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Structural bowel damage in quiescent Crohn’s disease
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Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Structural bowel damage in quiescent Crohn’s disease夽 Marianne M. Amitai a,b , Moran Zarchin b,c , Adi Lahat b,c , Doron Yablecovitch b,c , Sandra Neuman b,c , Nina Levhar b,c , Eyal Klang a,b , Benjamin Avidan b,c , Shomron Ben-Horin b,c , Rami Eliakim b,c,1 , Uri Kopylov b,c,∗,1 , on behalf of the Israeli IBD research Nucleus (IIRN) a
Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Israel Sackler Faculty of Medicine, Tel Aviv University, Israel c Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel b
a r t i c l e
i n f o
Article history: Received 3 December 2016 Received in revised form 31 January 2017 Accepted 1 February 2017 Available online xxx Keywords: Capsule endoscopy Crohn’s disease Lemann index Magnetic resonance enterography Structural damage
a b s t r a c t Background: Crohn’s disease is associated with accumulation of progressive structural bowel damage (SBD) leading to the development of stenotic and penetrating complications. The data pertaining to the course of progression of SBD is scarce. The Lemann index (LI) is a novel tool for evaluation of SBD that incorporates pan-enteric clinical, endoscopic and imaging data. Aims: To evaluate the progression of SBD in quiescent CD patients. Methods: Patients with known quiescent small bowel Crohn’s disease (CD) for at least 3 months (CDAI < 220) were prospectively recruited and underwent repeated magnetic resonance enterographies (MRE) and video capsule endoscopies (VCE). Patients were assessed for SBD on initial and follow-up evaluation using relevant clinicopathological data, MRE and VCE results. Significant structural bowel damage (SBD) was identified as LI > 4.8, and progression of SBD as LI > 0.3. Results: Sixty one patients were enrolled in the study. Significant SBD was detected 13 (21.4%) on enrollment. Duration of disease (p = 0.036) and history of CD-related surgery (p = 0.0001) were associated with significant BD. Forty one patients underwent a follow-up MRE (14.8 ± 2.5 months apart). LI was similar at baseline and follow-up. There was a negligible change in LI between the evaluations. Conclusions: In patients with quiescent Crohn’s disease, structural bowel damage was stable over a median of 14 months follow-up. © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Crohn’s disease (CD) is characterized by a chronic progressive course that is frequently associated with accumulation of structural bowel damage potentially leading to a development of structuring or penetrating complications. Up to 60% of CD patients will eventually develop complications necessitating surgical intervention [1]. However, it is clear that need for surgery is merely the “top of the iceberg” as far as bowel damage in CD is considered, and is preceded by gradual accumulation of more subtle evidence of ongoing destructive process. Until recently, no quantitative tools
夽 The study was partially supported by a generous grant from the Leona M. and Harry B. Helmsley Charitable Trust. ∗ Corresponding author at: Department of Gastroenterology, Sheba Medical Center, Hashomer, Israel. Fax: 972 3 560 5901. E-mail address: [email protected] (U. Kopylov). 1 Kopylov and Eliakim are equal contributors.
for assessment of bowel damage in CD were available. The Crohn’s Disease Digestive Damage Score (Lemann index (LI)) incorporates surgical, endoscopic and imaging findings from all segments of the digestive tract into one composite score [2,3]. Within the first 10 years of the disease, at least 2/3 of the patients demonstrate significant bowel damage that is manifested by gradual LI elevation [4]. As recently demonstrated, increasing LI is predictive of subsequent major abdominal surgery; moreover, anti-tumor necrosis factor ␣ (anti-TNF) agents are able to stabilize [5] or reverse BD in some CD patients [6,7]. It is likely that earlier initiation of effective anti-inflammatory treatment at an early phase of the disease before the development of bowel damage may alter the course of CD and prevent future complications [8–11]. This maybe especially important if we take into account a significant diagnostic delay that is characteristic of CD [10,12]. CD is frequently associated with periods of clinical remission that may occur spontaneously and independently of treatment. However, a vast majority of these patients will display at least some degree of mucosal inflammation even when in clinical remission
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Please cite this article in press as: Amitai MM, et al. Structural bowel damage in quiescent Crohn’s disease. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.02.001
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[13], and upon scrupulous evaluation of the small bowel with capsule endoscopy (VCE) or magnetic resonance enterography (MRE) significant changes in both disease location and phenotype in comparison to the original evaluation can be detected in over 50% of quiescent CD patients [14]. There is ample clinical evidence supporting the need to treat CD patients to a target of mucosal healing (MH) and not settle for clinical remission, as MH is associated with both durable clinical remission and lower risk of long-term complications [15]. However, the progression of bowel damage in quiescent CD patients is scarcely documented. Therefore, the aim of the current study was to evaluate the progression of BD in patients with clinically quiescent Crohn’s disease.
RAPID 8 software (Given Imaging, Yokneam, Israel). The adaptive frame rate mode was activated to ensure visualization of the entire small bowel. Mucosal inflammation was quantified using the Lewis score (LS) [17]. Mucosal healing was defined as LS < 135, mild to moderate inflammation as LS of 135–790, and moderate to severe inflammation as LS ≥ 790 [17].
2. Methods
2.2.4. Calculation of LI LI was calculated as previously described [3]. The gastrointestinal tract was divided segments [upper gastrointestinal tract—esophagus, stomach, and duodenum; small bowel—divided into 20 segments of 20 cm; 6 segments for colon and rectum]. Findings at MRE and CE were divided into stricturing and penetrating lesions, scored and adjusted for anatomical coefficients (Supplementary table). Upper GI was scored using capsule endoscopy. For evaluation of the small bowel we incorporated MRE and CE data. Colonic disease was scored using colonic capsule, MRE and the available colonoscopic data. For scoring of resected segments in patients who underwent surgery, original surgical and pathological reports were used in order to calculate the length of resection. Significant BD was defined as LI > 4.8, progression of SBD as LI > 0.3, and regression—as LI < −0.3 [7]. The scores were calculated at both the initial and the follow-up evaluations.
