Dra. Virginia Ollero Pena
Complejo Hospitalario Universitario de Ferrol
Endoscopic techniques play a fundamental role in treating patients with chronic inflammatory bowel disease (CIBD). This importance is not only limited to the time of diagnosis, but extends throughout the progression of the disease.
Of the endoscopic instruments available, colonoscopy continues to be the premier procedure in the case of ulcerative colitis (UC). In addition to its crucial importance in the initial diagnosis, colonoscopy is of great use in monitoring long-standing UC.
In the evaluation of the endoscopic follow-up of UC, activity and extent of the impairment must be considered as much as on the onset. Therefore, the endoscopic indices are the same as the ones used in the initial diagnosis, which are explained in the previous chapter.
In a colonoscopy performed on a patient with long-standing disease, in addition to possible signs of acute activity, it is common to find signs related to chronic inflammation, such as pseudo-polyps, cicatricial tracts or tubular colon due to a loss of haustration that sometimes can be accompanied by a reduction in the size of the lumen, forming a stenosis
(Fig. 1, Fig. 2, Fig. 3).
Numerous studies have proven that, both UC and Crohn’s disease (CD) show an increased risk of developing colorectal cancer (CRC) with respect to the general population, with this risk being dependent on the duration and extent of the disease. The accumulated risk of developing CRC has been estimated in 1.6%, 8.3% and 18.4% at 10, 20 and 30 years respectively1. A study that evaluated the risk, based on the extent, showed an incidence rate of 2.8% for left colitis versus 14.8% for pancolitis2. Furthermore, the risk of developing CRC has also been found to be related to the severity of endoscopic and histologic inflammation3,4. For this reason, endoscopic monitoring for the early detection of CRC in patients with UC is widely accepted and agreed upon, in order to identify pre-malignant lesions.
NEED FOR ASSESSING MUCOSAL HEALING IN ULCERATIVE COLITIS: DEFINITION AND CURRENT STATUS
Although traditionally the treatment for patients with UC had been geared towards achieving clinical remission, currently it has been given an increasing importance in assessing mucosal healing. There is more and more evidence in regards to the fact that mucosal healing reduces the risk of surgical intervention5, prolongs clinical remission5 and reduces the risk of dysplasia and CRC4. From a clinical standpoint, an endoscopic assessment allows for better decision-making in order to optimize treatment in a more objective manner (Fig. 4, Fig. 5, Fig. 6). With the emergence of biological drugs in the therapeutic arsenal for CIBD, previously unheard-of mucosal healing rates were reached and, as a result, mucosal healing began to be assessed as a therapeutic objective in clinical trials.
How is mucosal healing defined?
Currently there is no validated definition on what mucosal healing means. In the case of UC, the fact that a validated endoscopic activity index has not been established further complicates the consensus in obtaining common criteria. The International Organization for the Study of the Inflammatory Bowel Disease (IOIBD) has proposed that mucosal healing would be the absence of friability, bleeding, erosions and ulcers in all visualised segments of the mucosa6. In a simplified version, mucosal healing could be defined as the absence of ulceration and erosions. However, there is still a lack of studies that allow the degree of endoscopic improvement that involves a long-term clinical benefit to be determined.
Another aspect to take into account is the lack of homogeneity in the criteria for defining mucosal healing in different studies (Table I). This fact has caused significant differences in the data obtained on the mucosal healing rates.
The ASCEND studies have proven that extended-release mesalazines can induce endoscopic remission in UC7,8. A retrospective study of ASCEND I and II analysed the combined rates of mucosal healing on Week 6. Mucosal healing was examined in 80.8% of the group treated with 4.8 g/day, versus 68% of those that had received a dose of 2.4 g/day (p = 0.012)9.
Sandbord et al. published a meta-analysis of 2 randomised trials versus a placebo that evaluated the mucosal healing rates in Week 8 with different doses of multi-matrix mesalazine (MMX). It was observed that patients who had received a dose of 4.8 g/day achieved mucosal healing at a rate of 32.2% vs 32% of those with a dose of 2.4 g/day or 15.8% for the placebo group10.
