Abstract
Objective
Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn’s disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.
Design
Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.
Results
In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.
Conclusion
Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.
INTRODUCTION
A stricturing phenotype develops in more than half of patients with Crohn’s disease (CD)1 2 and can lead to symptomatic bowel obstruction requiring endoscopic3 4 or surgical intervention.5 6 Antifibrotic therapies for the treatment of stricturing CD is an unmet medical need. Given that considerable progress has been made in several fibrosing disorders, including liver, lung, skin, kidney and heart diseases,7–11 controlled studies of antifibrotic drugs will soon be initiated for stricturing CD.12
Successful drug development, however, depends on the availability and standardised use of appropriate and validated clinical trial endpoints. Assessment of biopsy histology is not an option for CD, due to the inability to evaluate transmural disease. Cross-sectional imaging is therefore likely to play a critical role in defining the efficacy of antifibrotic therapies.13 Candidate imaging modalities have been investigated in patients with symptomatic strictures who undergo imaging, subsequent bowel resection and postoperative histopathological assessment.14–21 Preoperative findings on cross-sectional imaging are correlated to post-surgical histopathological assessments of resected tissue. Validated histopathological scoring systems for independently quantifying inflammation and fibrosis in surgical specimens are required to establish the construct validity of cross-sectional imaging modalities.
The essential properties of validated scoring systems include content validity (ie, capacity of the instrument to measure what it intends in the target population), construct validity (ie, ability to distinguish among groups known to be different) and criterion validity (ie, correlation with established markers of disease activity). Additional properties include reliability (ie, intraobserver and interobserver agreement), responsiveness (ie, capacity to discriminate change in response to a treatment of known efficacy) and feasibility (ie, ease and time required for application).22 We previously concluded that a lack of validated scoring systems for assessment of stricturing CD was a rate-limiting step to progress in this field.23 An international working group composed of inflammatory bowel disease (IBD) pathologists and gastroenterologists was established under the umbrella of the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium to address this need. As a second step towards a validated histopathology scoring system, a global multidisciplinary panel was assembled to participate in a two-round modified RAND/University of California Los Angeles (UCLA) appropriateness process24 25 with the aim of standardising histopathological assessment of CD strictures.
MATERIALS AND METHODS
Systematic review of literature
Search methods for the systematic review can be found in online supplemental appendix 1.
Consensus process
Recruitment of panellists
A total of 12 experienced histopathologists and 3 gastroenterologists from the USA, Canada, Australia, Belgium, Germany, Portugal and the UK were chosen to participate. Panellists were selected based on publication record, international reputation in histopathology of stricturing CD and experience in the development and validation of evaluative scoring systems. After reviewing a list of potential experts, the final group of participants was selected by IOG, VJ, BGF and FR.
A modified RAND/UCLA appropriateness methodology was used to assess the face validity and feasibility of histopathologic items identified in the systematic review. Additional relevant items were included based on the opinions of the panellists after review of the initial item list. RAND/UCLA appropriateness methodology employs a modified Delphi panel approach to combine the best available evidence with the experience of relevant experts without requiring consensus.24 This process is widely accepted, iterative and evidence based.
The identified items were circulated and rated for the appropriateness of each statement in two voting rounds with a moderated teleconference in between to discuss the results of the first round. The process and the analysis followed previously described methodology26 and a detailed description can be found in online supplemental appendix 1.
RESULTS
Systematic review and survey development
The literature search retrieved a total of 3377 citations. Hand searching identified an additional 22 citations. After removal of duplicates, 2518 citations were screened using the predefined eligibility criteria. Of these, 2409 citations were deemed not eligible based on review of the title and abstract. An additional 58 citations were excluded based on full-text review (online supplemental figure 1). A total of 51 citations satisfied the inclusion criteria for the qualitative analysis of the transmural or full thickness histopathological scoring systems reported in the studies. Online supplemental table 1 includes a summary of the original study designs, author, year, % with strictures, scoring system, definitions for small bowel fibrosis, validated scoring system, comparing technique, and sensitivity/specificity for fibrosis and inflammation separately.