2.1. Patient population This study was a sub study of a prospective observational study aimed at detailed evaluation of CD patients with quiescent disease in order to identify clinical, biochemical and endoscopic predictors of pending clinical relapse [13]. The study population included adult (>18 years) CD patients with known SB disease in remission or mild disease symptoms, as determined by a Crohn’s disease activity index (CDAI) of <220. All patients were in corticosteroid-free remission for 3–24 months and were treated with a stable medication dose. The patients were prospectively followed by serial clinical evaluation and biomarker (CRP/fecal calprotectin (FCP) levels) once every 3 months, biannual VCE and annual MRE examinations. Patients were withdrawn from the study if they developed clinical relapse (CDAI > 220) or required a treatment change. All patients signed an informed consent and the study was approved by the institutional ethics review board. 2.2. Study procedures 2.2.1. MRI scans All MRE examinations were performed using a 1.5T GE Optima MR450w scanner with GEM Suite (GE Healthcare) with oral and intravenous contrast. MR image acquisition was performed using a previously described protocol [16]. SB distention was obtained by using oral contrast: 360 ml of Osmitrol 20% diluted in 1.5 l water. Patients were instructed to drink 4 doses of 465 ml every 15 min an hour before undergoing the MRE examination. During the last 15 min, patients received via infusion 150 ml of saline containing 0.5 mg of glucagon in slow drip. Axial and coronal LAVA sequences were acquired before and 40 s after intravenous administration of Gadolinium. A board-certified abdominal radiologist with 10 years of experience in reading MRE reviewed all MRE examinations. 2.2.2. Capsule endoscopy studies A patency capsule (PC) test (Given Imaging, Yokneam, Israel) was performed in all patients with active SB disease detected on MRE. If no active SB disease was detected by MRE, a PC study was not performed. If the PC was not eliminated from the SB within 30 h, the patients were withdrawn from the study. In patients with isolated SB CD (L1 by the Montreal classification), SB-III capsule (Given Imaging, Yokneam, Israel) was used. In patients with SB and colonic CD (L3 disease), a colonic capsule (PillCam colonic capsule 2, Given Imaging, Yokneam, Israel) was administered; in these patients, the SB data was reviewed and scored as described for the SB capsule. The preparation for VCE included intake of clear fluids only for 24 h prior to the procedure and a 12 h overnight fast. For a colonic capsule study, a split-dose PEG preparation was used. An additional fluid bolus was given after 2 h from ingestion of the capsule in order to facilitate small bowel transit. All images were reviewed using the
2.2.3. Inflammatory biomarkers Fecal calprotectin levels were measured using the Quantum blue calprotectin kit (BÜHLMANN Laboratories AG, Basel, Switzerland). The reported value range is 30–300 g/g. Levels >100 g/g were considered positive. CRP levels were considered elevated if >5 mg/l.
2.3. Statistical analysis Descriptive statistics were presented as means ± standard deviations (SD) or medians ± interquartile ranges (IQR) for continuous variables and percentages for categorical variables. Categorical variables were analyzed by Chi Square/Fisher’s exact test and continuous variables-by Student t-test/Mann Whitney test or paired t-test as appropriate. A two-tailed p value <0.05 was considered statistically significant. The analysis was performed using IBM SPSS statistic (Version 20.0) (Armonk, NY, USA). 3. Results 3.1. Baseline characteristics Sixty one patients were enrolled in the study and underwent the initial evaluation; 56/61 (91.8%) were in clinical remission (CDAI < 150) upon enrollment. Twenty five (41%) had normal inflammatory biomarkers; eight (13.3%) had small bowel mucosal healing. Significant mucosal inflammation (LS > 790) was demonstrated in 12/61 (19.6%) patients. Clinical and demographic characteristics of the included patients, as well as treatment at inclusion, are detailed in Table 1. 3.2. SBD assessment upon enrollment On initial evaluation, the mean LI was 3.7 ± 5.1 (if only patients with available follow-up were included—2.51 ± 3.71). No signs of bowel damage (LI = 0) were detected in 12 (19.6%) of the patients; mild BD (0–4.8) was detected in 36 (59%) of the patients; LI was above 4.8 in 13 (21.4%) of the patients. Duration of disease (8.1 ± 4.8 vs 8.1 ± 4.8 years, p = 0.036) and history of CD-related surgery (69% vs 2.1%, p = 0.0001) were associated with significant SBD. Other clinical characteristics including medical treatment were not associated with SBD (Table 2).
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M.M. Amitai et al. / Digestive and Liver Disease xxx (2017) xxx–xxx Table 1 Clinical and demographic characteristics of the included patients on enrollment. N = 61 Age at enrollment, years Disease duration, years Gender Disease location
Disease behavior
Perianal disease smoking
Male Female
32.6 ± 11 5.6 ± 4.9 35 (57.4%) 26 (42.6%)
L1 L2 L3
37 (60.6%) 2 (3.3%) 22 (36.0%)
B1 B2 B3
40 (65.5%) 11 (18.2%) 10 (16.3%)
Current Never used Previous
15 (24.6%) 11 (18.0%) 40 (65.6%) 10 (16.4%)
Previous surgery
10 (17.5%)
Current treatment
None Mesalamine Thiopurines Anti-TNFs
10 (16.3%) 10 (16.3%) 29 (47.5%) 23 (37.7%)
Small bowel mucosal healing Elevated calprotectin Elevated CRP
LS < 135 >100 g/g >5 mg/l
8 (13.3%) 29 (47.5%) 18 (29.5%)
CRP—C-reactive protein; TNF—tumor necrosis factor; LS—Lewis score. Montreal classification: Location: L1—ileal; L2—colonic; L3—ileocolonic. Phenotype: B1—non-stricturing non-penetrating; B2—structuring; B3—penetrating.
