# Diagnosis and Assessment of Crohn's Disease: The Present and the Future



## David in Seattle (Feb 13, 2011)

Gianluca Benevento; Claudio Avellini; Giovanni Terrosu; Marco Geraci; Ilva Lodolo; Dario Sorrentino

Expert Rev Gastroenterol Hepatol. 2010;4(6):757-766. © 2010 Expert Reviews Ltd.

Abstract and Introduction
Abstract

Diagnosis of Crohn's disease (CD) is often challenging and requires the utmost precision and perseverance in defining location, extent, severity and type of disease (inflammatory vs stricturing/penetrating), as well as in excluding septic complications and extraintestinal manifestations. Endoscopy and histology remain, as of today, the best tests for initial diagnosis of CD. Increasingly important roles are played by imaging techniques (small bowel MRI, computed tomographic enterography and intestinal ultrasound) and noninvasive markers of disease such as fecal calprotectin and specific autoantibodies. Here, we will review the main tools presently available to make the initial diagnosis of intestinal and perianal CD, to evaluate the response to treatment and to diagnose disease recurrence after surgery. Finally, we will discuss some of the future diagnostic challenges in CD.
Introduction

An accurate diagnosis of Crohn's disease (CD) represents a fundamental step in the general management of this disorder. This is true for CD more so than for other gastrointestinal disorders. CD diagnosis is challenging and requires the utmost precision and perseverance. Much of the difficulty comes from it's often 'difficult to reach' anatomic location and from the necessity to carefully define the extent and the severity of the disease, including the presence of septic complications and extraintestinal manifestations, all factors that may affect subsequent therapeutic decisions. CD can be limited to the intestine (in most cases the terminal ileum and colon) or affect the perianal region as well. Owing to its location and clinical features, CD may be mimicked by several intestinal and pelvic diseases such as appendicitis, Meckel's diverticulum, Yersinia enterocolitis and intestinal TB, as well as pelvic inflammatory disease, ovarian disorders, endometriosis and other gynecologic and abdominal diseases. Most importantly, the clinical picture of CD often overlaps with irritable bowel syndrome (IBS). Indeed, in clinical practice, it is not infrequent to encounter CD patients whose clinical management has been unduly delayed by the wrong diagnosis of a functional disturbance. Both IBS and CD affect young people, may present with abdominal pain and diarrhea, and can be exacerbated by stressful life events. There is no clear clinical feature that helps in distinguishing the two conditions unless CD is advanced and presenting with complications/red-flag signs (e.g., bleeding, weight loss and anemia). Since histology (and therefore endoscopy) is an important element in the initial diagnosis of CD, one of the major problems remains whether to promptly recommend colonoscopy in the presence of suggestive symptoms or to approach the patient with less-invasive tests. This issue partially overlaps with another aspect of modern CD management, that is, early diagnosis. Early diagnosis is fundamental for an effective clinical management because it may allow early therapy which, in turn, can change the natural history of the disease. Finally, it would be desirable to establish, by diagnostic tests, the duration of mucosal damage (and hence its degree of evolution) – rather than clinical disease – an aspect that may also bear implications for clinical management and the selection of patients for clinical trials.

In this article, we will review the main tools presently available to make the initial diagnosis of intestinal and perianal CD, to evaluate the response to treatment and to diagnose disease recurrence after surgery. Finally, we will discuss some of the future diagnostic challenges in CD.


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## David in Seattle (Feb 13, 2011)

Initial Diagnosis of Intestinal CD

The first diagnosis of intestinal CD often relies essentially on endoscopy and histology. However, for disease limited to the small bowel, imaging, blood and fecal tests, as well the clinical picture, play an important role.
Clinical Picture (History & Physical Findings)

The clinical picture of CD is largely dependent upon the localization, extent and severity of the disease itself. Extent and severity, in turn, may be a function of disease duration, since CD tends to extend locally and evolve over time from an inflammatory to a penetrating/stricturing disorder.[1] In addition, the likelihood of complications such as perianal disease, extraintestinal manifestations and septic complications increases over time.[2] Often, especially in patients in whom the initial diagnosis of CD had been unduly delayed by a diagnosis of IBS,[3] it is not unusual to find a complicated, advanced picture.

Still to this day, at the time of diagnosis, approximately 85% of patients complain of diarrhea (more than five loose bowel movements per day for at least 6 weeks).[4,5] Diarrhea is essentially due to inflammation, although nutrient and bile acid malabsorption may contribute to the symptoms.[4]

Abdominal pain is described in approximately 70% of cases, especially in the right lower quadrant (due to disease localization in the terminal ileum/cecum), and is often mistaken for acute appendicitis.[4] The genesis of pain is unclear, and may be related to intestinal strictures, if present. However, abdominal pain can also be simply associated with bowel inflammation.[4] In a typical patient, abdominal pain has been present for several months or even years before diagnosis.[3]

Weight loss, weakness and anorexia may be present in up to 60% of patients. Bloody stools and mucus are present in a variable percentage of patients (usually much smaller than in ulcerative colitis) at diagnosis, while tenesmus is restricted to patients with proctitis.[6] Finally, extraintestinal manifestations may be present in approximately a third of patients, with bone, skin and eye most frequently affected.[7] Depending on the context (i.e., the type of clinical practice, see later), 10–30% of patients may present with perianal disease, with obvious pain and/or discharge in the region.[8] Physical examination may trigger pain in the affected area or reveal the presence of fistulas, abscess or other complications.
Blood & Fecal Tests

There is no specific blood or fecal test that is diagnostic for CD. Elevated white blood cell, C-reactive protein, erythrocyte sedimentation rate (ESR) or platelet count are obvious signs of inflammation, especially in the presence of extensive/colonic disease. In case of blood and nutrient loss, the patient may present with anemia and/or low albumin levels.

