Parts of this chapter have been reproduced with permission from Kumar et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Background
Crohn’s disease (CD), a subtype of inflammatory bowel disease (IBD), is a chronic bowel disorder of uncertain aetiology that is progressive, can affect any part of the gastrointestinal (GI) tract from mouth to anus and typically has a relapsing and remitting disease course.2–4 In nearly 50% of cases, disease involvement can also affect organs outwith the GI tract, including the joints, skin, eyes, liver, biliary tract and urinary tract.5,6 The severity of bowel inflammation ranges from mild, superficial mucosal disease to advanced, transmural involvement.7,8 CD is associated with considerable morbidity, especially when complications arise such as bowel strictures, fistulae and abscesses.9,10 CD patients often require regular hospital care that may include surgery, posing substantial financial burden to the NHS, exceeding £10,000 per patient annually for those in clinical relapse.11,12
Current treatment strategies for Crohn’s disease and prediction of disease course
Previously, the treatment of CD involved a stepwise approach guided by symptomatology, with the gradual escalation of drug therapy, including corticosteroids, immunomodulators through to biologics such as anti-tumour necrosis factor (TNF) agents.13,14 However, there is a disconnect between clinical symptoms and the degree of underlying inflammatory activity, so this symptom-directed approach risks severe bowel damage if there is uncontrolled subclinical inflammation.15,16 The REACT (Randomised Evaluation of an Algorithm for Crohn’s Treatment) trial compared early combined immunosuppression using anti-TNF agents and antimetabolites with conventional stepwise ‘bottom-up’ therapy.17 At 2 years, the risk of major adverse outcomes was lower in the ECI group, despite no difference in symptom control between the two groups. Similarly, the CALM (Effect of tight control management on CD) trial showed that timely escalation with anti-TNF therapy based on both clinical symptoms and biomarkers resulted in superior clinical and endoscopic outcomes to treatment decisions driven solely by symptoms.18 Most recently, the PROFILE (Predicting Outcomes For Crohn’s disease using a molecular biomarker) trial reported that top-down treatment resulted in significantly better outcomes at 1 year compared to accelerated step-up treatment.19
Therefore, there is increasing interest in early treatment with biologic and immunomodulator therapy in a ‘top-down’ fashion to reduce the risk of progressive disease and subsequent complications.20 Although these agents are highly efficacious for improving symptoms and promoting bowel healing, they are associated with side effects and are relatively expensive, so administering these to all CD patients is not efficient.3,6,21,22 However, there are no validated or consensus definitions for which patients are most at risk of progressing to severe/disabling CD.23–26 Readily available biomarkers such as haemoglobin, C-reactive protein (CRP) and faecal calprotectin (FC) have a role in prognostication but have not been studied in newly diagnosed patients.27
A currently unmet major clinical need is the ability to robustly identify CD patients at initial diagnosis who are most at risk of developing future severe/disabling CD.28 It would allow gastroenterologists to target early, aggressive treatment in those most likely to benefit, and avoid unrequired overtreatment in others, with better treatment targeting reducing associated side effects, complications and costs while improving outcomes.29
The role of magnetic resonance enterography and its potential to predict the development of disabling Crohn’s disease
Diagnosis and follow-up of CD relies increasingly upon imaging, given the invasive nature of endoscopy and its inability to assess the entire small bowel (SB).30–33 Magnetic resonance enterography (MRE) has become a first-line investigation for CD because it is highly accurate for identifying disease activity, its extent and distribution, assessing treatment response as well as delineating complications.34–39 It has the additional benefits of conferring no exposure to ionising radiation and is generally well tolerated by patients.40,41 As opposed to clinical biomarkers such as CRP and FC which only assess inflammation, MRE is well placed to quantify both bowel damage and underlying inflammatory activity concurrently.42 Given its excellent performance characteristics for staging and monitoring CD, it has been postulated that MRE may also be able to predict clinical trajectory, but a recent systematic review found that primary research evaluating cross-sectional imaging is lacking.43
Jauregui-Amezaga et al. studied 112 patients with CD relapse from a single centre and compared the ability of MRE and colonoscopy to predict future disease course, defined as the need for subsequent major abdominal surgery.44 The presence of perianal disease, strictures and/or fistulae on MRE were independent predictors of resection surgery, but severe endoscopic lesions were not, implying that underlying bowel damage rather than the degree of inflammation is more important for prognostication. Similar findings were reported by Fiorino et al. in a European study of 142 CD patients; bowel damage in the form of strictures, fistulae and abscesses was associated with significantly higher future risk of surgery.45 In a single-centre longitudinal study, Fernández-Clotet and colleagues studied 72 CD patients who had at least 5 years’ follow-up.46 They found that stricturing disease, fistulae and ileal disease were associated with progressive CD. Finally, in a single centre of 52 patients, perienteric inflammation, restricted diffusion, penetrating disease and fibrofatty proliferation on outpatient MRE were associated with CD patients progressing to resective bowel surgery within 5 years. Longer length bowel involvement and more significant upstream bowel dilatation from strictures were also found in those patients progressing to surgery.47
The above studies suggest that MRE may have a predictive role to identify patients that are destined to develop severe/disabling CD. However, none have specifically studied newly diagnosed patients, which is fundamental since it is at this initial stage that gastroenterologists could administer early aggressive treatment while refraining from unwarranted treatment in others. To address this, we undertook the Magnetic resonance Enterography or ulTRasound In Crohn’s disease Extended Follow-up (METRIC-EF) for predicting disabling disease trial to answer the question: ‘Do MRE features at diagnosis improve prediction of disabling CD within 5 years of diagnosis?’