With respect to the data available on mucosal healing with corticoids in patients with UC, Gross et al. published the results of a trial with topical budesonide 2 g/day, comparing two different presentations, enemas and foam. At four weeks, 52% of patients treated with foam and 54% treated with enemas achieved endoscopic remission11.
Ardizzone et al. compared, in a randomised study, azathioprine (AZA) (2 mg/kg/day) vs mesalazine 3.2 g/day in cortico-dependent patients. At six months, the endoscopic remission rates were 53% and 19% for AZA and mesalazine respectively12.
Ogata et al. investigated the efficacy of oral tacrolimus in patients with moderate to severe UC. In the first dose assessment study, two groups with different target plasma levels were included: 10–15 ng/mL and 5–10 ng/mL, which were placebo controlled. In Week 2, mucosal healing rate was respectively 78.9%, 44.4% and 12.5% for the high-level, low-level and placebo group13. The same authors recently published a double-blind study in which 62 cortico-refractory patients were randomised into two groups: tacrolimus at a plasma dose of 10–15 ng/ml or placebo. In Week 2, the endoscopic remission rates were 43.9% for tacrolimus vs 13.3% for placebo14.
Respecto a los datos de adalimumab (ADA) y curación mucosa en CU, disponemos de los resultados de un estudio doble ciego aleatorizado frente a placebo en el que se evaluaba ADA en la inducción y el mantenimiento de la remisión en pacientes con CU moderada-grave. En este estudio, se incluyeron pacientes en dos regímenes de inducción: 160/80 mg, y 80/40 mg en las semanas 0 y 2. En la semana 8, obtuvieron la curación mucosa el 46,9 %, 37,7 % y 41,5 % de los pacientes tratados con 160/80 mg, 80/40 mg y placebo, respectivamente. Se ha de destacar que las diferencia obtenida de ADA vs. placebo no fue significativa16. En el estudio ULTRA 2 se evaluó la eficacia de ADA en la inducción y el mantenimiento de la remisión en pacientes con CU moderada-grave. Se estratificó a los pacientes en dos grupos en función de sihabían recibido o no nuevo tratamiento previo con antifactor de necrosis tumoral (antiTNF). En la semana 8 se observó que en el grupo naïve el 49,3 % del grupo ADA frente al 35,2 % del grupo placebo obtuvieron la remisión endoscópica (p = 0,014). En la semana 52, los resultados en el grupo ADA fueron del 31,3 vs 19,3 % (p= 0,018). En el caso de los pacientes previamente tratados con antiTNF, los resultados no fueron significativos (28,6 vs. 26,7 en la semana 8; 15,1 vs. 9,9 en la semana 52)17.
The Active Ulcerative Colitis Trial (ACT) studies indicated that infliximab (IFX) could also induce and maintain mucosal healing in patients with moderate to severe UC15. In ACT1, 62% of patients treated at the dose of 5 mg/kg and 10 mg/kg were in endoscopic remission at Week 8 versus 33.9% of the placebo group. The percentage of endoscopic remission in Week 54 was maintained at 45.5% for patients treated with IFX 5 mg/kg vs 18.2% of the placebo group.
With respect to the adalimumab (ADA) and mucosa healing data in UC, the results are available from a double-blind, randomised study versus a placebo in which ADA is evaluated in the induction and maintenance of the remission in patients with moderate to severe UC. In this study, patients were enrolled in two induction regimens: 160/80 mg, and 80/40 mg in Weeks 0 and 2. In Week 8, 46.9%, 37.7% and 41.5% of patients treated with 160/80 mg, 80/40 mg and placebo, respectively, achieved mucosal healing. We must note that the difference obtained in ADA vs placebo was insignificant16. In the ULTRA 2 study, the efficacy of ADA was evaluated in the induction and maintenance of remission in patients with moderate to severe UC. Patients were stratified in two groups based on whether or not they had previously received new anti-tumour necrosis factor (antiTNF) treatment. In Week 8, it was observed in the naïve group that 49.3% of the ADA group compared to 35.2% of the placebo group achieved endoscopic remission (p = 0.014). In Week 52, results in the ADA group were 31.3% vs 19.3% (p = 0.018). In the case of patients previously treated with antiTNF, the results were insignificant (28.6 vs 26.7 in Week 8; 15.1 vs 9.9 in Week 52)17.
