Dr. Yago González Lama
Hospital Universitario Puerta de Hierro- Majadahonda. Madrid
Gastrointestinal endoscopy has always been an essential tool in the diagnosis and follow-up of Crohn’s disease (CD), due to its nature as well as because of the medical specialists who are responsible for these patients, usually gastroenterologists with quick and simple access to endoscopic techniques.
However, for many years, the role of endoscopy in the follow-up of CD has not been totally clear, since more importance is being given to the patients’ clinical condition when making therapeutic decisions. It hasn’t been until recently that more importance has been given to the condition of the mucosa: the appearance of new biological treatments, just over a decade ago, has brought physicians to uncharted waters and, therefore, to new concepts on the nature of the disease and its management. Among them, the concept of mucosal healing (MH) is noteworthy, since, for the first time, it is possible to prove how the use of this type of treatment can be accompanied by not only clinical improvement, which is the ultimate goal of any therapeutic intervention, but also the disappearance of the endoscopic lesions that define the disease; whether or not this fact has any relevance for patients, it is something that we have been learning about over the past few years. Certainly, although it seems more clear that MH should be an objective when of designing efficacy studies for drugs in CD, in many cases this concept does not easily lead to standard medical practice.
VALUE OF MUCOSAL HEALING IN THE FOLLOW-UP OF CROHN’S DISEASE
It is best to try not to approach this topic solely from an endoscopic point-of-view, nor focus on the results of the various randomised trials via which the concept of MH has gained significance. The authentic value of MH can only be understood if we put it within the right context.
The knowledge we have on the progression of CD enables us to ensure that it is a chronic disease that can become incapacitating, and that the inflammatory disease activity is accompanied by structural lesions that the can become irreversible despite being able to control the former. Therefore, the mere control of symptoms does not ensure that the patient will be free from the long-term consequences of his or her disease1. In this regard, the tools at our disposal in medical practice to predict the disease progression in each case are scarce and almost fundamentally focused on clinical variables, such as age or the presence of perianal disease, which we should consider when determining the initial therapeutic strategy2,3.
Morever, today we know that the earliest stages of the disease are accompanied by a greater inflammatory component and therefore treatments administered earlier have a higher therapeutic potential and perhaps the possibility of changing the course of the disease by preventing bowel damage, functional impairment or complications such as fistulae or stenosis4,5; in fact, current recommendations highlight the importance of identifying patients who are at risk of poor progression, so they can be treated early and aggressively6.
In this manner, it has been confirmed that, in addition a better control of the disease symptoms, very high levels of MH are reached: in a European randomised study, 133 recently diagnosed patients were followed up on and divided into 2 cohorts, one received a conventional, “Step-up” approach and the other received the combined thiopurine and biological treatment from the “Top-down” diagnosis . At the end of 2 years of follow-up, it was possible to confirm that the more aggressive treatment strategy was accompanied by a better control of the disease, in terms of clinical remission and steroid sparing, in addition to the very significant MH rates, which were around 70%7. Furthermore, the SONIC study, in which 500 recently diagnosed patients were randomised in order to receive azathioprine or infliximab monotherapy, or both treatments combined, confirmed at the end of Weeks 26 and 50 that those who received the more aggressive treatment from the beginning not only were more likely to achieve better control of the disease, namely steroid-free clinical remission, but they also achieved higher MH rates8.
There are numerous data suggesting that the presence of MH, beyond mere clinical response, changes the patient’s progressions. In the IBSEN study, a Norwegian cohort of 354 patients with ulcerative colitis and 141 patients with CD who were followed up on for 5 years between 1990 and 1994 (before biological treatments became available), it was possible to confirm how MH was a marker for good progression, since it is associated with a lesser need for treatments and lesser need for surgery9. Since then, in scenarios more similar to current medical practice, various works have yielded results that reinforce this idea from different points of view. Thus the experience of Lovaina in the use of infliximab in medical practice in a single site with 614 consecutive patients, after an average follow-up of 55 months, proves not only the usefulness of this treatment to induce MH, but also that patients who achieved it had a better progression, which translated into a lesser number of hospitalisations and surgeries in this group10; on the other hand, the 4-year “Top-down”/”Step-up” study reveals that patients who achieved MH had a better progression and were able to control their disease and thus maintaining steroid-free remission at a higher rate than the group that did not achieve MH11; likewise, the presence of MH has also been related to improvement in the patients’ quality of life12,13.
