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Update on idiopathic colitides

Strobel, Sebastian; Abreu, Maria T.

Current Opinion in Gastroenterology: January 2013 - Volume 29 - Issue 1 - p 60–65
doi: 10.1097/MOG.0b013e32835abc93
LARGE INTESTINE: Edited by Ciarán P. Kelly

Purpose of review This article summarizes the latest developments for three types of idiopathic colitis: ulcerative colitis, Crohn's disease, and microscopic colitis.

Recent findings Crohn's disease and ulcerative colitis are highly related genetically. Colonoscopy remains the gold standard for making a diagnosis. The addition of chromoendoscopy can aid in identification and removal of colonic dysplasia in both disorders. The therapy for ulcerative colitis and Crohn's disease has been transformed with the introduction of anti-TNF treatment. For ulcerative colitis, recent data show that prolonged use of infliximab is effective, well tolerated and that early mucosal healing is associated with decreased risk of colectomy. There is no evidence of a significant increased risk for anti-TNF-induced malignancies. Combination therapy with azathioprine and infliximab for ulcerative colitis has now been shown to be superior to monotherapy. Natalizumab is effective in anti-TNF failures and patients can be risk stratified for progressive multifocal leukoencephalopathy by testing for John Cunningham virus antibodies. Microscopic colitis can often be related to medications, and symptoms may be worsened by coexisting celiac disease.

Summary Combination therapy with an anti-TNF and a thiopurine is currently the most effective treatment for moderate-to-severe Crohn's disease or ulcerative colitis. Stem cell therapy for perianal fistulas in patients with Crohn's disease is a promising new therapy approach.

Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA

Correspondence to Maria T. Abreu, MD, Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Gautier, 510 (D-149), 1011 NW 15th Street, Miami, FL 33136, USA. Tel: +1 305 243 6404; fax: +1 305 243 6125; e-mail:

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By definition, idiopathic colitides are characterized by chronic inflammation in the absence of a known pathogen. Inflammatory bowel disease (IBD) represents the most common example of idiopathic colitis. This includes ulcerative colitis, Crohn's disease, or indeterminate colitis [also referred to as IBD unclassified (IBDU)]. The genetics of IBD demonstrate that ulcerative colitis and Crohn's disease are highly genetically related disorders [1–3]. Therefore, it is not surprising that up to 15% of patients will have indeterminate colitis. Serologies and clinical clues can help predict the ultimate phenotype of the patient [4,5]. Whereas IBD can be visualized endoscopically, microscopic colitis currently requires a tissue biopsy for diagnosis. The incidence of microscopic colitis appears to have stabilized although there is growing awareness of the disease.

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The main treatment option for moderate-to-severe ulcerative colitis is infliximab. Data from two large randomized, placebo-controlled trials demonstrated the efficacy of 5 and 10 mg/kg doses for 30 and 54 weeks, respectively [6]. Additional data are now available to optimize long-term therapy with infliximab. Mucosal healing 8 weeks after the initiation of infliximab predicts whether patients will have long-term remission and avoid colectomy [7▪]. These data suggest that patients initiating therapy with infliximab should undergo an endoscopy at baseline and after induction to determine whether therapy has been effective.

An extension study followed patients on infliximab for up to three additional years [8▪▪]. The study showed several important points. First, patients who initially respond to infliximab are most likely to continue to do so over time. From the 229 enrolled patients, 94.3% (150 of 159) had no or mild disease at week 104. Patients who had greater than 8 weeks interruption of infliximab had more inflammation than those without a treatment gap. Also, patients with a treatment gap had higher titers of antibodies to infliximab, underscoring the importance of not allowing levels of infliximab to become undetectable. In the group of patients who permanently discontinued infliximab treatment (70 out of 229 patients), only 4.8% of those patients showed lack of efficacy, showing that infliximab remained effective in the majority of patients.

Box 1

Box 1

There is a need for additional biologic options for patients with ulcerative colitis – both for convenience and for loss of response to infliximab. Adalimumab has been evaluated in ulcerative colitis. Ulcerative colitis long-term remission and maintenance with adalimumab (ULTRA) 2 included both anti-TNF naïve and anti-TNF exposed patients with moderate-to-severe ulcerative colitis [9▪]. The treatment regimen was adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week. Even though adalimumab was more effective in both groups than placebo and had better results in anti-TNF-naïve patients, the remission rate was 16.5% at week 8 and 17.3% at week 52. The primary outcome in ULTRA 1 and 2 was clinical remission, whereas in Active Ulcerative Colitis Trial (ACT)1 and ACT2 it was clinical response [6,9▪,10]. ACT1 and ACT2 were published in 2005 in the New England Journal of Medicine. The RCT compared the efficacy of infliximab for induction and maintenance therapy in adults with moderate-to-severe ulcerative colitis. Patients received placebo or infliximab [5 or 10 mg/kg intravenous at week 0, 2, and 6, then every 8 weeks up to 46 weeks (ACT1) or 22 weeks (ACT2)] [6]. For both ULTRA and ACT, the Mayo score was used to define clinical remission and clinical response at week 8 and 30 (week 8 and 32 for ULTRA). The Mayo score includes assessment of stool frequency, rectal bleeding, endoscopy, and the physician's global assessment. Clinical response is defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%. Clinical remission is defined as a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point.