What is the importance of mucosal healing?
Rutters et al. showed that in patients with long-standing UC, the risk of CRC was directly related to the degree of endoscopic and histologic inflammation (Video 1 and Video 2) Furthermore, they observed during follow-up that the patients who were in endoscopic remission presented a risk of developing CRC comparable to the general population4. Therefore, it can be concluded that mucosal inflammation would increase the risk of neoplasm.
The most significant long-term data on mucosal healing in the stage prior to the appearance of biological data comes from a population study on a Norwegian cohort (IBSEN study) published by Froslie et al. in 200718.
In this study, 740 patients with CIBD, 513 with UC, were prospectively analysed for a period of 5 years. In patients with UC, in addition to performing an endoscopic study in the beginning, one colonoscopy was performed per year in 354 patients. Of these, only 3 patients with mucosal healing needed a colectomy at 5 years versus 13 who were not in endoscopic remission (p = 0.02). Therefore, this study showed that mucosal healing is associated with a decreased risk of colectomy in patients with UC. Moreover, in the case of patients with CD, we saw that the need for using corticoids decreased during follow-up.
In another more recent study, it was observed that patients with UC and mucosal healing at 3 months from the initiation of treatment presented lower hospitalisation rates (25% vs 49%; p <0.01), less need for the use of immunosuppressants (5% vs 26%; p <0.003) and less need for a colectomy (3 % vs 18%; p <0.0265)19.
Colombel et al. published the results of a study in which patients treated with IFX, and who had a lower Mayo index in Week 8, had a lower risk of needing a colectomy at Week 54 (p = 0,0004), and a high probability of maintaining corticoid-free clinical remission at Week 30 and Week 5
(p < 0.0001)20.
Histologic healing: The last step in monitoring the disease?
Recent studies have demonstrated a lower risk of relapse and need for surgery. However, evaluation of endoscopic remission as a variable is subject to interobserver subjectivity, which is not always correlated to histologic healing (Fig. 7). In 1956, Truelove and Richards published a study in which they proved that 37% of patients with UC and endoscopically normal mucosa presented mild to moderate histologic activity21. Currently, there are a small number of studies in which this data has been confirmed and that, in addition, indicate that histologic activity independent of mucosal healing is associated with a worse long-term prognosis22,23. Furthermore, is has been observed that the existence of basal plasmacytosis is a predictive factor in the risk of relapse, defined as the existence of plasmocyte infiltration at the deep part of the lamina propria or the base of the crypts23. A recent retrospective study published by Bessissow et al. evaluated histologic activity in patients with UC in endoscopic remission (Mayo 0). Basal plasmacytosis were observed in 21% of cases, and in 40%, neutrophils were observed in the epithelium (with or without crypt destruction or erosions). At 12 months, 21% of patients had experienced a breakout. The presence of basal plasmacytosis was the only independent predictive factor of clinical relapse (47% sensitivity; 85% specificity)24.
Despite the fact that these studies suggest the importance of histologic remission in the progression of UC, currently there is insufficient data to propose histologic healing as a final therapeutic objective in monitoring this disease.