Elevated CRP levels are associated with moderate-to-severe clinical activity in up to 45% of cases, and in up to 65% of cases with endoscopically visible inflammation.[9] However, there seems to be substiantial differences in the correlation between CRP and disease activity among individual CD patients, possibly due to genetic polymorphisms in CRP levels (reviewed in[10]).

Correlation between ESR and disease activity is usually poorer and has been reported in up to 30% of cases,[11] more often for colonic disease.

Fecal calproctectin and lactoferrin represent a large portion of total cytosolic protein in polymorphonuclear leukocytes. Therefore, their concentration in the feces is interpreted as a measure of polymorphonuclear leukocytes migration in the inflamed intestinal mucosa. Although very sensitive for intestinal inflammation, these markers lack specificity and can be found increased in a variety of disease states such as neoplasias, polyposis, NSAIDs use and increasing age.[12] Both fecal calproctectin and lactoferrin appear more sensitive then fecal elastases or CRP in diagnosing CD,[10] with calprotectin being slightly more accurate than lactoferrin.[9,12]

Importantly, these markers are extremely useful in distinguishing IBS from inflammatory bowel diseases (IBD), a crucial step in the initial evaluation of young patients with abdominal symptoms,[13] with a reported sensitivity of 89–98% and a specificity of 81–91%. Indeed, these tests have quickly become an extremely useful tool in the differential diagnosis of functional bowel diseases versus IBDs.

More sensitive and specific blood tests for CD are the anti-Saccharomyces cerevisiae antibodies (ASCAs) and perinuclear antineutrophil cytoplasmic antibodies (pANCAs). ASCA is an antibody against oligomannosidic epitopes associated with phosphopeptidomannan and other mannoproteins in the cell wall of the yeast S. cerevisiae.[14] ASCAs in IBD patients may be directed against S. cerevisiae itself or against an antigen that cross-reacts with S. cerevisiae antigens.[15] ANCAs are autoantibodies directed at antigens present in azurophilic granules of neutrophils.[14] There are two major staining patterns in immunofluorescence: cytoplasmic granular ANCAs and pANCAs, the latter being associated with IBDs. ASCAs are present in 60–70% of CD patients; by contrast, pANCAs are present in only 5–10% of cases.[16] The positive predictive value for CD for the combination ASCA+/pANCA− appears to be 92.5%.[16] However, the real value of these antibodies is in the discrimination of cases of indeterminate colitis, an initial diagnosis made in 10% of cases of IBDs. The combination of ASCA+/pANCA− predicts a subsequent diagnosis of CD in 80% of cases of indeterminate colitis, while the opposite combination predicts ulcerative colitis in 64% of cases. However, approximately 50% of patients initially diagnosed with indeterminate colitis will not develop such antibodies over time.[10] An interesting study from Israeli et al. suggests that ASCAs may be useful in predicting the development of CD before the clinical onset since, in that study, they were present in 31% of patients years before the actual diagnosis.[17]

New serological markers such as anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA) and anti-outer-membrane porin C (anti-OmpCs) have recently been proposed for CD diagnosis.

ACCA, ALCA and AMCA are antiglycan antibodies. Glycans are major components of the cell surface, they are highly immunogenic and may lead to a variety of antiglycan antibodies, including IgG, IgA, IgE and IgM, which have been described in several inflammatory and autoimmune diseases.[18] Anti-OmpCs are antibodies directed against specific bacterial antigens from Escherichia coli, such as the OmpC.[19]

Up to 76% of CD patients are positive for at least one of these markers, with a specificity ranging from 80 to 93%.[18] The individual marker's sensitivity is obviously lower, with values of ALCA = 17.7%, ACCA = 20.7%, AMCA = 28.1% and anti-OmpC = 29.1%.[18]

A recent study in children has also shown that these antibodies, in addition to anti-Cbir1 (flagellin) and to the presence of various caspase recruitment domain 15 (CARD15) variants, could be useful in predicting CD progression and development of complications.[20] The rate of complicated CD appears to increase in children as the number and magnitude of immune reactivity increases.


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## David in Seattle (Feb 13, 2011)

Endoscopy & Histology

Ileocolonoscopy with biopsies is the most accurate exam for the initial diagnosis of CD.[21] In addition, in up to 92.5% of cases, CD is within the reach of the colonoscope.[22] However, there is a definite risk of complications in performing colonoscopy, especially during active disease. Typical lesions at endoscopy include skip lesions, cobblestone mucosa and ulcerations with clear margins, usually surrounded by normal mucosa. Although very suggestive – especially for the location – endoscopy per se is sometimes insufficient for a definite diagnosis of CD[21] since the examination of tissue biopsies is also very important.