Among the 51 selected studies, a total of 9 histopathology scoring systems were identified based on the inclusion and exclusion criteria (online supplemental appendix 1).15 18 21 27–32 These scoring systems were included in the initial list of statements.
The initial draft survey consisted of 308 statements. After the first survey was circulated and responses analysed, a second teleconference was held to discuss the results and to modify the survey where necessary. The final survey consisted of 282 statements.
Although ‘stenosis’ and ‘stricture’ are used interchangeably in the literature, we refer to ‘stricture’ in this manuscript based on recommendations from the American Gastroenterology Association. This term encompasses the possibility of the coexistence of inflammatory fibrotic and muscular components.33
Appropriateness of statements
Of the 282 statements included in the final survey, 78 (27.6%) were rated appropriate (summarised in table 1), 49 (17.4%) were rated inappropriate and 155 (55.0%) were rated uncertain (full results are summarised in online supplemental table 2).
Table 1.
Summary of appropriate key findings on histopathological scoring of small bowel stricturing disease defined by the RAND/UCLA process
| Gross morphology | Naïve and anastomotic strictures can be defined by gross examination alone Increased bowel wall thickness, decreased internal circumference and decreased luminal diameter must be present to diagnose a stricture Increased bowel wall thickness should be defined as measurement from the serosal aspect to the mucosal aspect Decreased internal circumference should be defined as an internal circumference measurement less than that of the uninvolved bowel wall Decreased luminal diameter should be defined as decreased luminal diameter measurement compared with the uninvolved bowel wall Creeping fat and fat wrapping should be defined as white adipose tissue extension from the mesenteric attachment to partly or wholly cover the antimesenteric aspect of the intestine |
| Histopathology | A naïve or anastomotic small bowel stricture cannot be defined on microscopic examination alone A minimum of one cross section should be taken per centimetre length of stricture H&E staining must be performed before making a diagnosis of small bowel stricture on pathology Fibrosis of the submucosa is required to diagnose a small bowel stricture and should be defined as an increased collagen content in the stricture section compared with any non-stricture section A small bowel stricture on microscopic examination may be accompanied by the following changes:
No existing histopathological score for grading inflammation and fibrosis in small bowel stricturing Crohn’s disease was considered appropriate |
UCLA, University of California Los Angeles.
Gross pathology of strictures
The panel considered the appropriateness of statements relevant to gross pathological changes in CD-associated small bowel strictures. Definition of naïve and anastomotic strictures based on gross pathology alone was considered appropriate (based on inappropriate ratings for items suggesting this was not possible). It is noteworthy that the panel thought that naïve and anastomotic strictures can only be diagnosed in comparison to healthy adjacent tissue on gross/histological assessment. The presence of three components (rated separately) was considered appropriate and necessary to diagnose a small bowel stricture on gross examination: an increased small bowel wall thickness, decreased internal circumference and decreased luminal diameter. The presence of upstream dilation alone was considered of uncertain appropriateness for diagnosis. Additional definitions considered uncertain were (1) increased thickness of the bowel wall alone, (2) all definitions containing increased internal circumference or increased luminal diameter of the upstream bowel and (3) increased tissue rigidity (bowel does not lay flat and is difficult to open). Appropriateness ratings for gross pathological evaluation were similar for definitions of anastomotic (at the site of prior intestinal resection with anastomosis) and naïve small bowel strictures (online supplemental table 2; statement sections A to D, K and L).
The appropriateness of specific definitions for each component of a stricture on gross examination was also considered (online supplemental table 2; statement sections E to J). Increased bowel wall thickness of a naïve or anastomotic stricture defined as measurement from the serosal aspect across all layers of the bowel wall to the mucosal aspect (in areas without serosal fat) was rated appropriate. Measurements of only serosal fat and muscularis propria, muscularis propria only, or of submucosa and mucosa only were all considered inappropriate for estimating bowel wall thickness of naïve or anastomotic strictures.