The scenario that is possibly clearer to physicians is the post-surgical role that MH plays. The Rutgeerts Index classifies patients who undergo ileocaecal resection, based on the presence of endoscopic lesions six months after surgery and, thanks to this, it is capable of predicting the possibility of clinical recurrence. Hence, patients without lesions in the neo-terminal ileum (i0), or with very few lesions (<5 aphthae, i1 [Fig. 1]) have a less than 10% chance of experiencing a recurrence at 10 years; on the other hand, patients with significant endoscopic lesions, such as the presence of diffuse aphthous ileitis on the oedematous mucosa (i3, Fig. 2) or diffuse mucosal inflammation with ulcers, nodules or stenosis (i4, Figs. 3), are very likely to experience a clinical recurrence (up to 70% in the first year) and are highly likely to undergo re-operation. The intermediate stages deserve special mention, such as the presence of more than 5 aphthous lesions with normal mucosa between the lesions, or the presence of larger, discontinuous lesion areas on the normal mucosa, or even the presence of ulcers in anastomosis (i2, Fig. 4 and Fig. 5), which appear to have up to a 40% chance of clinical recurrence at 5 years. Taking all this into consideration at the present moment, and despite being an index that has never been validated, it is agreed that patients who present more severe lesions must receive immunomodulatory treatment, even when they are asymptomatic, since the chance of clinical recurrence and short-term complications are high14,15.
Hence, the concept that physicians have had regarding the treatment of the disease has evolved throughout recent years and has gone from merely treating the symptoms and complications of the disease to preventing these symptoms and complications, marking as therapeutic objectives clinical remission and steroid sparing, and later deep remission, which includes, in addition to clinical remission, many other variables that have actual repercussions on patient’s lives and prognoses, such as biologic remission, endoscopic remission, improvement of quality of life, growth in the case of paediatric patients, and the reduction of entries or surgeries13.
LIMITATION OF MUCOSAL HEALING IN THE FOLLOW-UP OF CROHN’S DISEASE
Despite that from a clinical standpoint the importance of MH is accepted in the assessment and follow-up of CD, there are numerous disputed limitations and aspects that easily limit the conversion of these concepts into daily medical practice. In fact, the clinical application of the concept of MH as a clinical marker and therapeutic objective still has not been addressed in the most recent clinical practice guidelines, since response, remission and relapse continue to be defined solely from a clinical standpoint6. Despite there being a clear lack of correlation between the endoscopic activity of the disease and clinical activity16-18, the truth is that to date no other therapeutic objective has been clearly established or universally accepted. This lack of correlation between the clinical and endoscopic situation, both in one sense as well as the other, causes certain confusion for the physician: there is a group of patients that experience improvement from the symptoms but not from the endoscopic findings, which is demonstrated by the difference that is found in clinical trials between the patients who achieve clinical remission but not MH8,10,19. On the other hand, and although in accordance with the results from different studies and from clinical experience, it seems easier to achieve clinical remission than MH. It is nevertheless true that there are patients who remain symptomatic despite having achieved MH; for example, in the “Top-down”/”Step-up” study, there are more patients in clinical remission with MH in the “Step-up” arm, while in the “Top-down” arm the exact opposite occurs, since the number of patients who achieve MH is higher that the number of patients who achieve clinical remission7. The discrepancy between the clinical and endoscopic situation can therefore be very evident and confusing.