The histopathological picture of endoscopic biopsies in CD may show different patterns.[23] Owing to the transmural nature of CD (and since endoscopic biopsies only allow collection of mucosal or submucosal samples), such patterns may be distinct from those observed in surgical specimens. In particular, lymphoplasmocytoid and granulocytic infiltration with the submucosal involvement is evident in both surgical and bioptic samples, while fissuring ulcerations may not be evident in biopsy specimens. Such ulcerations represent the origin of intramural abscesses, fistulae and sinuses, and are characteristically associated with formation of granulation tissue. The latter, together with vascular and neural damage, is at the basis of the fibrotic evolution of CD, often with transmural extent, another feature rarely evident in endoscopic biopsies. Follicular lymphoid hyperplasia with activation of germinative centers may be observed in all areas of the intestinal wall, while granulomatous sarcoid-like lesions (noncaseating granulomas) are present only in 40–60% of cases, either in intramural sites or in regional lymph nodes.[23] Secondary features of chronic inflammation in CD may include pseudopyloric-type gland metaplasia, neuromatoid changes and thickening of nerve fibers at the submucosal or muscular level and lymphangectasia. All these changes define a highly suggestive picture for CD diagnosis; nevertheless, infections such as Yersinia or intestinal TB, NSAID damage and ischemic disease[24] must be carefully excluded. In combination with typical endoscopic lesions, histologic examination of the affected areas still represents a fundamental test for the diagnosis of CD.[25] In the absence of endoscopic lesions the value of histology is obviously limited,[25] but not absent. Indeed, minimal endoscopic lesions may be associated with focal lymphocytic infiltration (aspecific inflammatory pattern), but also with subepithelial, eosinophilic, KP1-reactive macrophages and multiple microhemorrhages with fibrin trails in lamina propria in early CD as well as in postsurgical CD recurrence.[26] Such a picture may preceed the development of ulcerative and vascular inflammatory lesions as early steps in the pathogenesis of fibrotic phenomena. Thus, although the histological diagnosis of CD should be routinely associated with a suggestive endoscopic picture,[25] the hypothesis of early lesions, endoscopically less evident, should be borne in mind in the right clinical context (discussed later).
Imaging

The main objective of the available imaging techniques in the initial diagnosis of CD is to establish the location and extent of the diseases, especially in areas that cannot be reached by, or are not accessible with, the colonoscope. In addition, imaging techniques may visualize complications such as abscess, fistulas and extraintestinal pathology. More recently, some imaging techniques are being increasingly studied to quantify the degrees of inflammation and fibrosis in the small intestinal wall in CD.

At present, the major imaging techniques used to diagnose CD are the small bowel enteroclysis (SBE) and small bowel series (or follow through [SBFT]), computed tomographic enterography (CTE) of the small bowel MRI (SBMRI) and intestinal ultrasound (US).

Small bowel enteroclysis remains as of today one of the most frequently used techniques. However, although it has a good sensitivity (85–95%) and specificity (89–94%) in detecting typical CD lesions,[27] SBE is being gradually substituted by other techniques. Major pitfalls are the high dose of radiation, the scarce capability compared with other techniques of quantifying the degree of inflammation of the bowel wall and the scarce acceptance rate of patients. SBFT is also still used. It is still considered relatively reliable for evaluating stenoses and internal fistulas before surgery.[28] Compared with SBE, SBFT has similar sensitivity and specificity and is associated with a lower radiation exposure, is less expensive and less time-consuming.[27] In addition, mucosal detail is usually better identified with SBFT.

Computed tomographic enterography of the small bowel has a high sensitivity (82%) and specificity (89%) in identifying active transmural inflammation,[10] and it is therefore helpful in differentiating inflammatory from fibrostenosing CD. In addition, a CT scan is helpful in identifying intestinal complications of CD, in addition to unrelated abdominal pathology.[29] A good correlation has been reported between CT-diagnosed involvement of mesenteric adipose tissue and CRP levels.[30] Also, the number of CT-diagnosed fistulas and ESR have been reported to be correlated.[31]

The major advantage of SBMRI compared with CTE is the absence of ionizing radiations. The capability of differentiating inflammation from fibrosis seems to be similar to that of CTE, with a possible edge over the latter in defining penetrating disease.[4] In addition, SBMRI seems as sensitive as SBE in identifying intestinal strictures. A recent prospective study, as well as a meta-analysis, indicate that SBMRI and CTE are essentially comparable techniques with overlapping sensitivity and specificity.[4,10,32]

Intestinal US requires individual expertise in identifying useful CD-related parameters such as lumen diameter, intestinal wall stiffness and layers visualization, peristalsis and lymph node size.[4] In addition, an excess of fat in the abdominal wall or an excess of intestinal air may alter the interpretation of data. In general, for the initial diagnosis of CD, sensitivity has been reported to be 75–94% with a specificity of 67–100%.[4,33] In addition, abdominal US may be very useful to exclude other abdominal/gynecologic diseases and to diagnose septic complications of CD such as abscess.