Since the Study of Biologic and Immunomodulator Nave Patients In Crohn's Disease trial in 2010 showed superiority of infliximab plus azathioprine versus infliximab monotherapy or azathioprine (AZA) monotherapy in patients with Crohn's disease [11], the equivalent trial for ulcerative colitis was awaited. The UC Success trial showed that in biologic-naïve patients who were either naïve to or had stopped AZA at least 3 months ago, steroid-free remission at week 16 was achieved in a greater proportion of patients who received infliximab and azathioprine compared to azathioprine or infliximab monotherapy. These data show the same results in ulcerative colitis that are seen in Crohn's disease – namely that dual therapy is superior to monotherapy. The reasons for this additive effect could be improved levels of the biologic and complementary mechanisms of action on inflammation.

Other biologic options for ulcerative colitis are in clinical trials. Vedolizumab is a gut-selective monoclonal antibody targeting the α4β7 integrin that inhibits trafficking of gut homing lymphocytes and monocytes. The study compared vedolizumab infusion every 4 weeks to placebo in patients with active ulcerative colitis who had failed treatment with corticosteroids, purine antimetabolites, and TNFα antagonists. By week 6, a total of 16.9% of patients receiving the monoclonal antibody were in clinical remission compared with 5.4% of those on placebo (P = 0.001). In addition, 40.9% of the vedolizumab group had mucosal healing compared with 24.8% of the placebo group (P = 0.0013). A similar trend was seen in both anti-TNF naïve and anti-TNF treatment failure patients [12].

Extended release 9 mg oral budesonide in a multimatrix system (MMX) has been shown to be well tolerated and more effective than placebo to induce remission in mild-to-moderate ulcerative colitis [13]. This gives a great alternative to topical corticosteroids and avoids the side-effects of systemic corticosteroids. MMX mesalamine works on the same technique, making it possible to deliver oral drugs even to the distal colon that most commonly is affected in ulcerative colitis. Kane et al.[14] showed that mesalamine MMX at a dose of 2.4 g/day is effective for maintaining quiescence (no rectal bleeding) in ulcerative colitis patients.

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Although most patients with Crohn's disease have ileocolonic disease, an important minority has isolated colonic disease [15,16]. This group usually is older and has a shorter duration of disease before surgical resection. Most studies of Crohn's disease treatment have not specifically stratified patients into isolated colonic disease, but in general post hoc analyses have not seen any differences in the response rates for this subgroup [17–19].

In Crohn's disease, we have three approved anti-TNF drugs. The only biologic approved for Crohn's disease that works through a different mechanism of action is natalizumab. Natalizumab is a humanized monoclonal IgG4κ antibody that selectively binds to the α4-integrin component of adhesion molecules found on lymphocytes, monocytes, and eosinophils. The effect in Crohn's disease is most likely because of blockade of leukocyte adhesion factors α4β1 and α4β7 [20]. Unfortunately, a small group of patients treated with natalizumab develop progressive multifocal leukoencephalopathy (PML) from its use. A recent study provides hope that patients can be risk stratified for PML. The highest risk time to develop PML is around 2 years into treatment [21▪▪]. Prior use of an immunosuppressant was also more common in the group who developed PML. The group of patients who developed PML were all positive for antibodies to John Cunningham virus. But even for patients with a negative result, the risk to develop PML with natalizumab therapy may not be zero. This is for two reasons: first, there is a greater than 2% false-negative rate using the currently available test [22,23] and the other reason is that a patient can get infected during the time of therapy and seroconvert. This occurs at a rate of 2% per year. In summary, the study showed three risk factors to develop PML under natalizumab therapy: prior use of immunosuppressants, length of natalizumab therapy, and John Cunningham-virus antibody status. For the group with all three risk factors, there is an estimated incidence of PML of 11.1 cases per 1000 patients. On the other hand, 39% of patients were negative for antibodies to John Cunningham virus and therefore could relatively safely be treated with this effective therapy.