Decreased internal circumference of a naïve stricture (after opening the bowel lengthwise) was considered appropriately defined as an internal circumference measurement that is less than the average measurement of the uninvolved bowel wall (non-affected margin of the same bowel piece) or the average measurement distal to the stricture. An average measurement proximal to the stricture was considered inappropriate. Definitions for decreased internal circumference that were rated as uncertain or inappropriate included measurements between 1 and 4 cm (measurements of 3 and 4 cm were considered inappropriate and the panel was uncertain regarding the appropriateness of measurements of 1 and 2 cm) or measurements that included a 30% and 50% decrease compared with adjacent uninvolved bowel. Although definitions considered for decreased internal circumference for naïve strictures were also considered for anastomotic strictures, none were considered appropriate in the latter case.
A luminal diameter measurement that is less than the average measurement of the uninvolved bowel wall on gross examination was the only appropriate definition for decreased luminal diameter in naïve strictures. Definitions that considered luminal diameter measurement defined as less than the average measurement distal or proximal to the stricture, in ranges from 0.5 to 2 cm, or as 30% and 50% decreases relative to adjacent healthy bowel were not considered appropriate. When the same definitions were considered for anastomotic strictures, none were considered appropriate.
Although defining an inflammatory mass as fibrosis and adhesions involving bowel loops, such that the area resembles a mass on gross examination, was considered appropriate for naïve strictures, the definition was rated uncertain in the case of anastomotic strictures. White adipose tissue extension from the mesenteric attachment to partly or wholly cover the antimesenteric aspect of the intestine was considered an appropriate definition for fat wrapping or creeping fat for both naïve and anastomotic strictures. Whereas fat partly covering (as opposed to partly or wholly covering) the antimesenteric aspect of the intestine was appropriate for fat wrapping and creeping fat in the case of naïve strictures, this definition was considered appropriate only for creeping fat for anastomotic strictures. Next, fat wrapping and creeping fat wholly covering the antimesenteric aspect were rated separately and were uncertain. Of note, the panel considered gross/histopathological assessment in comparison to healthy adjacent tissue a requirement for diagnosis for both naïve and anastomotic strictures (online supplemental table 2; statement sections U to AH).
Technical parameters for gross pathology
With regard to technical parameters for gross pathology, a minimum of one cross section per centimetre of a stricture was considered appropriate. Samples taken perpendicular to the direction of flow in the area of stricture were appropriate for both naïve and anastomotic strictures, whereas samples taken parallel to the direction of flow were uncertain. Although a complete circumferential cross-sectional sample was rated appropriate for naïve strictures, the panel was uncertain about this approach in the case of anastomotic strictures. Taking sections to demonstrate fat wrapping and/or creeping fat was appropriate for naïve strictures, but the panel was uncertain regarding this approach for anastomotic strictures (online supplemental table 2; statement sections O to T, AI and AJ).
Histopathology of strictures
For the purpose of this study and based on general agreement among the panel, the appropriateness of statements relevant to histopathological evaluation were considered collectively for both naïve and anastomotic strictures. Microscopic examination alone was not considered appropriate to define either type of stricture. Additionally, while an H&E stain was considered appropriate and necessary prior to diagnosis of a small bowel stricture, the necessity of Movat and elastin stains prior to diagnosis was considered inappropriate, and the panel was uncertain regarding the need for a trichrome stain.
Histopathological features necessary to diagnose small bowel strictures
Among numerous microscopic features rated as potentially necessary for diagnosis of small bowel strictures, only fibrosis of the submucosa was considered appropriate. The presence of active mucosal injury, fistula, granulomas and eccentric fibrointimal hyperplasia of submucosal arteries or veins were considered inappropriate, and chronic mucosal injury, transmural inflammation, thickening of the muscularis mucosa, muscularisation of the submucosa, neural hyperplasia within the submucosa, and thickening of the inner, outer or entire muscularis propria were rated as uncertain (online supplemental table 2).