Another aspect that also complicates the transfer of MH from trials to clinical practice is the lack of uniformity in its definition. The absence of ulcerated lesions is the most accepted17, although it is true that this definition does not consider any of the other milder type of lesions that are unequivocally linked to CD, such as oedema, erythaema, some stenosis, etc. Moreover, other works adhere to low endoscopic activity index scores, generally CDEIS <4 points; this possibility also has many limitations, since it does not deal with simple indices that can be performed on a routine basis, which turns MH into something that is unattainable in daily medical practice. Not having the cut-off point is arbitrary and accepts the presence of any type of lesion, even ulcerated lesions20. It must be remembered that this type of index tends to underestimate severity when the extension is short, and overestimate it when dealing with an extensive disease (Video 1 and Video 2).
Deciding what would be the method and frequency with which the presence of MH in a patient in clinical remission would be assessed is also certainly disputed when incorporating MH into medical practice. Ideally, it should be a conventional colonoscopy, but it is an invasive, expensive, a priori procedure that is unlikely to be accepted by patients. Capsule endoscopy, due it its barely invasive nature, could be an attractive alternative in cases in which the small intestine is involved; although it is known that this method is capable of detecting lesions in a significant proportion of patients who do not undergo conventional endoscopy, the clinical significance of this type of lesion is still uncertain and, in addition, there is no validated index that enables it to be properly interpreted12,16. Magnetic resonance enterography enables the exclusion of any stenosis capable of causing complications in a study via capsule endoscopy, and it has shown a good correlation with endoscopy in colonic lesions. It has even been postulated as an alternative in cases of incomplete colonoscopies, although its role in this scenario is still undefined, as it will be addressed later on12,21,22.
But what really limits the incorporation of MH as a therapeutic objective into medical practice is the fact that, although the benefit of MH has been reported with all the therapeutic alternatives available, to a greater or lesser extent, with none of them is MH achieved in all cases, which is why therapeutic escalation does not ensure the achievement of MH. This aspect is especially disputed in the case of patients who are in clinical remission, symptom-free, and for whom assuming the risk that intensification or escalation poses in treating their disease is not always easy to justify23-25.
ENDOSCOPIC ACTIVITY INDICES IN CROHN’S DISEASE
Endoscopy can be an essential tool when assessing the activity and extent of the disease, establishing the prognosis and even assessing the response to various treatments. The most objective, standardised way to use this tool is the use of endoscopic indices, which try to classify each case based essentially on the severity of the endoscopic findings. In this regard, we can find two types of endoscopic indices: qualitative, which establish severity levels for the disease (inactive, mild, moderate, severe), and quantitative, which assign a numerical value to each of the variables considered and which, although they could be more accurate than the former, the fact is that they are usually complex and tedious, which is why their use is usually restricted to research.
In any case, the ideal activity index should use concepts that are commonly used by endoscopists and well known by physicians. It should also consider endoscopic lesions insusceptible of having interobserver variability to be reproducible, quick and simple, provide qualitative and quantitative results and be validated in regards to sensitivity, specificity and positive and negative predictive value. However, achieving all this for CD is difficult and, therefore, in medical practice we have limited tools.
The first validated index for assessing CD is the Crohn’s Disease Endoscopic Index of Severity (CDEIS [Table I]), proposed by the French group GETAID in 1989. It is based on the identification of elemental lesions as superficial and profound ulcers, or as the presence or absence of ulcerated stenosis, present in every one of the five segments evaluated (ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum). Of these five segments, the proportion of ulcerated surfaces or any type of lesion is recorded on a visual scale, in such a way that the combination of all values enables the calculation of a numerical degree of severity between 0 and 44, with the highest score corresponding to the highest severity26. It is a highly important index, since it was validated, is reliable and reproducible, with little interobserver variability, in such a way that it has come to be considered the gold standard for MH27,17; however, it is a complex, impractical index, poorly correlated to clinical activity and barely applicable to daily medical practice28; furthermore, it is not exempt from limitation, basically because it tends to underestimate severe, inextensive lesions (for example, in an exclusively ileal impairment) and because there is no clearly set value for defining endoscopic remission. In this regard, various cut-off points are suggested, which are more and more restrictive, with the most current tendency being to consider a cut-off point of 3 or 4 points
in order to establish MH or endoscopic remission20,29,30.