3.3. Follow-up evaluation Twenty (32.7%) patients were excluded from the study before a subsequent MRE was performed. The reason for exclusion were: clinical relapse (9 patients); change of treatment due to a significant endoscopic escalation (3 patients); pregnancy (3 patients); loss to follow-up/consent withdrawal (2 patients); refusal to undergo a second MRE (3 patients). A follow-up MRE was performed after 14.8 ± 2.5 months. Forty one patients remained clinically qui-
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Table 3 Comparison of the individual components of the Lemann index upon enrollment and on the follow-up evaluation.
Overall LI Upper GI Small bowel Colon
Enrollment
Follow-up
p
2.51 ± 3.71 0.00 ± 0.00 1.74 ± 2.21 0.13 ± 0.57
2.48 ± 3.67 0.00 ± 0.00 1.77 ± 2.30 0.10 ± 0.43
0.85 NA 0.9 0.3
LI—Lemann index.
escent and were available for analysis. Thirty seven (90.2%) of these patients during follow-up evaluation, 26/41 (63.4%) had elevated biomarkers, 10/41 (24.4%) patients had small bowel mucosal healing. No significant change in disease activity as measured by inflammatory biomarkers or LS occurred during follow-up. On follow-up evaluation, mean LI was 2.48 ± 3.67 (vs 2.51 ± 3.71 at baseline, p = 0.85). The overall change in LI was negligible (−0.038 ± 1.27, p = 0.85). A detailed comparison of SBD assessment at onset and follow-up appears in Table 3. No evidence of SBD was detected in 7 (17.1%) (p = 0.79 vs baseline), mild BD was detected in 28 (68.3%) (p = 0.81 vs baseline) and significant BD in 6 (14.6%) (p = 1 vs baseline) of the patients (Fig. 1). There was no change in LI in 14 (34.1%) patients. In 14 (34.1%) there was a progression (LI > 0.3%) of BD and in 13 (31.7%)—a regression (LI > −0.3%). No clinical parameter including current treatment was associated with progression or improvement of SBD. LI was was not significantly different between patients with and without small bowel mucosal healing (1.9 ± 4.3 vs 2.7 ± 4.1, p = 0.15) or in patients with elevated baseline CRP (2.5 ± 3.8 vs 2.5 ± 3.6, p = 0.92). The results did not change when limited to patients in clinical remission (CDAI < 150). 4. Discussion Our study demonstrates no change in bowel damage in stable CD patients that remain in clinical remission and do not show biochemical or endoscopic evidence of disease exacerbation. The main clinical parameter associated with presence of bowel damage
Table 2 Comparison of patients with and without evidence of significant bowel damage upon study enrollment.
Age at enrollment, years Disease duration, years
LI < 4.8 N = 47
LI > 4.8 N = 14
p
26.3 ± 10.8 4.9 ± 4.7
29.4 ± 12.9 8.1 ± 4.8
0.37 0.036
Gender
Male Female
25 (53.2%) 22 (46.8%)
10 (71.4%) 4 (28.6%)
0.23
Disease location
L1 L2 L3
29 (61.7%) 2 (4.3%) 17 (36.1%)
9 (64.2%) 0 (0.0%) 5 (35.7%)
0.9
Disease behavior
B1 B2 B3
34 (72.3%) 7 (14.9%) 5 (10.7%)
5 (35.7%) 4 (28.6%) 5 (35.7%)
0.075
Previous surgery
1 (2.2%)
9 (75.0%)
0.0001
Perianal disease
12 (25.5%)
3 (21.4%)
0.75
Current treatment
None Mesalamine Thiopurines Anti-TNFs
9 (19.1%) 9 (19.1%) 20 (42.6%) 17 (36.2%)
1 (7.1%) 1 (7.1%) 9 (64.3%) 6 (42.9%)
0.42 0.42 0.15 0.65
Elevated calprotectin Elevated CRP Small bowel mucosal healing
>100 g/g >5 mg/l LS < 135
15 (31.9%) 22 (46.8%) 7 (15.2%)
3 (21.4%) 7 (50.0%) 1 (7.1%)
0.78 0.45 0.44
LI—Lemann index; CRP—C-reactive protein; TNF—tumor necrosis factor; LS—Lewis score. Montreal classification: Location: L1—ileal; L2—colonic; L3—ileocolonic. Phenotype: B1—non-stricturing non-penetrating; B2—structuring; B3—penetrating. The significance level was p < 0.05. The numbers in bold are p values that are <0.05.
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Fig. 1. Lemann index upon enrollment and on follow-up evaluation.