Histopathological definitions relating to fibromuscular or fibrotic changes
Definitions of microscopic changes rated as appropriate included increased thickness of all layers of the bowel wall both in the presence of wrapped fat (from serosa (including wrapped fat) to mucosa) and in areas at a distance from wrapped fat, compared with adjacent healthy bowel. When considering the different layers separately, microscopic changes including increased thickness of the muscularis propria and of the inner muscularis propria compared with adjacent healthy bowel were considered appropriate, whereas increased thickness of the outer muscularis propria was considered uncertain. Additional changes on microscopic examination considered appropriate included fibrosis of the submucosa and bowel wall, as well as increased thickness of the muscularis mucosa and muscularisation of the submucosa. Fibrosis of the mucosa was considered appropriately defined as submucosal collagen content greater in the stricture section than in any of the non-stricture sections, as seen on H&E. The same definition was rated uncertain when observed on trichrome stain.
Microscopic changes within the submucosa that may accompany a stricture rated uncertain included increased fat (defined as fat content greater in the stricture section than in any of the non-stricture sections), neural hyperplasia (defined as increased number and/or size of nerve bundles as compared with non-strictured sections; uncertain when compared with non-Crohn’s sections) and eccentric fibromuscular hyperplasia (online supplemental table 2; statement sections AK to T, AI and AJ to AN).
Histopathological definitions relating to inflammatory stricture changes
Statements considered appropriate to define active mucosal inflammatory disease included neutrophilic inflammation in the lamina propria, and within crypts (cryptitis) in an intact surface epithelium, as well as erosion, ulcer and fistula. Statements defining active mucosal inflammation as neutrophilic inflammation only in deep crypts (cryptitis) or in at least 50% of crypts, lamina propria eosinophils, eosinophilic crypt abscesses, epithelioid granuloma, microgranuloma and oedema were considered inappropriate, while damaged crypts and those including crypt rupture granuloma/histiocytic response were uncertain.
Statements considered appropriate to define chronic mucosal inflammatory disease included crypt architectural distortion, crypt loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, basal fibrosis and prominent lymphoid aggregates at the mucosa/submucosa interface. Those defining chronic mucosal inflammatory disease as eosinophilic crypt abscesses, microgranuloma and oedema were considered inappropriate, and those including lamina propria eosinophilia or epithelioid granuloma were uncertain. The panel considered it appropriate to use the term ‘chronic mucosal injury’ in preference to ‘chronic inflammation’.
Statements considered appropriate to define transmural inflammation included lymphoid aggregates with or without germinal centres at the interface of the muscularis propria and the serosal or mesenteric adipose tissue, fistula tract, inflammation across all four aspects of the bowel wall, and granulomas in the muscularis propria or in the serosal or mesenteric adipose tissue. Statements considered inappropriate to define transmural inflammation included lymphoid aggregates with or without germinal centres at the interface of the mucosa and submucosa, knife-like ulcers and neutrophilic inflammation extending into the submucosa. Uncertain statements for defining transmural inflammation included lymphoid aggregates with or without germinal centres within the submucosa, neutrophilic inflammation extending into the muscularis propria, or into the serosal or mesenteric adipose tissue, and granulomas in the submucosa (online supplemental table 2; statement sections AP to AS).
Scoring systems for inflammation and fibrosis
Previously published scoring systems measuring both inflammation and fibrosis were also assessed for appropriateness for measuring disease activity in stricturing CD. With respect to assessing inflammation (online supplemental table 2; statement sections AT to BB), none of the overall disease activity scoring systems15 18 27–32 34 were rated appropriate (all were rated as uncertain). Component items of the scoring systems assessing inflammation were also rated as uncertain, with the exception of items describing grade 0 inflammation as the absence of inflammation30 31 35 or as no inflammation.36 The nominally highest median score for appropriateness of scoring inflammation (overall and item level) was observed for the scoring system described by Chen et al32; however,the appropriateness of the overall scoring system was nevertheless uncertain.
