolonoscopy vs 9/206 (45%) at imaging vs 12/207 (60%) at biomarkers Post-operative group: 20/23 (87%) vs 16/238 (70%) at ileocolonoscopy vs 0/239 (0%) at imaging vs 13/23 (57%) at biomarkers	Surgery-naïve group: 6/20 (30%) Post-operative group: 12/23 (52%)
Hansel et al[84], 2018	Prospective	50	Known CD with normal imaging	NA	Diffuse erythema and edema, linear or circumferential ulceration(s), ≥ 3 aphthous ulcers, or stenosis	14/50 (28%) with proximal SB lesions (duodenum, jejunum)	17/50 (34%)
González-Suárez et al[33], 2018	Retrospective	47	Known CD (n = 32) or suspected (n = 15) CD	MRE	Lewis score ≥ 135	36/47 (76.6%) vs 21/47 (44.7%) at MRE, P = 0.001, of which jejunal lesions: 15/47 (31.9%) vs 3/47 (6.4%), P = 0.02	-
Xavier et al[34], 2018	Retrospective	71	Perianal CD (n = 17) and non-perianal CD (n = 54)	NA	Villous edema, erosions, ulcers or stenosis	Perianal CD: 94.1% vs 66.6% in non-perianal CD (P = 0.03), with more frequently a Lewis Score ≥ 135: 94.1% vs 64.8% (P = 0.03), and higher Lewis scores in the first and second tertiles but not in the third tertile	-
Reclassification of inflammatory bowel disease type
Maunoury et al[35], 2007	Prospective	30	IBD-U with negative ASCA/ANCA and normal SBFT	NA	≥ 3 ulcerations	5/30 (16.7%) (jejunum, n = 4)	-
Lopes et al[36], 2010	Prospective	18	IBD-U (n = 14) or IC (n = 4) with negative ASCA/ANCA	NA	Diagnostic if ≥ 4 erosions/ulcers and/or stricture(s) Suspicious if < 4 and/or focal villi denudation	Diagnostic: 7/18 (38.9%) Suspicious: 9/18 (50.0%) Jejunum and proximal ileum lesions: 8/18 (44.4%)	0 (0%)
Long et al[37], 2011	Retrospective	124	CD (n = 86) or IC (n = 15) or pouchitis (n = 23)	NA	Erythema, few aphthae/ulcers, multiple aphthae/ulcers, stenosis	CD: 67/86 (77.9%) IC: 7/15 (46.7%) Pouchitis: 15/23 (65.2%)	Medication: CD: 34/86 (39.5%) IC: 6/15 (40.0%) Pouchitis: 13/23 (56.5%) Surgery: CD: 11/86 (12.8%) IC: 6/15 (40.0%) Pouchitis: 1/23 (4.4%)

¹Change in the dose or change of immunomodulatory agent, or initiation of biologic treatment, or avoidance of surgery;

²Ongoing symptoms or iron deficiency anemia despite negative upper/lower endoscopy and/or small bowel follow-through and/or abdominal computed tomography scan;

³Increased C-reactive protein and/or erythrocyte sedimentation rate;

⁴Enteroclysis was unsuccessful in two patients;

⁵Enteroclysis was unsuccessful in six patients;

⁶Imaging (CTE or MRE) was not performed in 5 patients;

⁷Fecal lactoferrin and CRP were not performed in 1 patient;

⁸Ileocolonoscopy was not performed in 1 patient;

⁹Imaging (CTE or MRE) was not performed in 15 patients. ANCA: Anti-neutrophil cytoplasmic antibodies ; ASCA: Anti-Saccharomyces cerevisiae antibodies ; CD: Crohn’s disease; CE: Capsule endoscopy; CRP: C-reactive protein; CTE: Computed tomography enterography; FL: Fecal lactoferrin; IBD: Inflammatory bowel disease; IC: Indeterminate colitis; MRE: Magnetic resonance enterography; NA: Not applicable; NPV: Negative predictive value; OR: Odds ratio; PPV: Positive predictive value; SB: Small bowel; SBFT: Small bowel follow-through; Se: Sensivity; SICUS: Small intestine contrast ultrasonography; Sp: Specificity.