After 15 years, a similar index was published but it was intended to exceed the previous in simplicity and applicability, which is why it was called the Simple Endoscopic Score for Crohn’s Disease (SES-CD, Table II). It emerged in order to serve as a useful tool both in clinical practice as well as in the field of research, in a simpler and more comfortable way, being validated and also having demonstrated an excellent correlation with CDEIS, which is considered a benchmark, but also with clinical and biological activity18,29,31-33. However, being an index similar to the previous one, it has the same limitations, since it tends to underestimate the severity of shorter involvements, such as isolated ileal disease, and there is no cut-off point that defines remission or MH in a universally accepted manner, although it is commonly accepted that between 0–2 points the disease would be endoscopically inactive.
Lastly, the endoscopic activity index that is actually implemented in medical practice, even despite not having been validated, is the Rutgeerts Index for assessing post-surgical recurrence, since it is able to stratify the severity of the recurrence and assign each stage a probability for clinical relapse, based on which it is generally accepted that the immunosuppressant indication can be established in order to prevent recurrence14, as previously explained. The fact that it has not been validated penalises this excellent tool, in such a way that there are certain gaps when interpreting endoscopic findings in light of this index. This is the case for the intermediate stage (i2), which initially included patients who had the involvement described in the neoterminal ileum (i2b, Fig. 4), but also those with anastomotic involvement. Over time, it has been speculated whether cases in which involvement is confined to the anastomosis (i2a, Fig. 5) could have a different, more favourable progression, which has been confirmed in some series34.
INDICATION OF ENDOSCOPY IN THE FOLLOW-UP OF CROHN’S DISEASE: DO WE HAVE ANY LESS AGGRESSIVE ALTERNATIVES?
The daily work of a gastroenterologist involved in treating CD always deals with the activity of the disease, and basically consists of detecting it, confirming it, localising it, quantifying it and ruling out complications that can accompany it; only in this way is the physician capable of planning a therapeutic strategy, adequately performing follow-up, establishing a prognosis and assessing the response to an intervention, whether medical or surgical. Therefore, there are many clinical scenarios in which assessing the disease activity is essential for making any decision throughout the follow-up of CD. This not only includes cases in which the presence of symptoms causes suspicion regarding the existence of active disease, or causes doubt; in asymptomatic patients, whether the disease is adequately controlled must also be continually reviewed, since the absence of symptoms does not exclude poor disease control, which is usually associated with a poor diagnosis. The physician’s problem is that he or she never has access to all the information necessary to make the best decision at the time, since the tools available have, even today, many limitations.
Clinical activity indices are the most commonly used tool; they basically measure symptoms and, therefore, have a subjective nature. Their lack of correlation with endoscopic activity shows that the mere presence or absence of symptoms cannot be considered, in many cases, a reliable marker of disease progression; in other words, what has been traditionally considered a clinical-endoscopic dissociation characteristic of the disease is indicated by a poor correlation between the clinical indices and the endoscopic disease activity indices, which is perhaps less noteworthy in the case of SES-CD28,35,36. As previously discussed in this chapter, clinical evidence that the absence of symptoms is not a sufficient marker for good progression has in many cases caused physicians to delve into the concept of deep remission and MH.
Another commonly used tool are biological disease activity markers, also called biomarkers. Although its combination with clinical parameters constitutes standard practice in many cases, especially in the follow-up of patients with CD, it is nevertheless true that it is a strategy not exempt from limitations. Certainly, the most used biomarker is serum quantification of the polymerase chain reaction (PCR), since it is not influenced by any treatment and maintains a close relation to the variations of the underlying pathological process, which is why it is generally considered a reliable marker of disease progression, and it has even been confirmed that elevated PCR levels are associated with a high probability of response to biological treatments in patients with CD. However, its main limitation is the lack of specificity for CD and the unquestionable fact that a relevant proportion of patients, traditionally established at 10–20%, do not present serum PCR elevation accompanying inflammatory disease activity37,38. Faecal markers deserve special mention, though initially not considered due to the discomfort involved when working with this type of sample, and due to their possible interaction with the concentration of anti-inflammatory drugs or proton-pump inhibitors. However, both calprotectin and faecal lactoferrin are specific for intestinal pathology since they imply expression in the faeces of neutrophil migration to the intestinal mucosa, are very stable in faeces and are determined via simple and inexpensive procedures such as ELISA. Thus, it has been suggested that high calprotectin levels in faeces could relate to more severe lesions, and that the normalisation of calprotectin values could be an reliable indicator of MH37. More recent studyes have managed to establish a cut-off point in faecal calprotectin concentrations
(250 µg/g) for the presence of mucosal lesions, as well as to identify the normalisation of faecal calprotectin as a factor for a good prognosis compared to the maintenance of clinical remission in patients on biological treatments32,39.