None of the scoring systems evaluated15 18 27–32 34 were considered appropriate for assessment of fibrosis (seven were rated by the panel as uncertain15 28–32 34 and two were rated as inappropriate18 27 in this context) (online supplemental table 2; statement sections BE to BM). Interestingly, scores that used the terms ‘no or minimal fibrosis’15 or ‘no or mild fibrosis’34 to define the least fibrotic state were considered uncertain. Classification of bowel strictures as predominantly fibrotic when abnormal deposits of collagen are identified in the edges of mucosal ulceration was considered inappropriate.27 Defining fibrosis (visualised by Sirius Red staining) and muscular hypertrophy (visualised by immunohistochemical staining for smooth muscle actin) using software-based calculation of affected intramural areas with an smooth muscle actin to Sirius Red (SMA:SR) ratio <1 indicating increased fibrosis and >1 indicating increased muscular hypertrophy18 was also considered inappropriate. Additionally, the panel rated defining fibrosis in a stricture on a stepwise four grade scale (absent, mild, moderate, severe) for adipocyte hyperplasia in the mucosa, submucosa, muscularis propria and subserosal adventitia32 as inappropriate. All remaining component items proposed for defining fibrosis in a stricture were uncertain (online supplemental table 2).
General pathophysiologic/research statements for fibrosis
Increased muscularis propria thickness is a component of a CD stricture. The panel determined that thickness of the muscularis propria can be visibly increased and increased when compared with adjacent non-strictured areas and to adjacent areas unaffected by CD, were appropriate statements. Uncertainty was present regarding whether normal muscularis propria thickness is well defined, and if measurements of muscularis propria thickness are necessary to define increased thickness within a stricture compared with adjacent non-strictured areas, adjacent areas unaffected by CD or a known control thickness measurement. Muscular hypertrophy and fibrosis within the muscular layer were considered appropriate causes of muscularis propria changes in a stricture, whereas change due to muscular hyperplasia was considered uncertain (online supplemental table 2; statement sections BN).
Additional statements can be found in online supplemental appendix 1.
DISCUSSION
Identification of effective treatment for stricturing CD is one of the most important and greatest challenges facing the IBD research community and clinicians. Furthermore, development of robust biomarkers and trial outcome measures is required for successful drug development in this field. However, before progress can be made towards this goal, a valid instrument to evaluate the histopathology of small bowel strictures in CD resection specimens is needed. This instrument would serve as a foundation for the validation of non-invasive imaging technologies and biomarkers critical to the evaluation of new treatments, and a lack of such a tool is a rate-limiting step towards progress. Therefore, creation of a fully validated histopathological scoring system is a research priority. This will not only assist drug developers through validation of clinical trial endpoints, but will also benefit clinicians and patients due to the future availability of effective antifibrotic therapies.
The STAR Consortium is an international group with a mission to build endpoints for clinical trials in fibrostenosing CD.37–39 Initial steps towards development and validation of a stricture histopathology scoring system included a systematic review of existing histopathological scoring systems for small bowel stricturing CD.23 In this review, we identified important limitations to the existing scoring systems, for instance, significant heterogeneity among the scoring systems and none of the scoring systems were developed using the required rigorous evaluative methodological standards. Additionally, the operating properties (reliability, responsiveness) of the scoring systems had been inadequately studied.40 Importantly, we found that the complex multilayer and multicellular changes that are intrinsic to small bowel strictures were not adequately reflected in the scoring systems. A histopathological index should measure these distinct processes independently in each layer.
The RAND/UCLA24 exercise described in this paper is the second step towards establishing a valid stricture histopathology scoring system. We developed a comprehensive list of statements based on systematic literature review23 and expert opinion and evaluated the appropriateness of various histopathological methods, scoring systems and definitions. This widely accepted approach was chosen to combine the best available evidence with the histopathologic and clinical experience of international experts.