CORRELATION OF NON-INVASIVE MARKERS WITH ENDOSCOPY
As previously mentioned, mucosal healing has begun to be considered a therapeutic objective for UC, since it has been observed to be associated with a decreased risk of surgery and hospitalisation, as well as sustained clinical remission. For assessing mucosal healing, endoscopy continues to be the “gold standard”. However, colonoscopy is an invasive procedure that is uncomfortable for the patient, arduous and expensive and, moreover, not exempt from complications. For this reason, in recent years research has been conducted on the collection of biomarkers that can indirectly evaluate the degree of mucosal impairment. The characteristics of an ideal biomarker would consist of it being a noninvasive, quick, reproducible test that not only allows CIBD to be differentiated from other inorganic pathologies, but to also allows disease activity to be monitored.
With respect to non-specific serological markers, the erythrocyte sedimentation rate (ESR) and C-reactive protein are among those that have been evaluated. Although it has been observed that both biomarkers are frequently high in active UC, the results obtained have not been successful with regard to trying to correlate these parameters with mucosal inflammation25,26.
Of those evaluated to date, the most promising are the faecal markers. In patients with UC, mucosal inflammation is associated with the migration of leukocytes at this level, which would cause the degradation and elimination of proteins in the intestinal lumen. The fact that faecal material is in close contact with intestinal mucosa would facilitate the elimination of these products of inflammation with the faeces, which also reflects the degree of involvement. The first markers evaluated did not provide good results. This is the case for a1-antitrypsin or myeloperoxidase27,28.
Calprotectin is a calcium binding protein with antimicrobial activity that is essential in the cytoplasm of neutrophils, and to lesser extent in the cytoplasm of macrophages. It is part of the S100 family of proteins, which act as inflammation markers in a great number of diseases. Therefore, it could play a role in the pathogenesis of CIBD. Furthermore, it has the advantage of remaining stable for a week at room temperature, which would facilitate its collection by the patient. It has been observed that faecal calprotectin levels are more elevated in patients with CIBD, and in other gastrointestinal disorders, than in healthy subjects. Therefore, it is helpful to differentiate patients with CIBD from those with a functional pathology, as in the case of irritable bowel syndrome (IBS)29. There is evidence that calprotectin levels are directly related to the level of mucosal inflammation, thus enabling distinction between patients with active disease and those in remission. It has also been used as a predictive marker for clinical relapse in patients with UC30,31. However, currently there is little data on the correlation of the calprotectin levels with endoscopic indices. D’Haens et al. demonstrated that a calprotectin level >250 µg/g is an indicator of mucosal inflammation (Mayo >0), with a 71% sensitivity and a 100% specificity32, recommending intensification of the treatment via the monitoring of the levels until they have returned to normal. A recent study published by Schoepfer et al. analysed the correlation between endoscopic activity in patients with UC and calprotectin levels, among other parameters. For the endoscopic assessment, the Modified Baron Index is used. It was observed that calprotectin was the only marker capable of differentiating between various degrees of endoscopic inflammation. Using a cut-off value of 57 µg/g for CP, a 91% sensitivity and a 90% specificity were obtained in order to detect endoscopic activity (Modified Baron ≥ 2)33.
Lactoferrin is an iron binding glycoprotein that is found in neutrophils and secreted in most external fluids because of its antibacterial properties, including breast milk, saliva, lacrimal fluid or faeces. Numerous studies have proven the use of this glycoprotein in assessing CIBD activity34,35. Furthermore, lactoferrin would also be of use in differentiating inflammatory disease from IBS. A study showed that both lactoferrin and calprotectin were able to differentiate between active CIBD and CIBD in remission, in addition to differentiating between patients with IBS in 80% of cases compared to 74% with polymorphonuclear elastase, or 64% with CRP36.
Another faecal marker that has been evaluated is S100A12 protein or calgranulin C, which is present in neutrophil cytoplasm. This protein has pro-inflammatory activity and could therefore contribute to the process of intestinal inflammation, and reflect the existence and severity of this process. Faecal S100A12 is correlated with serum levels and remains stable in faeces for 7 days. It has been observed that S100A12 allows patients with CIBD to be differentiated from those with inorganic pathologies or healthy controls, with high sensitivity and specificity, and with a better correlation with endoscopic and histologic findings than calprotectin and other biomarkers37.