In reality, the ideal tool would be endoscopy, since it is able to precisely assess the condition of the disease in situ, which allows us to draw conclusions about the benefits of the therapeutic strategy in each specific patient and act accordingly. However, its invasive, uncomfortable, not risk-free nature40 hinders its generalised use and requires that it be kept only for select cases in which an endoscopic assessment becomes indispensable. This circumstance seems evident in cases of long-standing Crohn’s colitis in which it is important to perform adequate early detection of dysplasia, but it also seems reasonable in cases in which there is doubt about clinical condition, namely cases in which there is a discrepancy between clinical symptoms and biomarkers, or even in some cases in which the decision to be made is especially relevant for the patient, such as therapeutic escalation, or even de-escalation, since the presence of endoscopic activity has been revealed as a poor prognosis marker in this scenario41-43.
Various radiologic techniques have been developed in order to assess the bowel without needing to resort to an invasive technique such as colonoscopy44. However, most cases do not deal with standardised techniques and its use is not generalised. Ultrasound, even with contrast, has many technical limitations and its yield depends immensely on the explorer, which is why the results from some highly specialised sites are not easily exportable to other hospitals. CT enteroclysis provides useful, relevant information with sufficient clinical impact, and although the use of ionising radiation limits its use, it is nonetheless true that increasingly better results are being obtained with less amounts of radiation45.
Magnetic resonance (MR) enterography is perhaps the current radiologic technique of choice, since it enables assessment of the activity, extent and severity of the disease, as well as the presence of complications such as stenosis, fistulae or abscesses, and it even assesses the therapeutic response to various treatments. All of this is facilitated by it being a quick, accessible and ionising radiation-free technique that has shown a superb correlation with the endoscopic findings of CD, particularly CDEIS, in such a way that a radiologic disease activity index has been designed and validated 21,46,47. Only time will tell whether the usefulness and reliability of MR enterography when assessing CD activity is sufficient in order to expand its use beyond the limits of clinical research, and whether it constitutes a useful tool in the follow-up of this type of patient, although it is highly likely that its noninvasive nature will enable the technique to be more frequently used in this scenario and we will increasingly have more access to information regarding its reliability and clinical impact48. However, there are some limitations in medical practice that could hinder this from occurring: the technical specifications of the MR device itself are not always adequate for performing this type of test properly and access to it is not easy in many sites or under many circumstances, which usually does not occur for endoscopy in the hands of gastroenterologists. There are other scenarios in which the use of CT or MR enterography has shown its usefulness in the clinical management of these patients, whether it be in the detection of complications such as abscesses and fistulae, in which they have proven to be better than barium or ultrasound techniques44,49, or in stenosis assessment, in which sectional techniques with luminal and intravenous contrast may allow a predominant inflammatory or fibrotic component to be distinguished, which could guide the therapeutic approach, although this has not been confirmed nor translated to medical practice50,51.
In conclusion, although it is conceivable that endoscopic assessment could normally be ideal for CD follow-up, thus detecting patients in which, even in the absence of symptoms, the disease is not well-controlled, this approach is not possible due to the invasive nature of the procedure. Hence, follow-up based on biomarkers and clinical signs and symptoms of disease activity could be acceptable in many cases, reserving colonoscopy for special cases in which a mucosal assessment is indispensable. Whether MR enterography is capable of improving this scenario and whether this type of disease-monitoring test can direct us is something that we will see in upcoming years.
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