on study onset was disease duration. A gradual progression of CD phenotype from inflammatory to structuring/perforating is a well described paradigm [1,18], further augmented by a significant diagnostic delay frequent in CD. We gauged the degree of bowel damage using the Lemann index, the only comprehensive composite bowel damage that incorporates various sources of structural data from all compartments of the digestive tract [2,3]. Until recently, we estimated progression of bowel damages by development of major complications manifesting phenotype shifts (surgery, appearance of new abscesses and fistulae), trailing behind the complications as they develop. The declared aim of LI is to predict the appearance of such structural complications by quantification of the accumulating damage before the emergence of such complications. Recently, LI was demonstrated to be predictive of surgery risk [4,7], and was also useful to monitor reversal of structural damage in patients treated with biologics [7]. In another recent study of CD patients followed for a median of 29 months, biologic treatment was associated with stabilization of LI, while patients treated with thiopurines or mesalamine demonstrated increasing bowel damage [5]. While it it’s quite intuitive that bowel damage is likely to accumulate while the disease is clinically active, our knowledge of disease course progression in quiescent patients is relatively vague. In the recent years, ample evidence supporting the need to target treatment to mucosal healing and not mere clinical improvement has accumulated. Mucosal healing and “deep remission “ (a combination of clinical and endoscopic remission ± biomarker normalization) [19] are associated with improved long and shortterm outcomes [15]. However, it is unclear whether progression of bowel damage can be detected in clinically quiescent patients, and whether we could or should address these patients as targets for potential disease course modification by treatment escalation despite lack of symptoms necessitating intervention. Our study focused on a rarely targeted population of quiescent CD patients. Although only 13% were in complete small bowel mucosal healing at the entrance to the study, significant endoscopic inflammation was rare. As only patients who remained quiescent and did not necessitate treatment modification were retained for analysis, the remaining cohort was comprised of highly stable patients, as also
manifested by absence of any significant change in fecal calprotectin or CRP levels, as well as mucosal inflammation, during the course of the follow-up. In this selected patient population, bowel damage was very stable, with minor fluctuations after a year. No significant impact of ongoing treatment on the progression of BD was detected (however our study was underpowered for stratification by treatment). In a recent study by Bhattacharya et al. [20], elevated CRP was a predictor of worsening disease trajectory as gauged by LI during a multiyear follow-up of a clinically quiescent CD cohort. In our study, elevated biomarkers (calprotectin and CRP) did not predict a worsening of bowel damage; however this may be attributed to a relatively low number of patients with elevated CRP and shorter duration of follow-up. Currently there is no agreement regarding the LI value that signifies significant structural bowel damage and significant progression of bowel damage. In our study we utilized the values suggested by Fiorino et al. [7]; in that study, albeit relatively small, LI was correlated with an independent blinded physician evaluation to detect LI values that were best correlated with detectable bowel damage. In patients with clinical remission, LI of 4.8 was the most accurate for detection of baseline bowel damage, while a change of 0.3 in the score was the minimal detectable value associated with progression of the bowel damage [7]. Several limitations of our study should be acknowledged. Primarily, our study cohort was limited to quiescent patients. Due to the limitations of the study protocol, patients that developed a relapse were excluded from the study without a subsequent MRE, so we were not able to access bowel damage progression in those patients. In addition, the interval between MRE studies was slightly over 1 year; accumulation of bowel damage is a gradual and lengthy process, and the current duration of follow-up may have been insufficient for some patients that were prone to develop addition structural abnormalities upon longer follow-up. In addition, our study utilized MRE and capsule endoscopy for assessment of bowel damage. Although CE was not a part of the original and validated LI [2,3], it allows for accurate and thorough assessment of the entire small bowel with detection of small bowel damage previously not accounted for by other diagnostic modalities [14]. All patients with
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colonic disease in our study were evaluated using a colonic capsule in a protocol that allowed evaluation of both the colon and the small bowel. Importantly, although the original LI was based on ileocolonoscopy, gastroduodenoscopy (in patients with upper GI involvement), MRE and CT enterography, it is evident that bowel damage can be assessed using a similar methodology by alternative diagnostic modalities (as demonstrated by a recent study by Rispo et al. [21] that compared assessment of LI using MRE and ultrasonography). Despite the aforementioned limitations, our study is among the first to gauge and monitor progression of structural bowel damage in clinically quiescent CD patients. No progression of bowel damage in these patients could be detected over the course of one year. These results do not support the need to adjust anti-inflammatory treatment to target progression of structural damage in these stable patients. Our results merit replication and verification in a large prospective cohort with an extended follow-up. Conflict of interest None declared. References [1] Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflammatory Bowel Diseases 2002;8:244–50. [2] Pariente B, Mary JY, Danese S, et al. Development of the Lemann index to assess digestive tract damage in patients with Crohn’s disease. Gastroenterology 2015;148, 52–63.e3. [3] Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lemann score. Inflammatory Bowel Diseases 2011;17:1415–22. [4] Gilletta C, Lewin M, Bourrier A, et al. Changes in the Lemann index values during the first years of Crohn’s Disease. Clinical Gastroenterology and Hepatology 2015;13:1633–40,. e3. [5] Bodini G, Giannini EG, De Maria C, et al. Anti-TNF therapy is able to stabilize bowel damage progression in patients with Crohn’s disease: a study performed using the Lemann Index. Digestive and Liver Disease 2016. [6] Fiorino G, Bonifacio C, Peyrin-Biroulet L, et al. Preventing collateral damage in crohn’s disease: the Lemann index. Journal of Crohn’s & Colitis 2016;10:495–500.