Table 2 Studies evaluating the use of small bowel capsule endoscopy in the assessment of mucosal healing in patients diagnosed with Crohn’s disease

Ref.	Study design	Sample size	Treatment evaluated	Prior biologic exposure	Interval between the CE	CE findings considered for assessing mucosal healing	Positive SB findings before treatment	Positive SB findings after treatment	P-value
Efthymiou et al[85], 2008	Prospective, blinded	40	CS (60%) Mesalamine (70%) Azathioprine (10%) Infliximab (5%) Metronidazo-le (20%)	-	After achievement of clinical remission: 4 wk (75%)	Number of apthous ulcers, mean ± SE	26.0 ± 7.5	12.7 ± 2.3	0.07
					6 wk (15%)	Number of large ulcers, mean ± SE	8.3 ± 1.4	5.0 ± 0.8	0.01
					8 wk (10%)	Percentage of the SBTT in which any endoscopic lesion was visible, mean ± SE	22.0 ± 3.1	17.8 ± 2.5	0.08
Tsibouris et al[86], 2013	Prospective, blinded	1021	-	-	≥ 15 d after CDAI dropped < 150: 2-3 mo; (26.5%) 3-6 mo; (19.6%) 6-12 mo; (53.9%)	CECDAI score, mean ± SD	14 ± 6	4 ± 2	-
Niv et al[44], 2014	Prospective, blinded	19	Copaxone (68.4%) 5-ASA (52.6%) Antibiotics (15.8%) CS (5.3%) IS (10.5%) Vitamins (26.3%) Others (36.8%)	-	12 wk	Lewis score, mean ± SD	1730 ± 1780	No correlation between changes in CDAI/IBDQ and Lewis score2	-
Hall et al[42], 2014	Prospective, blinded	43	Adalimumab (84%) 160 mg W0, 80 mg W2, then 40 mg /2 wk or Azathioprine (16%) 2-2.5 mg/kg	Naïve 38/43 Exposed 5/43	52 wk3	Complete MH = Absence of ulcers, n (%) Normalizatio-n of CECDAI score < 3.5, n (%) Change in CECDAI score, n (%)	- - CECDAI < 3.5: 4/43 (9%) 3.5 ≤ CECDAI < 5.8: 13/43 (30%) CECDAI ≥ 5.8: 26/43 (61%)	Complete MH: 12/28 (43%) CECDAI < 3.5: 2/28 (7%) CECDAI ≤ 3.5 < 5.8: 6/28 (21%) CECDAI ≥ 5.8: 8/28 (29%)	< 0.0001
Kopylov et al[45], 2015	Prospective	52	None (15.4%) 5-ASA (9.6%) Thiopurine (36.6%) Anti-TNF (26.9%) Anti-TNF+IS (11.5%)	-	NA Included patients were all in clinical remission (CDAI < 150) and had only one CE.	MH = Lewis score < 135	NA	MH: 8/52 (15.4%) 135 ≤ Lewis < 790: 33/52 (63.5%) Lewis score ≥ 790: 11/52 (21.2%)	-
Shafran et al[43], 2016	Prospective, open-label	15	Certolizumab pegol 400 mg W0, W2, W4 then /4 wk	Naïve 3/15 Exposed 12/154	24 wk in responders	Lewis score, mean	1663	226	-
Aggarwal et al[46], 2017	Prospective, blinded	43	None (14%) 5-ASA (60%) CS (12%) IS (74%) Anti-TNF (21%)	-	NA Included patients were all in clinical remission (CDAI < 150) and had only one CE.	MH = Lewis score < 135	NA	MH: 17/43 (40%) 135 ≤ Lewis < 790: 19/43 (44%) Lewis score ≥ 790: 7/43 (16%) Significant correlation between Lewis score and fecal calprotectin (r = 0.82, P < 0.0001)	-
Mitselos et al[47], 2018	Retrospective	30	None (37%) 5-ASA (17%) Budesonide (10%) Azathioprine (10%) Anti-TNF (20%) Anti-TNF+IS (6%)	-	NA Included patients had only one CE (60% in both clinical and biochemical remission)	MH = Lewis score < 1355	NA	MH: 6/15 (40%) Weak correlation between CDAI and Lewis score (r = 0.32, P = 0.088) and between CRP and Lewis score (r = 0.52, P = 0.004)	-
Nakamura et al[87], 2018	Prospective, blinded	92	None (27%) 5-ASA (18%) Thiopurines (17%) Infliximab (20%); Adalimumab (10%) Elemental diet (5%) CS (3%)	Naïve 38/92Exposed 54/92	6 mo in the active group (40/92) Non-active patients ended the study at baseline (52/92)	Lewis score, mean MH = Lewis score of 0 Active CD: Lewis score > 135	458	233 MH: 2/296 Improvement of LS in all 7 patients who received biologics, and in 8/11 (73%) of asymptomatic patients receiving additional medication	0.0004