Key findings based on appropriate panel ratings are summarised in table 1. Naïve and anastomotic strictures can be diagnosed by gross pathology alone using the criteria of bowel wall thickness, decreased internal circumference or decreased luminal diameter. One recommendation based on this exercise is that each of these findings should be compared with healthy adjacent bowel in individual patients. Interestingly, the panel was uncertain regarding the value of prestenotic dilation for diagnosing strictures. This observation, in contrast with the previously devised radiologic definitions of CD strictures,39 may be explained by the fact that faecal stream leads to increased pressure upstream of luminal narrowing and bowel dilation, a feature that cannot be recapitulated ex vivo. Although gross morphology of naïve and anastomotic strictures was considered separately, no major differences in the appropriateness of the relevant statements considered in this study were observed. After discussion, the consensus panel determined that the interindividual variability of the human gut precluded the use of metrics such as mm, in the definitions. Definitions were intentionally ‘vague’ as comparison the healthy bowel of the same patient is considered the most accurate metric for comparison. The reliability of this assumption/metric will be evaluated in an ongoing reliability study.
Based on the panel’s rating of appropriate technical parameters, histopathological sampling should ideally be performed perpendicular to the direction of flow and a minimum of one cross section should be taken per centimetre of stricture, a method that reflects the heterogeneity within CD-associated strictures. The only stain considered mandatory for diagnosis of small bowel strictures was H&E. Matrix enhancing techniques were not deemed essential. Multiple techniques to quantify fibrosis on tissue sections exist and may become relevant for a future fibrosis score and are discussed and summarised in the Supplemental Material (online supplemental appendix 1 and supplemental table 3).
As previously mentioned, histopathological features of naïve and anastomotic strictures were considered collectively based on the opinion of the panel that these entities are histopathologically similar. Strictures were defined as an increased thickness of all layers of the bowel wall both in areas of wrapped fat and in areas away from wrapped fat. The increased thickness of the strictured bowel wall appears to be explained by widening of the muscularis mucosa and muscularis propria. While fibrosis of the submucosa was considered a critical feature for diagnosis, the panel remained uncertain regarding appropriate definitions for this finding. The development of well-accepted and standardised definitions for submucosal fibrosis will be an important step towards a histopathology scoring system. This is being explored in ongoing reliability exercises.
Based on panel ratings, a clear distinction between active inflammation (neutrophils, erosion and ulcers) and chronic mucosal injury (architectural changes) can be made. Appropriate novel features of transmural disease were defined in this study. This is particularly noteworthy given that all validated scoring systems (references can be found in previous works41–43) have focused exclusively on mucosal biopsies that do not typically extend deeper than the superficial submucosa. A critical role for the muscularis propria in stricturing CD has recently been highlighted and summarised in several publications, as thickening of this layer may be the strongest contributor to luminal narrowing in CD.32 44 45 Based on panel responses, this thickening is believed to result as a consequence of hypertrophy and fibrosis in the muscle layer. Strikingly, no single histopathological feature was considered critical or mandatory for defining strictures, perhaps reflecting the multifactorial nature of the stricturing process. Combinations of individual items were not queried for defining a stricture and this may also be relevant. This potential is being explored in ongoing reliability studies.
None of the previously published scoring systems that include assessment of both inflammation and fibrosis were considered appropriate by the panel for assessment of small bowel strictures. This outcome reflects the panel’s opinion that the existing scoring systems have not been developed adequately nor validated for this context of use. This heterogeneity of histopathology scoring systems prevents direct comparisons across studies.37 The panel extensively discussed whether a detailed score should be proposed in this publication, but there was a strong consensus to defer such a recommendation until further research has been completed. This opinion is rooted in the need to develop and validate a future score based on contemporary methodological standards that include assessment of index validity, reliability and responsiveness.46 The panel agreed that a pragmatic approach to generate items for a future reliability study would include (1) separate assessment of all mural layers, (2) evaluation of each anticipated pathological process (eg, fibrosis, muscle hyperplasia, etc) separately among the mural layers, followed by (3) determination of whether aggregate or individual scoring of layers is most appropriate. The panel also advised that a future CD stenosis scoring system may include histopathological changes unique to each mural layer, for example, fibrosis in the subserosa, hypertrophy/hyperplasia and fibrosis in the muscularis propria, fibrosis and muscularisation in the submucosa and hypertrophy/hyperplasia and fibrosis in the muscularis mucosa. A four-tiered scoring system (eg, none, mild, moderate, severe) applied to each site (ie, mucosa, muscularis mucosa, submucosa, muscularis propria and subserosa) could also be considered. Definitions for qualitative items such as muscularisation of the submucosa are not trivial and the reliability study includes development of a training manual for assessment that includes representative tissue sections definitions for each item. We recognise that refinement of definitions may be required for items with suboptimal reliability. To this end, we should re-emphasise that the steps described above are required prior to the development of a validated scoring index. Proposed example items that will be considered in the reliability study are included in table 2. We chose terminal ileal CD as the previously proposed ‘ideal’ study population for a proof-of-concept clinical trial.12
Table 2.