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[7] Fiorino G, Bonifacio C, Allocca M, et al. Bowel damage as assessed by the Lemann index is reversible on anti-TNF therapy for Crohn’s disease. Journal of Crohn’s & Colitis 2015;9:633–9. [8] Peyrin-Biroulet L, Loftus Jr EV, Colombel JF, et al. Early Crohn disease: a proposed definition for use in disease-modification trials. Gut 2010;59:141–7. [9] Safroneeva E, Vavricka SR, Fournier N, et al. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn’s disease. Alimentary Pharmacology & Therapeutics 2015;42:977–89. [10] Magro F, Rodrigues-Pinto E, Coelho R, et al. Is it possible to change phenotype progression in Crohn’s disease in the era of immunomodulators? Predictive factors of phenotype progression. The American Journal of Gastroenterology 2014;109:1026–36. [11] Kopylov U, Eliakim R. The Lemann index—a glance through the window of opportunity? Journal of Crohn’s & Colitis 2016. [12] Danese S, Fiorino G, Fernandes C, et al. Catching the therapeutic window of opportunity in early Crohn’s disease. Current Drug Targets 2014;15:1056–63. [13] Kopylov U, Yablecovitch D, Lahat A, et al. Detection of small bowel mucosal healing and deep remission in patients with known small bowel Crohn’s disease using biomarkers, capsule endoscopy, and imaging. The American Journal of Gastroenterology 2015;110:1316–23. [14] Greener T, Klang E, Yablecovitch D, et al. The impact of magnetic resonance enterography and capsule endoscopy on the re-classification of disease in patients with known Crohn’s disease: a prospective Israeli IBD Research Nucleus (IIRN) study. Journal of Crohn’s & Colitis 2016;10:525–31. [15] Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. The American Journal of Gastroenterology 2015;110:1324–38. [16] Shrot S, Konen E, Hertz M, et al. Magnetic resonance enterography: 4 years experience in a tertiary medical center. The Israel Medical Association Journal: IMAJ 2011;13:172–7. [17] Gralnek IM, Defranchis R, Seidman E, et al. Development of a capsule endoscopy scoring index for small bowel mucosal inflammatory change. Alimentary Pharmacology & Therapeutics 2008;27:146–54. [18] Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140:1785–94. [19] Pineton de Chambrun G, Blanc P, Peyrin-Biroulet L. Current evidence supporting mucosal healing and deep remission as important treatment goals for inflammatory bowel disease. Expert Review of Gastroenterology & Hepatology 2016:1–13. [20] Bhattacharya A, Rao BB, Koutroubakis IE, et al. Silent Crohn’s disease predicts increased bowel damage during multiyear follow-up: the consequences of under-reporting active inflammation. Inflammatory Bowel Diseases 2016;22:2665–71. [21] Rispo A, Imperatore N, Testa A, et al. Bowel damage in Crohn’s disease: direct comparison of ultrasonography-based and magnetic resonance-based Lemann index. Inflammatory Bowel Diseases 2017;23:143–51.
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ARTICLE IN PRESS Digestive and Liver Disease xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Structural bowel damage in quiescent Crohn’s disease夽 Marianne M. Amitai a,b , Moran Zarchin b,c , Adi Lahat b,c , Doron Yablecovitch b,c , Sandra Neuman b,c , Nina Levhar b,c , Eyal Klang a,b , Benjamin Avidan b,c , Shomron Ben-Horin b,c , Rami Eliakim b,c,1 , Uri Kopylov b,c,∗,1 , on behalf of the Israeli IBD research Nucleus (IIRN) a
Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Israel Sackler Faculty of Medicine, Tel Aviv University, Israel c Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel b
a r t i c l e
i n f o
Article history: Received 3 December 2016 Received in revised form 31 January 2017 Accepted 1 February 2017 Available online xxx Keywords: Capsule endoscopy Crohn’s disease Lemann index Magnetic resonance enterography Structural damage
a b s t r a c t Background: Crohn’s disease is associated with accumulation of progressive structural bowel damage (SBD) leading to the development of stenotic and penetrating complications. The data pertaining to the course of progression of SBD is scarce. The Lemann index (LI) is a novel tool for evaluation of SBD that incorporates pan-enteric clinical, endoscopic and imaging data. Aims: To evaluate the progression of SBD in quiescent CD patients. Methods: Patients with known quiescent small bowel Crohn’s disease (CD) for at least 3 months (CDAI < 220) were prospectively recruited and underwent repeated magnetic resonance enterographies (MRE) and video capsule endoscopies (VCE). Patients were assessed for SBD on initial and follow-up evaluation using relevant clinicopathological data, MRE and VCE results. Significant structural bowel damage (SBD) was identified as LI > 4.8, and progression of SBD as LI > 0.3. Results: Sixty one patients were enrolled in the study. Significant SBD was detected 13 (21.4%) on enrollment. Duration of disease (p = 0.036) and history of CD-related surgery (p = 0.0001) were associated with significant BD. Forty one patients underwent a follow-up MRE (14.8 ± 2.5 months apart). LI was similar at baseline and follow-up. There was a negligible change in LI between the evaluations. Conclusions: In patients with quiescent Crohn’s disease, structural bowel damage was stable over a median of 14 months follow-up. © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Crohn’s disease (CD) is characterized by a chronic progressive course that is frequently associated with accumulation of structural bowel damage potentially leading to a development of structuring or penetrating complications. Up to 60% of CD patients will eventually develop complications necessitating surgical intervention [1]. However, it is clear that need for surgery is merely the “top of the iceberg” as far as bowel damage in CD is considered, and is preceded by gradual accumulation of more subtle evidence of ongoing destructive process. Until recently, no quantitative tools
夽 The study was partially supported by a generous grant from the Leona M. and Harry B. Helmsley Charitable Trust. ∗ Corresponding author at: Department of Gastroenterology, Sheba Medical Center, Hashomer, Israel. Fax: 972 3 560 5901. E-mail address: [email protected] (U. Kopylov). 1 Kopylov and Eliakim are equal contributors.
for assessment of bowel damage in CD were available. The Crohn’s Disease Digestive Damage Score (Lemann index (LI)) incorporates surgical, endoscopic and imaging findings from all segments of the digestive tract into one composite score [2,3]. Within the first 10 years of the disease, at least 2/3 of the patients demonstrate significant bowel damage that is manifested by gradual LI elevation [4]. As recently demonstrated, increasing LI is predictive of subsequent major abdominal surgery; moreover, anti-tumor necrosis factor ␣ (anti-TNF) agents are able to stabilize [5] or reverse BD in some CD patients [6,7]. It is likely that earlier initiation of effective anti-inflammatory treatment at an early phase of the disease before the development of bowel damage may alter the course of CD and prevent future complications [8–11]. This maybe especially important if we take into account a significant diagnostic delay that is characteristic of CD [10,12]. CD is frequently associated with periods of clinical remission that may occur spontaneously and independently of treatment. However, a vast majority of these patients will display at least some degree of mucosal inflammation even when in clinical remission
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[13], and upon scrupulous evaluation of the small bowel with capsule endoscopy (VCE) or magnetic resonance enterography (MRE) significant changes in both disease location and phenotype in comparison to the original evaluation can be detected in over 50% of quiescent CD patients [14]. There is ample clinical evidence supporting the need to treat CD patients to a target of mucosal healing (MH) and not settle for clinical remission, as MH is associated with both durable clinical remission and lower risk of long-term complications [15]. However, the progression of bowel damage in quiescent CD patients is scarcely documented. Therefore, the aim of the current study was to evaluate the progression of BD in patients with clinically quiescent Crohn’s disease.