Patients and physicians wish to know whether some patients can discontinue therapy with infliximab. The STORI trial investigated the clinical course of patients on dual therapy with infliximab and an antimetabolite who discontinue infliximab. Almost half of the patients experienced a relapse 1–2 years after discontinuation of infliximab. But the interruption of infliximab for several months did not result in decreased effectiveness and 93% of the re-treated patients were in remission after 30 days [24]. This might be because of concomitant therapy with a thiopurine and corticosteroid preinfusion prophylaxis. The STORI study found that risk factors for relapse after infliximab cessation include male sex, absence of surgical resection, leukocyte counts greater than 6 × 109/l, HgB 14.5 g/dl or less, CRP of at least 5 mg/l, and fecal calprotectin of at least 300 μg/g. These data together suggest that in most patients who respond to infliximab for Crohn's disease, the therapy should be continued. However, a subset with low-risk factors and who are on thiopurines may be safely stopped.

A relatively new field of treatment for fistulas has been the injection of stem cells directly into the fistulas [25–29]. Either derived from adipose tissue or bone marrow, the injection of stem cells resulted in complete closure (7 of 12 patients) [30,31] of fistulas with only few side-effects over the 12 months patients were followed. A recently finished phase III trial compared different concentrations of adipose tissue-derived stem cells in combination with fibrin glue to fibrin glue alone in 200 patients [32▪], showing promising healing rates ranging from 52.4 to 57.1% in the stem cell group compared to 37.3% in the fibrin glue group 12 months after injection.

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In the CESAME observational cohort study (Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France) that includes 19 486 patients, 6 patients fulfilled the diagnostic criteria for primary intestinal lymphoproliferative disorder (PILD). The calculated odds ratio (OR) with ongoing exposure to any immunosuppressant vs. immunosuppressant naïve status was 2.81 [95% confidence interval (CI), 0.28 to infinity; P = 0.40]. The conclusion of this study was that middle-aged male patients with prior exposure to thiopurines were at highest risk for PILD [33]. From the same database, the risk to develop nonmelanoma skin cancer [(NMSC) basal cell and squamous cell carcinoma] showed that ongoing and a prior exposure to thiopurines increases the risk for IBD patients to develop NMSC (hazard ratio 5.9; 95% CI 2.1–16.5; P = 0.0006 and hazard ratio 1.08; 95% CI, 1.05–1.11; P < 0.0001, respectively) [34]. For the use of anti-TNF, most data are available on infliximab in rheumatoid arthritis (RA). The meta-analysis from these registries and long-term extension studies did not show an increased risk of total malignancy in patients undergoing anti-TNF therapy. Similar results are seen in IBD [35▪▪]. Lichtenstein et al. performed a pooled analysis including 10 IBD trials (seven Crohn's disease and three ulcerative colitis) and a total of 2385 patients. A total of 13 patients (two placebo-treated patients and 11 infliximab-treated patients) developed malignancies. Of the two cases with lymphoma, both patients in addition were exposed to azathioprine. Comparing placebo versus immunomodulator therapy, results support that thiopurines (AZA and 6-MP) may increase the risk for lymphoproliferative disorders.

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Overall, the incidence of the two subtypes collagenous colitis and lymphocytic colitis has risen to an average incidence of 24.9 per 100 000 people in several studies from the USA and Europe [36–39]. It is unclear if this is because of increased awareness and more biopsies or a true rise in the incidence. The two major studies that reported an increase in incidence were from Sweden and the USA [40–42]. In a recent study from Spain, the mean annual standardized incidence rate of microscopic colitis was 18 cases per 100 000 inhabitants and microscopic colitis was found in 13.7% of patients with diarrhea of unknown origin. In patients with ROME III criteria for IBS, microscopic colitis was present in 10.7% [43▪▪]. Microscopic colitis was found in about 10% of all patients with nonbloody diarrhea [41].

Recent research has shown several new aspects of this disorder. Microscopic colitis is still more common in women than in men with an OR of 2.98 and 95% CI of 2.84–3.12 [44]. The age of onset is usually in the 6th decade, and the most commonly associated autoimmune disease remains celiac disease [39]. In the general population, the disease concomitance with celiac disease is 50 times higher than expected, mostly in middle-aged women. Patients who develop malabsorption or weight loss with microscopic colitis or who have refractory diarrhea should be evaluated for celiac disease.

Bile acid diarrhea is also seen and is the most common nonautoimmune disease associated with collagenous colitis and lymphocytic colitis [39]. In the classic description of microscopic colitis, the endoscopic appearance of the colon is normal and histopathology is used to make the diagnosis. A recent study showed that an inflamed terminal ileum was seen in 37–57% of patients with microscopic colitis [36]. In contrast to the recent evidence that inflammation increases the risk for neoplasia, a case–control study of 647 microscopic colitis patients found that microscopic colitis was negatively correlated with Colorectal Cancer and adenoma [45]. This could be because of differences in the nature of the inflammation and the increased surveillance performed in the evaluation of the disease itself by colonoscopy and biopsies.