Proposed items based on the RAND/UCLA process for further consideration for index development
| Fibrosis items | Inflammation items |
|---|---|
| Mucosa | Mucosa |
| Fibrosis | Neutrophils in lamina propria |
| Muscularis mucosa thickening | Neutrophils in epithelium |
| Erosion | |
| Submucosa | Ulcer |
| Fibrosis | Lymphoplasmacytic infiltrates in lamina propria |
| Muscularisation | Crypt architectural distortion and loss |
| Fat content | Pyloric gland metaplasia |
| Nerve content | Paneth cell hyperplasia |
| Muscularis propria | Bowel wall |
| Fibrosis | Lymphoid aggregates |
| Thickening | Fistula |
The inflammation and fibrosis items are proposed to be included on the pathway towards a validated score. The type of scoring system (dichotomous, semiquantitative, categorical, etc) remains to be determined using reliability and responsiveness exercises.
UCLA, University of California Los Angeles.
The strength of our study lies in the inclusion of internationally recognised IBD histopathologists and clinical experts and use of rigorous methods to minimise bias. Items identified in this study are not intended to be considered in isolation, and although statements were rated appropriate, their operating properties are largely unknown. Our study has some limitations. Given that research in stricturing CD is sparse, and that no randomised controlled trials have been conducted, most of our recommendations are based on observational data that are vulnerable to bias. Assessment of statement appropriateness was subjective because no validated scoring systems currently exist. However, the methods used in this study are recommended as precursor steps to the development of evaluative scoring systems, and an extensive and iterative process based on the outcomes is currently underway. Given the possible limitations of isolated evaluation by traditional histopathology in this context, ‘high resolution’ cross-sectional imaging of strictures in vivo or ‘medium resolution’ imaging of surgical specimens ex vivo may provide complementary tissue architectural information to enhance scoring systems.
In conclusion, modified RAND/UCLA methodology was used to standardise CD histopathology definitions and statements to aid development of a CD stricture histopathology scoring system. Initiatives are currently underway to determine the reliability of relevant items identified in this study. Development of a fully validated set of standardised criteria assessing both inflammation and fibrosis in a global score for use in clinical trials and for drug development is the final goal. The precise contribution of the affected bowel wall layers to the process of stricture formation is unclear; therefore, considering each histopathological component separately in all bowel wall layers may be a sensible approach. It should also be determined whether an aggregate score based on a summation of findings in all layers or an approach based on scores of individual layers or a single layer is optimal. As few items can be scored on a continuous scale, semiquantitative scales applied to each layer may be most appropriate. Finally, this new histopathology scoring system will enable the development of novel biomarkers and support the construction of imaging endpoints for clinical trials in stricturing CD.
Supplementary Material
Significance of this study.
What is already known about this subject?
Cross-sectional imaging is currently being considered for use in clinical trials of stricturing Crohn’s disease (CD), an area of great clinical need.
Histopathological findings from subsequent surgically resected specimens are the gold standard for correlation with cross-sectional images for evaluation of intestinal strictures.
No validated histopathological scoring systems for small bowel stricturing CD are currently available, which also constrains progress for the validation of cross-sectional imaging in clinical trials.
What are the new findings?
Naïve and anastomotic strictures can be diagnosed by increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa.