The pyruvate kinase enzyme in dimer form (M2-PK) has recently begun to be assessed as a marker in CIBD. This enzyme is found in undifferentiated and proliferative tissues, and it can be detected in serum and faeces. It has been observed that M2-PK activity is higher in patients with pouchitis38. However, its role in the intestinal inflammatory cascade remains unknown. Chung-Faye et al. conducted a study in which M2-PK levels were assessed in 148 patients: 50 with UC, 31 with CD, 7 with CRC, 43 with IBS, and 17 with other pathologies (excluded). We observed that M2-PK levels were significantly more elevated in patients with CIBD and CRC than in patients with IBS. In addition, in the case of CIBD, this elevations was significant in patients with active disease versus those who presented no activity (UC 40 vs 1.2 U/ml,
p = 0,006; 30 vs 0.55 U/ml, p <0.005)39.
Moreover, a recent study evaluated the correlation of faecal occult blood (FOB) with mucosal healing via a quantitative immunologic test analogous to those used in CRC screening. The authors proved that the existence of a positive result (>100 ng/ml) in the FOB test was an indicator of mucosal inflammation (Mayo ≥ 2), with an 87% sensitivity and a 60% specificity. A negative result was an indicator of mucosal healing (Mayo 0), with a 92% sensitivity and a 71% specificity. The authors concluded that the results of immunologic FOB tests could effectively assess mucosal healing and, therefore, could be useful in the follow-up of UC in a manner that is quick and comfortable for the patient, along with being low cost40.
ENDOSCOPY IN SPECIAL SITUATIONS: POUCHITIS
Aproximately 30% of patients with UC
have presented a lack of response to medical treatment during the progression of their disease, making of colectomy necessary41. Complete proctocolectomy with ileal pouch-anal anastomosis (IPAA), proposed by Parks in 197842, currently constitutes the surgical treatment of choice in patients with medical treatment-refractory UC, or with UC associated with dysplasia, as well as patients with familial adenomatous polyposis (FAP). Various types of ileal pouches have been designed, with the “J” pouch (double ileal loop) being the most commonly performed. Also used in performing the pouch are those with a triple (“S” pouch) and a quadruple (“W” pouch) ileal loop (Figure 8 and Figure 9).
The main advantages of IPAA include re-establishing transit and improving the quality of life. However, patients with UC who have undergone IPAA are exposed to the development of complications during progression, with an accumulated risk of pouch failure that ranges from 4%-10%43. The most common would be:
• Pouch CD.
• Irritable pouch syndrome.
Pouchitis is the most common complication, affecting more than 50% of patients with UC and IPAA during its progression44, for which an incidence of over 40% has been reported in the first 12 months after closure of the ileostomy45. In most cases, pouchitis manifests as a non-specific inflammation of the ileoanal pouch. The typical presenting symptoms include an increased number of stools, rectal bleeding, tenesmus, urgent defecation, incontinence and pelvic discomfort. However, these symptoms are not specific to pouchitis, since they can also be present in other inflammatory and non-inflammatory pouch disorders. For this reason, the definition of pouchitis cannot be based solely on clinical criteria, but it also includes endoscopic and histologic criteria. Due to the absence of standardised diagnostic criteria, various endoscopic indices have been developed. One of the most significant indices is the Pouchitis Disease Activity Index (PDAI) (Table II), established in 1994, which includes the definition of the Mayo Clinic and St. Marks criteria46. PDAI is the most used index in clinical studies and includes three sections for its calculation: clinical symptoms, endoscopic findings and histologic abnormalities. However, PDAI has not been incorporated into standard medical practice due to the complexity of the calculation and the diagnostic delay that the assessment of the histologic criteria implies. In an attempt to simplify the diagnostic criteria for PDAI, Shen et al. have developed a modified index (mPDAI)47, which only includes clinical and endoscopic criteria, with a total score of 12, so that a mPDAI ≥5 would entail a diagnosis of pouchitis.