Regardless of performance, the current preference for one technique over another often depends largely on institutional standards, availability of local expertise and individual experience. CT scan or MRI should be preferred to traditional techniques, however, when an abscess or additional pathologic findings are expected.


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## David in Seattle (Feb 13, 2011)

Miscellaneous

Although seldom used for this purpose, the initial diagnosis of CD can also be provided by nuclear scintigraphy and other nuclear medicine techniques.

Of the various radiotracers and techniques used so far, 99mTc-hexamethylpropyleneamine oxime-labeled leukocyte scintigraphy seems the best suited to localize small and large bowel pathology in IBD,[34] as well as for the assessment of CD activity and treatment response.[34] The drawbacks of this imaging technique are linked to its kinetics; to the vicinity of several tissues and organs with the bowel with consequent absence of anatomic information and to its technical constraints (time-consuming and scarcely available).[35] Other radiotracers such as indium (111In) may provide additional information, but some of the major limitations outlined previously still remain.[36] Thus, although scintigraphy is well accepted, does not require bowel preparation, is not contraindicated during active disease and the radiation dose is minimal compared with the other techniques, its role in CD diagnosis is limited to cases in which the clinical suspicion is high despite a negative endoscopy and imaging procedure.[36]

Fluorine-18 fluorodeoxyglucose (F-18 FDG)-PET is a promising method for the detection of intestinal inflammation. The rationale behind this technique is that uptake of FDG takes place preferentially in metabolically active inflammatory cells during infection and inflammation.[37] In a pediatric study, FDG-PET correctly identified intestinal inflammation in 80% of children with IBD (81.5% with CD and 76.4% with ulcerative colitis) while showing no uptake (i.e., no inflammation) in children with recurrent abdominal pain without IBD.[37] The same technique also holds promise to differentiate inflammatory from fibrotic stenoses in CD.[38]

Capsule endoscopy (CE) has similar indications in the initial diagnosis of CD – that is, high suspicion despite a negative endoscopy/imaging test – provided a clear stricture has been excluded a priori.[6,39] Sensitivity of capsule endoscopy appears superimposable to that of CTE (83 vs 82%) but with a lower specificity (53 vs 89%).[40,41] However, CE appears more accurate than MRI in diagnosing Crohn's-like lesions of the small intestine.[39] A major limit of this technique is the impossibility to perform biopsies, and hence, to be properly compared with the gold standard.[39] In addition, this technique should be avoided if there is a suspicion of bowel obstruction, a frequent complication of CD. In theory, some of the limitations of CE could be circumvented by double balloon enteroscopy, a technique that allows full investigation of the small bowel, biopsy collection and even theraputic procedures. Initial promising studies demonstrate that this technique can detect significant small bowel lesions missed by CE.[40]
Conclusion

The real challenge in making a prompt CD diagnosis in the presence of clinical suspicion is the decision to perform an ileocolonoscopy. While this technique allows a diagnosis in up to 92.5% of cases,[22] it still remains an invasive procedure with a definite risk of complications, especially perforation. Factors that may affect the decision to perform endoscopy immediately include the duration and severity of symptoms (long-standing symptoms with mild abdominal discomfort make CD less likely), the patient's smoking habits and family history of IBD (which increase the likelyhood of CD diagnosis), known food allergies/intolerance and gynecologic diseases (which are frequent differential diagnoses). Useful initial tests may include complete blood count, thyroid hormones, CRP and ESR, as well as an abdominal/pelvic US. ASCA/ANCA may be useful to distinguish UC from CD, but do not appear to be accurate enough to be used for the initial diagnosis of CD. Most importantly, fecal calprotectin, if elevated, will support the decision to perform an ileocolonoscopy. Once a histological diagnosis is firmly established, the patient should undergo an imaging test of the small bowel to define extent, gravity and type of disease (inflammatory vs fibrotic), as well as to exclude the presence of septic complications (fistulas, abscess) of CD. A proposed algorithm for the initial assessment of a patient with suspected CD is illustrated in Figure 1.

Figure 1.

Proposed diagnostic algorithm in the initial assessment of a patient with suspected CD.
CBC: Complete blood count; CD: Crohn's disease; CE: Capsule endoscopy; CRP: C-reactive protein; CTE: Computed tomographic enterography; ESR: Erythrocyte sedimentation rate; SBE: Small bowel enteroclysis; SBMRI: Small bowel MRI; US: Ultrasound.