RAPID 8 software (Given Imaging, Yokneam, Israel). The adaptive frame rate mode was activated to ensure visualization of the entire small bowel. Mucosal inflammation was quantified using the Lewis score (LS) [17]. Mucosal healing was defined as LS < 135, mild to moderate inflammation as LS of 135–790, and moderate to severe inflammation as LS ≥ 790 [17].
2. Methods
2.2.4. Calculation of LI LI was calculated as previously described [3]. The gastrointestinal tract was divided segments [upper gastrointestinal tract—esophagus, stomach, and duodenum; small bowel—divided into 20 segments of 20 cm; 6 segments for colon and rectum]. Findings at MRE and CE were divided into stricturing and penetrating lesions, scored and adjusted for anatomical coefficients (Supplementary table). Upper GI was scored using capsule endoscopy. For evaluation of the small bowel we incorporated MRE and CE data. Colonic disease was scored using colonic capsule, MRE and the available colonoscopic data. For scoring of resected segments in patients who underwent surgery, original surgical and pathological reports were used in order to calculate the length of resection. Significant BD was defined as LI > 4.8, progression of SBD as LI > 0.3, and regression—as LI < −0.3 [7]. The scores were calculated at both the initial and the follow-up evaluations.
2.1. Patient population This study was a sub study of a prospective observational study aimed at detailed evaluation of CD patients with quiescent disease in order to identify clinical, biochemical and endoscopic predictors of pending clinical relapse [13]. The study population included adult (>18 years) CD patients with known SB disease in remission or mild disease symptoms, as determined by a Crohn’s disease activity index (CDAI) of <220. All patients were in corticosteroid-free remission for 3–24 months and were treated with a stable medication dose. The patients were prospectively followed by serial clinical evaluation and biomarker (CRP/fecal calprotectin (FCP) levels) once every 3 months, biannual VCE and annual MRE examinations. Patients were withdrawn from the study if they developed clinical relapse (CDAI > 220) or required a treatment change. All patients signed an informed consent and the study was approved by the institutional ethics review board. 2.2. Study procedures 2.2.1. MRI scans All MRE examinations were performed using a 1.5T GE Optima MR450w scanner with GEM Suite (GE Healthcare) with oral and intravenous contrast. MR image acquisition was performed using a previously described protocol [16]. SB distention was obtained by using oral contrast: 360 ml of Osmitrol 20% diluted in 1.5 l water. Patients were instructed to drink 4 doses of 465 ml every 15 min an hour before undergoing the MRE examination. During the last 15 min, patients received via infusion 150 ml of saline containing 0.5 mg of glucagon in slow drip. Axial and coronal LAVA sequences were acquired before and 40 s after intravenous administration of Gadolinium. A board-certified abdominal radiologist with 10 years of experience in reading MRE reviewed all MRE examinations. 2.2.2. Capsule endoscopy studies A patency capsule (PC) test (Given Imaging, Yokneam, Israel) was performed in all patients with active SB disease detected on MRE. If no active SB disease was detected by MRE, a PC study was not performed. If the PC was not eliminated from the SB within 30 h, the patients were withdrawn from the study. In patients with isolated SB CD (L1 by the Montreal classification), SB-III capsule (Given Imaging, Yokneam, Israel) was used. In patients with SB and colonic CD (L3 disease), a colonic capsule (PillCam colonic capsule 2, Given Imaging, Yokneam, Israel) was administered; in these patients, the SB data was reviewed and scored as described for the SB capsule. The preparation for VCE included intake of clear fluids only for 24 h prior to the procedure and a 12 h overnight fast. For a colonic capsule study, a split-dose PEG preparation was used. An additional fluid bolus was given after 2 h from ingestion of the capsule in order to facilitate small bowel transit. All images were reviewed using the
2.2.3. Inflammatory biomarkers Fecal calprotectin levels were measured using the Quantum blue calprotectin kit (BÜHLMANN Laboratories AG, Basel, Switzerland). The reported value range is 30–300 g/g. Levels >100 g/g were considered positive. CRP levels were considered elevated if >5 mg/l.
2.3. Statistical analysis Descriptive statistics were presented as means ± standard deviations (SD) or medians ± interquartile ranges (IQR) for continuous variables and percentages for categorical variables. Categorical variables were analyzed by Chi Square/Fisher’s exact test and continuous variables-by Student t-test/Mann Whitney test or paired t-test as appropriate. A two-tailed p value <0.05 was considered statistically significant. The analysis was performed using IBM SPSS statistic (Version 20.0) (Armonk, NY, USA). 3. Results 3.1. Baseline characteristics Sixty one patients were enrolled in the study and underwent the initial evaluation; 56/61 (91.8%) were in clinical remission (CDAI < 150) upon enrollment. Twenty five (41%) had normal inflammatory biomarkers; eight (13.3%) had small bowel mucosal healing. Significant mucosal inflammation (LS > 790) was demonstrated in 12/61 (19.6%) patients. Clinical and demographic characteristics of the included patients, as well as treatment at inclusion, are detailed in Table 1. 3.2. SBD assessment upon enrollment On initial evaluation, the mean LI was 3.7 ± 5.1 (if only patients with available follow-up were included—2.51 ± 3.71). No signs of bowel damage (LI = 0) were detected in 12 (19.6%) of the patients; mild BD (0–4.8) was detected in 36 (59%) of the patients; LI was above 4.8 in 13 (21.4%) of the patients. Duration of disease (8.1 ± 4.8 vs 8.1 ± 4.8 years, p = 0.036) and history of CD-related surgery (69% vs 2.1%, p = 0.0001) were associated with significant SBD. Other clinical characteristics including medical treatment were not associated with SBD (Table 2).