Pouch endoscopy constitutes an essential tool in the diagnosis of pouchitis, and it enables a differential diagnosis to be established with other entities that present with similar symptoms. The endoscopic findings include the presence of oedema, erythaema, granularity, loss of vascular pattern, haemorrhage, friability, erosion and ulcers (Fig. 10). A typical histologic exam in pouchitis shows acute inflammatory changes with polymorphonuclear infiltration, ulceration and crypt abscesses. Chronic inflammatory changes such as villous atrophy, crypt hyperplasia, and an increase of mononuclear cells in the lamina propria would constitute part of the adaptive changes in the ileal mucosa for faecal stasis, and would not be indicative of pouchitis. Moreover, endoscopic examination enables the ileum proximal to the pouch and the mucosa of the rectal loop of the anal transitional zone to be evaluated in order to exclude the existence of cuffitis, pouch CD or reflux ileitis. It is also used in the diagnosis and treatment of pouch stenosis via balloon dilation.
Moreover, biopsies during endoscopy enable the follow-up of dysplasia, as well as the assessment of other causes of pouchitis.
Cuffitis is an inflammation of the rectal mucosa retained over the anal transitional zone (ATZ) in patients in which a mechanical anastomosis has been performed. Clinically, it presents as anal discomfort, perianal irritation and generally mild pouch dysfunction
The development of a de novo pouch CD is another relatively common entity, and it can appear early or years after the performance of an IPAA due to UC or indeterminate colitis. The phenotypes of pouch CD can vary from inflammatory impairment to a penetrating phenotype with the formation of fistulae and abscesses. To obtain a diagnosis of pouch CD, it is important to perform an endoscopic assessment (Video 3) with a biopsy and a radiologic assessment. Endoscopic findings that are geared towards the diagnosis of this entity primarily include the presence of isolated ulcerations in the mucosa proximal to the pouch.
Irritable pouch syndrome is a functional disorder with symptoms similar to those of pouchitis. Pouch endoscopy establishes the differential diagnosis between pouchitis and irritable pouch syndrome, with the latter therefore being an exclusion diagnosis.
In most patients, the aetiology and pathogenesis of pouchitis is not exactly known, thus in these cases idiopathic pouchitis is diagnosed. However, in 20–30% of patients who have antibiotic-refractory chronic pouchitis, it is possible to identify specific causal factors43. Under these circumstances, we would speak of secondary pouchitis. It should be noted that in most secondary pouchitis, patients benefit from the eradication of the triggering factor, with improvement of both symptoms and pouch inflammation (Table III).
Moreover, there are complications stemming from surgery, such as anastomotic stenosis and ischemic pouchitis. In the case of ischemic pouchitis, the ischemic process occurs at the mucosa level, primarily due to tension in the vascular irrigation of the distal ileum48. This manifests as antibiotic-refractory pouchitis with typical endoscopic impairment, in which we observe asymmetrical pouch inflammation, with involvement of the efferent loop, keeping the afferent loop undamaged. Sometimes this ischemic process can lead to the appearance of stenosis.
Anastomotic stenosis after performing IPAA is a relatively common complication. Stenosis can be found in the pouch-anal anastomosis (external) or the neo-terminal ileum-pouch (internal) area. There are also other causes that may determine the development of stenosis at the pouch, such as pouch CD, non-steroidal anti-inflammatory drugs or the aforementioned ischemic pouchitis.
In many cases, digital dilation is usually sufficient for treating anal stenosis. In the event of a more proximal stenosis, various techniques are employed. In regards to endoscopic procedures, it has been observed that balloon dilations, sometimes associated with medical treatment, provides good results with regard to safety and effectiveness49. Other alternative endoscopic methods are dilation via bougies or surgery (strictureplasty, reconstruction or removal of the pouch).
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