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## David in Seattle (Feb 13, 2011)

Initial Diagnosis of Perianal & Complicated CD
Clinical Picture

The most frequent manifestations of perianal disease are skin tags, fissures, low and high fistulas, perianal abscess, anorectal strictures, hemorroids and anal ulcers. It has been reported that, in referral centers, up to 40% of CD patients may present with perianal manifestations, in particular fistulas, during the course of their disease.[8,42–45] Such a figure is probably much lower in daily clinical practice in nonreferral centers.[8] Rectovaginal fistulas may appear in approximately 9% of cases.[44] However, only a minority of patients (25%) will present with a fistula before diagnosis of their intestinal disease.[8] Apparently, 5% of patients only present with perianal disease without involvement of the intestine.[8] The risk of perianal disease is greater if the intestinal disease is localized in the rectum, especially in the presence of an anorectal stricture.[8,45] Typically, fistulas are classified as either simple or complex depending on their localization (below or above the dentate line), the number of external orifices (one or more) and the absence/presence of abscesses and rectovaginal fistulas.[46]

The clinical picture of perianal disease will depend on the type of lesion.

In the presence of an abscess there may be local pain, swelling and fever.[8,42] Physical examination may reveal a tense, reddened fluctuating perianal mass with or without an external orifice.[42]

Anal strictures may present with pain, constipation and blood per rectum. They should be differentiated from postsurgical strictures, cancer, radiotherapy, TB and sexually transmitted diseases.

Anal fissures are usually symptomatic during defecation: they may present with pain, bleeding and itching.[8] However, often they are asymptomatic.[47]

Anal ulcerations occur in a minority of patients: they usually manifest themselves with unremitting, severe pain and bleeding or itching. They should be differentiated from similar lesions resulting from sexually transmitted diseases, TB, leukemia and skin cancer. It is important to biopsy all ulcers and perform histology and microbiology tests.[47]

Skin tags are relatively frequent manifestations of perianal disease and can be associated with fissures or fistulas. They are usually asymptomatic; however, especially in children, they may raise the suspicion of CD and lead to further investigations.[47]

Hemorrhoids are also usually asymptomatic and have a modest clinical meaning.[8]

It should be remembered that the patient with perianal disease associated with anal strictures, long-standing fistulas and severe colitis is at greater risk of developing anal or rectal carcinoma.[48] Therefore, a high level of suspicion and careful surveillance is always indicated in the presence of perianal disease.
Imaging & Endoscopy

Endoscopy represents an essential part of the evaluation of perianal disease in CD because rectal and colonic disease are very often (although not always) associated with it and should also be treated.[43] Indeed, the disease seems to spread from the mucosa into the deeper layers of the intestinal wall until it reaches the anal glands and causes fistula and abscess formation.[43]

The major techniques currently used to diagnose the presence of fistulas and abscesses in perianal CD are endoscopic US, pelvic MRI and surgical examination under anesthesia (EUA) that have an individual accuracy superior to 85%.[44,49] In this regard, the three techniques appear to be roughly equivalent. However, the high, complex fistulas appear to be better diagnosed by pelvic MRI than other techniques.[45] EUA with biopsies appears essential, particularly to exclude anorectal carcinoma.[44] By contrast, one of the major limits of endoscopic US is the pain provoked by the probe introduction during active disease, a maneuver that makes the examination intolerable.

The association of MRI or endoscopic US with EUA brings accuracy to 100%.[38] Such association is necessary in approximately 10% of cases that may not be correctly classified with a single technique.[44,45,50]

Fistulography and CT scans are considered unreliable in the diagnosis and classification of fistulas, although CT scans may play a role in abscess diagnosis and/or when other techniques are not available or tolerated by the patient.[44,45]


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## David in Seattle (Feb 13, 2011)

Evaluation of Response to Treatment
Clinical Picture

Traditionally, response to therapy has been evaluated by the clinical picture (i.e., patient's wellbeing, number of bowel movements per day, abdominal pain, etc). Typically, the severity of each symptom/sign (together with other parameters) has been assigned a value in clinical scoring systems, of which the CD Activity Index (CDAI) has often been used as a primary outcome in clinical trials.[51] However, as our knowledge evolves, it has become clear that this and other indices are poorly correlated with the endoscopic activity of disease.[52] Indeed, we believe that the CDAI should be abandoned as a sole parameter of response to therapy. In clinical practice, a patient's subjective satisfaction and quality of life (usually measured by the scoring system IBD questionnaire) do remain a useful indicator of treatment efficacy.
Blood & Fecal Tests

Of the blood tests, only CRP seems to have a role in predicting the response to treatment in CD, although current data are controversial. In particular, one study has demonstrated that a high basal level of CRP (>9 mg/ml) is associated with a seven-times higher risk of developing a symptomatic recurrence of disease.[53] Likewise, a significant reduction of CRP after anti-TNF treatment has been reported in drug responders only, and is correlated with the outcome of disease.[53] However, other studies have failed to demonstrate any significant correlation between CRP and response to therapy.[54]

Fecal calprotectin seems to be more accurate than CRP in predicting the response to therapy or the likelihood of a symptomatic flare, even in patients with quiescent CD.[55] The ability of fecal calprotectin to predict clinical recurrence stems from its close correlation with the mucosal status[52] which, in turn, closely reflects the response to treatment (see following section). Values higher than 340 mg/kg have been reported to be associated with a severe prognosis in the following 12 months, with a risk of clinical recurrence of disease up to 18-times higher than that associated with values below the cut-off,[55] with a sensitivity of 80% and a specificity of 91%. On this basis, it has been proposed that elevation of this marker should represent an indication for a more aggressive therapy.[55]
Endoscopy