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M.M. Amitai et al. / Digestive and Liver Disease xxx (2017) xxx–xxx Table 1 Clinical and demographic characteristics of the included patients on enrollment. N = 61 Age at enrollment, years Disease duration, years Gender Disease location
Disease behavior
Perianal disease smoking
Male Female
32.6 ± 11 5.6 ± 4.9 35 (57.4%) 26 (42.6%)
L1 L2 L3
37 (60.6%) 2 (3.3%) 22 (36.0%)
B1 B2 B3
40 (65.5%) 11 (18.2%) 10 (16.3%)
Current Never used Previous
15 (24.6%) 11 (18.0%) 40 (65.6%) 10 (16.4%)
Previous surgery
10 (17.5%)
Current treatment
None Mesalamine Thiopurines Anti-TNFs
10 (16.3%) 10 (16.3%) 29 (47.5%) 23 (37.7%)
Small bowel mucosal healing Elevated calprotectin Elevated CRP
LS < 135 >100 g/g >5 mg/l
8 (13.3%) 29 (47.5%) 18 (29.5%)
CRP—C-reactive protein; TNF—tumor necrosis factor; LS—Lewis score. Montreal classification: Location: L1—ileal; L2—colonic; L3—ileocolonic. Phenotype: B1—non-stricturing non-penetrating; B2—structuring; B3—penetrating.
3.3. Follow-up evaluation Twenty (32.7%) patients were excluded from the study before a subsequent MRE was performed. The reason for exclusion were: clinical relapse (9 patients); change of treatment due to a significant endoscopic escalation (3 patients); pregnancy (3 patients); loss to follow-up/consent withdrawal (2 patients); refusal to undergo a second MRE (3 patients). A follow-up MRE was performed after 14.8 ± 2.5 months. Forty one patients remained clinically qui-
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Table 3 Comparison of the individual components of the Lemann index upon enrollment and on the follow-up evaluation.
Overall LI Upper GI Small bowel Colon
Enrollment
Follow-up
p
2.51 ± 3.71 0.00 ± 0.00 1.74 ± 2.21 0.13 ± 0.57
2.48 ± 3.67 0.00 ± 0.00 1.77 ± 2.30 0.10 ± 0.43
0.85 NA 0.9 0.3
LI—Lemann index.
escent and were available for analysis. Thirty seven (90.2%) of these patients during follow-up evaluation, 26/41 (63.4%) had elevated biomarkers, 10/41 (24.4%) patients had small bowel mucosal healing. No significant change in disease activity as measured by inflammatory biomarkers or LS occurred during follow-up. On follow-up evaluation, mean LI was 2.48 ± 3.67 (vs 2.51 ± 3.71 at baseline, p = 0.85). The overall change in LI was negligible (−0.038 ± 1.27, p = 0.85). A detailed comparison of SBD assessment at onset and follow-up appears in Table 3. No evidence of SBD was detected in 7 (17.1%) (p = 0.79 vs baseline), mild BD was detected in 28 (68.3%) (p = 0.81 vs baseline) and significant BD in 6 (14.6%) (p = 1 vs baseline) of the patients (Fig. 1). There was no change in LI in 14 (34.1%) patients. In 14 (34.1%) there was a progression (LI > 0.3%) of BD and in 13 (31.7%)—a regression (LI > −0.3%). No clinical parameter including current treatment was associated with progression or improvement of SBD. LI was was not significantly different between patients with and without small bowel mucosal healing (1.9 ± 4.3 vs 2.7 ± 4.1, p = 0.15) or in patients with elevated baseline CRP (2.5 ± 3.8 vs 2.5 ± 3.6, p = 0.92). The results did not change when limited to patients in clinical remission (CDAI < 150). 4. Discussion Our study demonstrates no change in bowel damage in stable CD patients that remain in clinical remission and do not show biochemical or endoscopic evidence of disease exacerbation. The main clinical parameter associated with presence of bowel damage
Table 2 Comparison of patients with and without evidence of significant bowel damage upon study enrollment.
Age at enrollment, years Disease duration, years
LI < 4.8 N = 47
LI > 4.8 N = 14
p
26.3 ± 10.8 4.9 ± 4.7
29.4 ± 12.9 8.1 ± 4.8
0.37 0.036
Gender
Male Female
25 (53.2%) 22 (46.8%)
10 (71.4%) 4 (28.6%)
0.23
Disease location
L1 L2 L3
29 (61.7%) 2 (4.3%) 17 (36.1%)
9 (64.2%) 0 (0.0%) 5 (35.7%)
0.9
Disease behavior
B1 B2 B3
34 (72.3%) 7 (14.9%) 5 (10.7%)
5 (35.7%) 4 (28.6%) 5 (35.7%)
0.075
Previous surgery
1 (2.2%)
9 (75.0%)
0.0001
Perianal disease
12 (25.5%)
3 (21.4%)
0.75
Current treatment
None Mesalamine Thiopurines Anti-TNFs
9 (19.1%) 9 (19.1%) 20 (42.6%) 17 (36.2%)
1 (7.1%) 1 (7.1%) 9 (64.3%) 6 (42.9%)
0.42 0.42 0.15 0.65
Elevated calprotectin Elevated CRP Small bowel mucosal healing
>100 g/g >5 mg/l LS < 135
15 (31.9%) 22 (46.8%) 7 (15.2%)
3 (21.4%) 7 (50.0%) 1 (7.1%)
0.78 0.45 0.44
LI—Lemann index; CRP—C-reactive protein; TNF—tumor necrosis factor; LS—Lewis score. Montreal classification: Location: L1—ileal; L2—colonic; L3—ileocolonic. Phenotype: B1—non-stricturing non-penetrating; B2—structuring; B3—penetrating. The significance level was p < 0.05. The numbers in bold are p values that are <0.05.