¹Eighteen percent of patients had Crohn’s disease restricted to the colon;

²Nine patients did not have CE at week 12;

³Fifteen patients did not have CE at week 52;

⁴Two patients had an allergic reaction to infliximab, 10 patients were secondary non-responders to infliximab and/or adalimumab;

⁵Data presented for patients in both clinical and biochemical remission (CDAI<150 and CRP < 5 mg/L);

⁶Of 40 patients in the active group, 29 (72%) underwent follow-up CE to assess the therapeutic effect on MH. ASA: Aminosalicylic acid; CD: Crohn’s disease; CE: Capsule endoscopy; CECDAI: Capsule Endoscopy Crohn's Disease Activity Index; CS: Corticosteroids; IS: Immunosuppressant; LS: Lewis score; MH: Mucosal healing; SB: Small bowel; SBTT: Small bowel transit time.

Table 3 Studies assessing the use of small bowel capsule endoscopy in the monitoring of patients with Crohn’s disease in the post-operative setting

Ref.	Study design	Sample size	Indication for surgery	Risk factors for POR	Post-operative prophylac-tic treatment	Compared modality	Interval between surgery and endosco-pic re-assess-ment	CE findings considered for defining POR	Rate of clinical recurrence, n (%)	Rate of endosco-pic recurren-ce, s (%)
Bourreille et al[49], 2006	Prospective, blinded	32	Resistance to medical treatment (19%) Stenosis (37%) Fistula/abs-cess (44%)	-	None (28%) 5-ASA (22%) CS (3%) IS (9%) Others (44%)	Ileocolono-scopy	Median (IQR): 6 mo (4-7)	Rutgeerts score ≥ i,1	-	Colonosco-py: 19/311 (61%) Se 90%, Sp 100% WCE: 21/31 (68%) Se 76%, Sp 91% SB lesions up to 72%
Biancone et al[50], 2007	Prospective, blinded	22	Resistance to medical treatment (9%) Stenosis (64%) Fistula/abs-cess (14%) Other (13%)	Smoking (32%) Penetrating phenotype (23%)	Mesalamine (100%)	Ileocolono-scopy (gold standard), SICUS	1 year	Ulcers, strictures, or stenosis in the neoterminal ileum and/or anastomosis	0 (0%)	Ileocolonosc-opy: 16/172 (94%) SICUS: 17/172 (1 FP) (100%) WCE: 16/172 (94%) Se 93%, Sp 67%
Pons Beltrán et al[51], 2007	Prospective, blinded	24	Resistance to medical treatment (21%) Stenosis (63%) Other (16%)	Smoking (50%) Penetrating phenotype (38%)	None (100%)	Ileocolono-scopy	Median (range): 254 d (118-439)	Rutgeerts score ≥ i,2	0 (0%)	Ileocolonos-copy: 6/24 (25%) WCE: 15/24 (63%) Jejunal lesions (54%)
Kono et al[52], 2014	Prospective, blinded	19	-	Smoking (11%) Penetrating phenotype (58%) Prior resection (68%)	5-ASA (39%) Anti-TNF (61%)	Ileocolono-scopy at 6-8 mo	mean ± SD: 17.3 ± 5.6 d then 216.9 ± 23.6 d	Lewis score ≥ 135, n (%) and Mean (range)	0 (0%)	Week 2-3: 14/183 (78%) 428.3 (8-4264) 6-8 mo: 9/134 (69%) vs 3/6 (50%) at colonoscopy 196.1 (8-450) 5/13 (38%) with LS higher by ≥ 100 than shortly after surgery
Hausmann et al[53], 20175	Prospective, blinded	22	-	Penetrating phenotype (18%) Prior resection (50%)	None (76%) Azathiopri-ne (6%) Adalimum-ab (18%)	Ileocolono-scopy at 4-8 mo	Mean (range): 57.5 (34 – 83) d then 220 (159 – 322) d	Modified Rutgeerts score ≥ i,2	-	Week 4-8: 3/166 (19%) 4-8 mo: 7 6/12 (50%) vs 5/15 (33%) at colonoscopy
Han et al[54], 2018	Retrospec-tive, blinded	83	Resistance to medical treatment (24.3%) Stenosis (75.7%)	None (100%)	None (100%) before date 1 After date 1 if POR: None (53.1%) Azathiopri-ne (21.6%) Infliximab (25.3%)	Group 1 (37/83): ileocolono-scopy + CE (date 1) then repeat colonoscopy (date 2) Group 2 (46/83): ileocolono-scopy (date 1 and 2)	Date 1: 3-7 mo; after surgery Date 2: 1 year after date 1	Rutgeerts score ≥ i,2 in the terminal ileum or > 5 aphthous lesions in proximal SB or ulcers in proximal SB	Group 1: 1/37 (2.7%) Group 2: 10/46 (21.7%) P = 0.019	Date 1: Group 1: 13/37 (35.1%) at IC vs 24/37 (64.9%) at CE Group 2: 15/46 (32.6%) at IC (P = 0.809) Date 2: Group 1: 8/37 (21.6%) Group 2: 20/46 (43.5%) (P = 0.036)
Kusaka et al[55], 2018	Prospective	25	-	Smoking (22%) Penetrating phenotype (7%) Prior resection (48%)	5-ASA (96%) Elemental diet (30%) IS (19%) Anti-TNF (59%)8	-	< 3 mo	Lewis score ≥ 135	5/25 (20%)	21/25 (84%) mean ± SD: 751.3 ± 984.0 Clinical recurrence rate significantly higher in the group with highest third tertile score (distal SB)