Traditionally, endoscopy has not been considered useful in monitoring response to therapy, since available treatments were not capable of healing the mucosa. However, the introduction of immunosuppressives and especially biologics – medications capable of reinducing mucosal integrity – in the management of CD has made endoscopy an essential tool in evaluating the response to therapy.[56,57] Currently, mucosal healing appears the best predictor of clinical remission since it is negatively correlated to hospital admission, surgery[58] and use of medications up to 2 years after its induction.[59]

However, there seems to be a discrepancy in approximately 25% of patients between the clinical picture and the mucosal status at endoscopy.[56,57] Whether such discrepancy depends on the transmural nature of the disease (i.e., the inability to verify healing in deeper layers of the intestinal wall) or to the concomitant presence of IBS-like symptoms, is unclear.
Imaging

Small bowel MRI is a sensitive technique potentially capable of quantifying the two components of CD, inflammation and fibrosis in the intestinal wall, and is strongly correlated with endoscopy.[60,61] Thus, at least in theory, this technique could potentially guide therapeutic decisions (medical vs surgical) in many CD patients and monitor the response to therapy. Although considerable progress has been made in the last few years, the latter task may require a level of accuracy of this technique that has yet to come.


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## David in Seattle (Feb 13, 2011)

Recurrence of Disease after Surgery

Crohn's disease recurs after 'curative' surgery in the majority of patients within 1 year. Traditionally, recurrence is classified as endoscopic, radiologic or clinical.[62]

Clinical recurrence is unlikely before 6–8 months after surgery; however, symptoms may be present earlier on in many patients after surgery and may be due to a number of reasons such as short bowel, inflammation caused by surgery, altered anatomy, adhesions and bile salt diarrhea. For this reason, the clinical index CDAI (which relies on symptoms common to both recurrence and the normal postsurgical state) is not considered reliable.[63] Therefore, the gold standard for evaluating postsurgical recurrence of CD remains endoscopy. With endoscopy, a validated classification of damage has established the role of different mucosal lesions in predicting clinical recurrence.[64,65] Endoscopically, the earliest signs of recurrence appear within the first few months after surgery and consist of ulcerations in the neoterminal ileum. By contrast, lesions confined to the anastomosis per se do not seem to have a negative prognostic value (since they can be caused by ischemia or surgical staples) and are not considered part of the endoscopic recurrence picture. Histology per se is also seldom considered a diagnostic parameter of recurrence.[51]

More recently, fecal calprotectin has demonstrated great potential in diagnosing postsurgical recurrence of CD. In particular, fecal calprotectin appears closely associated with mucosal status, since it normalizes within 2 months after surgery in nonrelapsers [Sorrentino D, Unpublished Data], whereas in the presence of recurrence fecal calprotectin values tend to increase over time.[66] We have also shown that this marker is closely related to the status of the intestinal mucosa in postsurgical CD depending on the response to different doses of infliximab.[67] CRP, in this regard, appears less accurate, whereas ESR shows no correlation (Figures 2 & 3).[67] 

Figure 2.

Markers of inflammation vs infliximab dose in postsurgical Crohn's disease. The figure shows that fecal calprotectin (A), but not CRP or ESR (B & C), inversely correlate with increasing doses of infliximab in postsurgical Crohn's disease. The doses of 5 and 3 mg/kg were associated with mucosal integrity in all patients. By contrast, at doses of 2 and 1 mg/kg, the endoscopic recurrence score was progressively elevated. Broken lines: upper limit of the normal ranges.
CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate. Reproduced with permission from [67].


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## David in Seattle (Feb 13, 2011)

Figure 3.

Fecal calprotectin vs endoscopic scores in postsurgical Crohn's disease. The figure shows a close positive correlation (p < 0.0001) between fecal calprotectin and endoscopic scores in postsurgical Crohn's disease using different infliximab doses. Individual data points appear superimposed owing to graph compression. Fecal calprotectin (mg/kg) is expressed in natural logarithms (ln). Solid line: estimated median regression line.
Reproduced with permission from [67].



Other techniques such as CE have a minor role in diagnosing postsurgical CD recurrence if compared to traditional endoscopy. In the absence of strictures CE can evaluate the occasional anastomosis that cannot be reached by colonoscopy.[68] Both CTE and SBMRI (seldom used for the purpose) show a good sensitivity and specificity[69,70] at least in patients with severe endoscopic recurrence. Also infrequently used but reported to be capable of diagnosing postsurgical recurrence is intestinal US with or without contrast medium.[71]


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## David in Seattle (Feb 13, 2011)

Expert Commentary

At present, CD diagnosis is often made too late or is incomplete. And yet, it is essential that diagnosis closely defines location, extent, severity and type of disease, which are all factors fundamental for subsequent patient management. The main reason for the diagnostic delay may stem from the intrinsic complexity of the disease. More importantly, we still have an incomplete comprehension of the natural history of CD. Even when it is properly made, CD diagnosis is made late, when important symptoms and tissue/organ damage might have already taken place. For this reason, both the clinical management, as well as basic and clinical research in CD, tend to lag behind those of other gastrointestinal and medical disorders. Indeed, early diagnosis of this disease remains, at present, one of the main, albeit still challenging, tasks in the field of IBDs.