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Fig. 1. Lemann index upon enrollment and on follow-up evaluation.
on study onset was disease duration. A gradual progression of CD phenotype from inflammatory to structuring/perforating is a well described paradigm [1,18], further augmented by a significant diagnostic delay frequent in CD. We gauged the degree of bowel damage using the Lemann index, the only comprehensive composite bowel damage that incorporates various sources of structural data from all compartments of the digestive tract [2,3]. Until recently, we estimated progression of bowel damages by development of major complications manifesting phenotype shifts (surgery, appearance of new abscesses and fistulae), trailing behind the complications as they develop. The declared aim of LI is to predict the appearance of such structural complications by quantification of the accumulating damage before the emergence of such complications. Recently, LI was demonstrated to be predictive of surgery risk [4,7], and was also useful to monitor reversal of structural damage in patients treated with biologics [7]. In another recent study of CD patients followed for a median of 29 months, biologic treatment was associated with stabilization of LI, while patients treated with thiopurines or mesalamine demonstrated increasing bowel damage [5]. While it it’s quite intuitive that bowel damage is likely to accumulate while the disease is clinically active, our knowledge of disease course progression in quiescent patients is relatively vague. In the recent years, ample evidence supporting the need to target treatment to mucosal healing and not mere clinical improvement has accumulated. Mucosal healing and “deep remission “ (a combination of clinical and endoscopic remission ± biomarker normalization) [19] are associated with improved long and shortterm outcomes [15]. However, it is unclear whether progression of bowel damage can be detected in clinically quiescent patients, and whether we could or should address these patients as targets for potential disease course modification by treatment escalation despite lack of symptoms necessitating intervention. Our study focused on a rarely targeted population of quiescent CD patients. Although only 13% were in complete small bowel mucosal healing at the entrance to the study, significant endoscopic inflammation was rare. As only patients who remained quiescent and did not necessitate treatment modification were retained for analysis, the remaining cohort was comprised of highly stable patients, as also
manifested by absence of any significant change in fecal calprotectin or CRP levels, as well as mucosal inflammation, during the course of the follow-up. In this selected patient population, bowel damage was very stable, with minor fluctuations after a year. No significant impact of ongoing treatment on the progression of BD was detected (however our study was underpowered for stratification by treatment). In a recent study by Bhattacharya et al. [20], elevated CRP was a predictor of worsening disease trajectory as gauged by LI during a multiyear follow-up of a clinically quiescent CD cohort. In our study, elevated biomarkers (calprotectin and CRP) did not predict a worsening of bowel damage; however this may be attributed to a relatively low number of patients with elevated CRP and shorter duration of follow-up. Currently there is no agreement regarding the LI value that signifies significant structural bowel damage and significant progression of bowel damage. In our study we utilized the values suggested by Fiorino et al. [7]; in that study, albeit relatively small, LI was correlated with an independent blinded physician evaluation to detect LI values that were best correlated with detectable bowel damage. In patients with clinical remission, LI of 4.8 was the most accurate for detection of baseline bowel damage, while a change of 0.3 in the score was the minimal detectable value associated with progression of the bowel damage [7]. Several limitations of our study should be acknowledged. Primarily, our study cohort was limited to quiescent patients. Due to the limitations of the study protocol, patients that developed a relapse were excluded from the study without a subsequent MRE, so we were not able to access bowel damage progression in those patients. In addition, the interval between MRE studies was slightly over 1 year; accumulation of bowel damage is a gradual and lengthy process, and the current duration of follow-up may have been insufficient for some patients that were prone to develop addition structural abnormalities upon longer follow-up. In addition, our study utilized MRE and capsule endoscopy for assessment of bowel damage. Although CE was not a part of the original and validated LI [2,3], it allows for accurate and thorough assessment of the entire small bowel with detection of small bowel damage previously not accounted for by other diagnostic modalities [14]. All patients with
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colonic disease in our study were evaluated using a colonic capsule in a protocol that allowed evaluation of both the colon and the small bowel. Importantly, although the original LI was based on ileocolonoscopy, gastroduodenoscopy (in patients with upper GI involvement), MRE and CT enterography, it is evident that bowel damage can be assessed using a similar methodology by alternative diagnostic modalities (as demonstrated by a recent study by Rispo et al. [21] that compared assessment of LI using MRE and ultrasonography). Despite the aforementioned limitations, our study is among the first to gauge and monitor progression of structural bowel damage in clinically quiescent CD patients. No progression of bowel damage in these patients could be detected over the course of one year. These results do not support the need to adjust anti-inflammatory treatment to target progression of structural damage in these stable patients. Our results merit replication and verification in a large prospective cohort with an extended follow-up. Conflict of interest None declared. References [1] Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflammatory Bowel Diseases 2002;8:244–50. [2] Pariente B, Mary JY, Danese S, et al. Development of the Lemann index to assess digestive tract damage in patients with Crohn’s disease. Gastroenterology 2015;148, 52–63.e3. [3] Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lemann score. Inflammatory Bowel Diseases 2011;17:1415–22. [4] Gilletta C, Lewin M, Bourrier A, et al. Changes in the Lemann index values during the first years of Crohn’s Disease. Clinical Gastroenterology and Hepatology 2015;13:1633–40,. e3. [5] Bodini G, Giannini EG, De Maria C, et al. Anti-TNF therapy is able to stabilize bowel damage progression in patients with Crohn’s disease: a study performed using the Lemann Index. Digestive and Liver Disease 2016. [6] Fiorino G, Bonifacio C, Peyrin-Biroulet L, et al. Preventing collateral damage in crohn’s disease: the Lemann index. Journal of Crohn’s & Colitis 2016;10:495–500.
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