Histopathologically, a stricture is accompanied by microscopic changes that may include increased thickness of all layers of the bowel wall compared with adjacent healthy bowel wall, fibrosis of the submucosa or bowel wall, muscularisation of the submucosa, or increased thickness of the muscularis mucosa compared with adjacent healthy bowel wall.
None of the existing histopathological scoring systems for evaluation of strictures were considered valid and appropriate for use in clinical trials.
How might it impact on clinical practice in the foreseeable future?
These consensus criteria for small bowel stricturing CD will standardise gross pathological and histopathological assessment, as well as inform development of a validated histopathology score that can be used in clinical trials.
Funding
All authors approved the final version of the manuscript. This work was supported by grants from the National Institutes of Health (K08DK110415, P30DK097948 and R01DK123233) to FR and the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium to FR, BGF and JGF. WJS is supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).
Competing interests
IOG receives grant support from UCB, Celgene, Morphic and Pliant Therapeutics. DB is on the advisory board or consultant for Amgen, AbbVie, Celltrion, Dr Falk Foundation, Ferring, MSD, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts Pharma and Vifor. GdH reports fees to his institution (KULeuven) for his participation as a central pathology reviewer in clinical trials sponsored by GlaxoSmithKline, Shire Pharmaceuticals, Teva Pharma, Galapagos, Genentech, Novartis Pharma, Fast Forward Pharmaceuticals, Takeda and Janssen R&D. MR reports Merck, speaker panel; Bayer, pathologist on a clinical trial; Chief Scientific Officer of Beyond Celiac, a non-profit patient support organisation, outside of the submitted work. NH is a consultant for AbbVie, BMS, Celgene and Lilly USA. PB reports personal fees from MSD, personal fees from Roche and personal fees from AstraZeneca, outside the submitted work. RiKP has received consulting fees from Genentech, Eli Lilly, Allergan, AbbVie and Alimentiv. RF is a central reader for Alimentiv (formerly Robarts Clinical Trials) and received speaker’s fees in 2020 from Takeda. CEP, LG, LMS and TN are employees of Alimentiv. WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv (formerly Robarts Clinical Trials), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences. Spouse: Iveric Bio—consultant, stock options; Progenity—stock; Oppilan Pharma—consultant, stock options; Prometheus Biosciences—employee, stock, stock options; Ventyx Biosciences—stock, stock options; Vimalan Biosciences—stock, stock options. VJ receives salary support from the John and Susan McDonald Endowed IBD Chair at Western University, London, Ontario, Canada; has received has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Pfizer, Fresenius Kabi, Bristol Myers Squibb, Roche, Ferring, Sandoz, Merck, Takeda, Janssen, Alimentiv (formerly Robarts Clinical Trials), Topivert, Celltrion, Mylan, Gilead; speaker’s fees from Takeda, Janssen, Shire, Ferring, AbbVie, Pfizer. MB receives no direct support. Cleveland Clinic receives support for him from Siemens Healthineers in the form of salary, software and hardware for the investigation of reduced exposure in CT Enterography, as well as from The Leona and Harry Helmsley Charitable Trust and from Pfizer grants through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium in the form of salary. DHB is a consultant for and receives research support from Medtronics, and receives research support from Takeda. JGF receives research funding support from grants from Siemens Healthineers, Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium, Takeda Pharmaceuticals and National Institutes of Health (R01 EB017095, U24 EB28936, R01 DK120559). Funds from all grants are paid to Mayo Clinic. He is a consultant for Takeda Pharmaceuticals, Medtronic, Janssen, Pfizer, GlaxoSmithKline and Boheringer-Ingelheim, with fees paid to institution. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, AstraZeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie and J&J/Janssen. FR is on the advisory board or consultant for Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene/BMS, CDISC, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Janssen, Koutif, Mestag, Metacrine, Morphic, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB. AB, CR, JI, ReKP, LMS, MAV, RF, RO and RM report no conflicts of interest.
Footnotes
Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/gutjnl-2021-324374).
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.