Five-year View

Use of biologic (rather than clinical) disease activity indices involving the mucosal integrity, the histology or even the specific tissue cytokine pattern will be more widespread both in clinical trials and in daily practice. For this reason, endoscopy will become more important in making initial CD diagnosis, in evaluating the response to therapy and in the early diagnoses of postsurgical recurrence. However, the high accuracy of this technique will still be counterbalanced by its invasiveness. Therefore, it is expected that imaging techniques such as MRI and CT scan will also be widely used and developed to the point of allowing a virtual biopsy of the intestinal wall. Markers of disease activity such as fecal calprotectin and others will be used more frequently, not only in the initial patient evaluation, but also in the general management of CD, such as the response to therapy.

As we increasingly become aware that early therapy means a greater likelihood of treatment success in CD, a greater effort will be made in the future to diagnose CD at an earlier stage, possibly asymptomatic. In this regard, isolated ileal mucosal alterations can be found in the absence of symptoms. However, their meaning, as early CD lesions, is still uncertain. Current studies aimed at diagnosing CD at an early stage are scarce and may suffer from methodological limitations. For example, it has been claimed that in patients with isolated, minor ileitis without a clinical history of IBD, CD could be predicted by the presence of symptoms[72] rather than histology. However, in such a study, diagnosis was made in many cases, shortly thereafter, on the basis of advanced (and therefore previously undiagnosed) clinical CD features. Isolated ileal lesions can also be idiopathic in many cases or due to NSAIDs or bowel preparation based on PEG-electrolyte lavage solution,[73,74] even though in the latter cases histology may not reveal aspects compatible with CD. Despite these limits, early CD diagnosis may be possible in selected populations, such as first-degree relatives of CD patients.[75] The challenge will be to develop, in the near future, a series of noninvasive screening tests that may eventually lead to colonoscopy in patients at high risk of having the disease.

A major effort will also be made to establish biologic disease duration as a potentially predictive factor of response to therapy and as a criterion for patient selection in clinical trials. At present, clinical diagnosis of CD is probably made several years after its biologic onset. In addition, diagnostic delay after symptoms onset is common (see earlier). Therefore, using the time elapsed from diagnosis as a surrogate for disease duration is inappropriate. An important feature of CD that may help in establishing disease duration is its evolution from an inflammatory to a fibrostenosing disease.[1] In theory, therefore, accurately quantifying such components in the intestinal wall may provide us with an estimate of biologic disease duration.

Finally, although the use of more effective medications earlier during the course of disease has already reduced the incidence of colon cancer in IBD patients,[76] this complication remains a real challenge in the follow-up of patients with long disease duration. It is likely that new endoscopic techniques such as high-definition endoscopy, chromoendoscopy, computed virtual chromoendoscopy and confocal endomicroscopy will be of great help in establishing effective surveillance protocols for prevention of this complication.[56,57] 

Sidebar

Key Issues

    * Diagnosis of intestinal Crohn's disease (CD) is challenging, since its signs/symptoms can be mimicked by many abdominal and gynecologic diseases.
    * Initial tests may include complete blood count, inflammatory indices, specific autoantibody, fecal calprotectin (FC) and abdominal/pelvic ultrasound.
    * Final diagnosis relies on ileocolonoscopy and biopsies.
    * Additional tests are required to define location, extent, severity and type of disease, and may include small bowel enteroclysis, small bowel MRI, computed tomographic enteroclysis and intestinal ultrasound.
    * Septic complications, as well as extraintestinal manifestations, should also be excluded during the initial assessment of CD.
    * Pelvic CD is usually suspected in the presence of local signs and symptoms (mass, pain and discharge).
    * Final diagnosis of pelvic CD relies on MRI, endoscopic ultrasound or examination under anesthesia. Endoscopy is also necessary during initial assessment.
    * Response to therapy in CD is best and most objectively evaluated by endoscopy (mucosal healing). Inflammatory indices and FC may also play a role.
    * Recurrence of disease after surgery is also most objectively evaluated by endoscopy. Inflammatory indices and FC may also play a role.
    * Unmet needs in CD diagnosis and assessment include diagnosis of early (asymptomatic) disease, accurate evaluation of disease duration and better diagnostic protocols for colon cancer surveillance.