¹The neoterminal ileum was reached and explored by ileocolonoscopy in 31 patients;

²WCE was not performed because of luminal narrowing or stenosis in 5 patients, thus 17 of the 22 patients had all 3 techniques performed;

³In one patient CE did not reach beyond the middle segment of the ileum during the 8 h of recording;

⁴The follow-up CE at 6-8 mo; after surgery was possible in 13 of the 18 patients;

⁵Study assessing the use of pan-intestinal capsule endoscopy (PICE);

⁶Seventeen of the 22 patients (77%) underwent CE at 4-8 wk. Another CE could not be analyzed due to an insufficient large bowel preparation;

⁷Of 17 patients included in the study at follow-up, 14 (82%) underwent CE, and in two cases, analysis of CE videos was hampered by a technical defect and an insufficient large bowel preparation, and 15 (88%) underwent ileocolonoscopy;

⁸Patients could have more than one treatment. ASA: Aminosalicylic acid; CE: Capsule endoscopy; CS: Corticosteroids; FP: False positive; IC: Ileocolonoscopy; IQR: Interquartile range; IS: Immunosuppressant; POR: Post-operative recurrence; SB: Small bowel; Se: Sensitivity; SICUS: Small intestine contrast ultrasonography; Sp: Specificity.

Table 4 Advantages and limitations of small bowel capsule endoscopy in Crohn’s disease

Advantages	Limitations
Less invasive than conventional endoscopy	Risk of capsule retention in stricturing CD
No need for sedation	No therapeutic or biopsy capability
High diagnostic yield comparable to other endoscopic or imaging modalities	SB evaluation may be incomplete due to:
	Uncontrolled air insufflation
	Retention or delayed transition
	Limited battery life
	Impossible to maneuver
Direct mucosal evaluation	Longer procedure time compared to other modalities
Patient-friendly	Analysis is time-consuming for the physician

CD: Crohn’s disease; SB: Small bowel.