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## David in Seattle (Feb 13, 2011)

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      •• Study of great interest with far-reaching consequences, demonstrating that Crohn's disease (CD) evolves, in time, from an inflammatory to a fibrotic/penetrating disease.
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      •• Excellent study demonstrating that fecal calprotectin can discriminate between inflammatory bowel diseases and irritable bowel syndrome in young people.
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## David in Seattle (Feb 13, 2011)

# Sandborn WJ, Feagan BG, Hanauer SB et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology 122(2), 512–530 (2002).
# Schoepfer AM, Beglinger C, Straumann A et al. Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am. J. Gastroenterol. 105(1), 162–169 (2010).
# Esters N, Vermeire S, Joossens S et al. Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease. Am. J. Gastroenterol. 97(6), 1458–1462 (2002).
# Sostegni R, Daperno M, Scaglione N, Lavagna A, Rocca R, Pera A. Review article: Crohn's disease: monitoring disease activity. Aliment Pharmacol. Ther. 17(Suppl. 2), 11–17 (2003).
# Kallel L, Ayadi I, Matri S et al. Fecal calprotectin is a predictive marker of relapse in Crohn's disease involving the colon: a prospective study. Eur. J. Gastroenterol. Hepatol. 22(3), 340–345 (2010).
# Fefferman DS, Farrell RJ. Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice. Clin. Gastroenterol. Hepatol. 3(1), 11–24 (2005).
# Leighton JA, Shen B, Baron TH et al. ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointest. Endosc. 63(4), 558–565 (2006).
# Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133(2), 412–422 (2007).
•• Important study showing for the first time that mucosal healing is associated with a better clinical outcome in inflammatory bowel diseases.
# Baert F, Moortgat L, van Assche G et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 138(2), 463–468 (2010).
•• Excellent study proposing de facto for the first time that mucosal healing should be our first goal in treating CD patients.
# Sinha R, Murphy P, Hawker P, Sanders S, Rajesh A, Verma R. Role of MRI in Crohn's disease. Clin. Radiol. 64(4), 341–352 (2009).
# Sempere GA, Martinez Sanjuan V, Medina Chulia E et al. MRI evaluation of inflammatory activity in Crohn's disease. AJR Am. J. Roentgenol. 184(6), 1829–1835 (2005).
# Sachar DB. Recurrence rates in Crohn's disease: predicting the future and predicting the past. Gut 55, 1069–1070 (2006).
# Sorrentino D, Paviotti A. Postoperative recurrence of Crohn's disease: the beginning of the end? Gastroenterology 137(3), 1181–1182 (2009).
# Rutgeerts P, Geboes K, Vantrappen G et al. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery. Gut 25, 665–672 (1984).
# Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn's disease. Gastroenterology 99, 956–963 (1990).
# Lamb CA, Mohiuddin MK, Gicquel J et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn's disease. Br. J. Surg. 96(6), 663–674 (2009).
# Sorrentino D, Paviotti A, Terrosu G, Avellini C, Geraci M, Zarifi D. Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn's Disease. Clin. Gastroenterol. Hepatol. 8(7), 591–599 (2010).
• This study shows, inter alia, that fecal calprotectin closely correlates with mucosal status and drug response in postsurgical recurrence of CD.
# Bourreille A, Jarry M, D'Halluin PN et al. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn's disease: a prospective study. Gut 55(7), 978–983 (2006).
# Koilakou S, Sailer J, Peloschek P et al. Endoscopy and MR enteroclysis: equivalent tools in predicting clinical recurrence in patients with Crohn's disease after ileocolic resection. Inflamm. Bowel Dis. 16(2), 198–203 (2010).
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# Castiglione F, Bucci L, Pesce G et al. Oral contrast-enhanced sonography for the diagnosis and grading of postsurgical recurrence of Crohn's disease. Inflamm. Bowel Dis. 14(9), 1240–1245 (2008).
# Courville EL, Siegel CA, Vay T, Wilcox AR, Suriawinata AA, Srivastava A. Isolated asymptomatic ileitis does not progress to overt Crohn disease on long-term follow-up despite features of chronicity in ileal biopsies. Am. J. Surg. Pathol. 33(9), 1341–1347 (2009).
# Goldstein NS. Isolated ileal erosions in patients with mildly altered bowel habits. A follow-up study of 28 patients. Am. J. Clin. Pathol. 125(6), 838–846 (2006).
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# Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology 119(6), 1740–1744 (2000).
• Very interesting case report demonstrating that CD could be diagnosed in an asymptomatic stage in a first-degree relative.
# Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 130(4), 1030–1038 (2006).

Papers of special note have been highlighted as:
• of interest
•• of considerable interest


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## Trysha (Feb 14, 2011)

Hello David
This is an excellent and very comprehensive review of all the Crohn's parameters.
I found it to be excellent reading.
Well done
Trysha


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## David in Seattle (Feb 14, 2011)

Trysha - I think it's a great review, too.  Probably deserves a sticky.  Glad you found it useful.


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## tummygirl (Feb 14, 2011)

This is great! I vote to Sticky it. 

Do you have a link to the article?


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## David in Seattle (Feb 14, 2011)

tummygirl said:


> This is great! I vote to Sticky it.
> 
> Do you have a link to the article?


T.G. - Sorry, no, it's not generally available online.  Glad you found it useful, though!


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## ChefShazzy (Feb 15, 2011)

Good one.  The forum is sure lucky to have you posting all this great stuff, David!  

Sticky!


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## David in Seattle (Feb 15, 2011)

ChefShazzy said:


> Good one.  The forum is sure lucky to have you posting all this great stuff, David!
> 
> Sticky!


Ohh, thank you, Shazzy!  I'm glad to do it!


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