The treatment of choice for moderately or severely symptomatic microscopic colitis and for mild disease that does not respond to more conservative measures remains oral budesonide [38]. Patients treated with budesonide have a higher response than with prednisone and tend to have a lower risk of recurrence [46]. Only very limited data are available on treatment for refractory microscopic colitis, though there is some response to anti-TNF therapy in three out of four patients treated with infliximab or adalimumab for over 1 year [47]. Possible benefits of steroids could be restoration of normal eosinophil and T-cell activation state, amplification of bile acid transporter expression, and decreased colonic water secretion [48–50].

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The general principles guiding endoscopy in idiopathic colitis are a delineation of the extent and severity of inflammation, intubation of the terminal ileum, and obtaining biopsies of both involved and uninvolved mucosa. For diagnosing microscopic colitis, the question always remains if left-sided biopsies are sufficient as some prior studies have suggested that collagen thickening and lymphocyte infiltrate are less prominent in the distal colon [51,52]. Bjørnbak et al.[53] found that left-sided biopsies are sufficient most of the time as 95–98% of patients have changes in both the left and right colon. Until further evidence is available, left and right colon biopsies remain the gold standard [53].

In addition to white light endoscopy, confocal laser endomicroscopy (CLE) is a way of performing ‘real time’ pathology. It provides a great tool to examine mucosal healing and dysplasia, and enables the endoscopist to take targeted biopsies in patients with Crohn's disease [54]. This has also been shown in ulcerative colitis, in which CLE was found to be reliable in evaluating the inflammatory activity in macroscopically normal mucosa [55]. CLE was also able to identify cell shedding and barrier loss of the intestinal epithelial cell via passage of fluorescein; this predicted relapse of IBD therefore might become an important tool for both surveillance and stratifying patients for risk of relapse [56▪].

CLE has been studied to differentiate mild ulcerative colitis from microscopic colitis. In 150 patients, CLE showed a specificity of 100% to differentiate between ulcerative colitis and microscopic colitis. In ulcerative colitis, mild crypt abnormalities were seen, whereas a thickened collagenous band was seen in microscopic colitis [57].

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Introduction of the anti-TNF agents as therapy for Crohn's disease and ulcerative colitis has revolutionized the treatment of these chronic diseases. Long-term treatment with these agents seems to be both effective and well tolerated, though cessation of therapy can be considered for a subset of patients in deep remission and on thiopurines. New agents are currently being evaluated including vedolizumab, which represents an alternative to anti-TNF strategies. In microscopic colitis, budesonide remains the treatment of choice, but in refractory cases anti-TNFs or thiopurines can been used.

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Conflicts of interest

Disclosures: This study was supported by NIH CA137869 to M. T. A. and a Bankhead Coley Team Science Grant to M. T. A. In addition, M. T. A. has served as a consultant to Abbott, AMGEN, Merck, Prometheus, Salix Laboratories, Sanofi Aventis, Takeda Pharmaceuticals and UCB.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 102).

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An important study outlining the importance of mucosal healing as a predictor for colectomy.

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A landmark study that evaluates the long-term effectiveness, safety and tolerance of infliximab treatment.

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A study that evaluates the efficacy of an infliximab alternative, adalimumab, in the treatment of ulcerative colitis.

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A landmark study that provides important tools to select patients eligible for natalizumab therapy while minimizing the risk for the feared side-effect of PML.

22. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68:295–303.
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An impressive study evaluating a relatively new strategy and technique for the treatment of perianal fistulas in patients with Crohn's disease.

33. Sokol H, Beaugerie L, Maynadie M, et al. Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:2063–2071. doi: 10.1002/ibd.22889.
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35▪▪. Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol 2012; 107:1051–1063.

A very important article summarizing the safety and in particular the possible risk for malignancy under TNF treatment. This will help providers and patients to better understand the safety profile of the different available treatment options.

36. Bjornbak C, Engel PJ, Nielsen PL, et al. Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther 2011; 34:1225–1234.
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An important study outlining the incidence of microscopic colitis in patients presenting with diarrhea, increasing the general awareness for this disease.

44. Sonnenberg A, Genta RM. Geographic distributions of microscopic colitis and inflammatory bowel disease in the United States. Inflamm Bowel Dis 2012; 18:2288–2293. doi: 10.1002/ibd.22932.
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53. Bjørnbak C, Engel PJH, Nielsen PL, et al. Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther 2011; 34:1225–1234.
54. Neumann H, Mnkemüller K, Günther C, et al. Advanced endoscopic imaging for diagnosis of Crohn's disease. Gastroenterol Res Pract 2012; 2012:301541.
55. Li CQ, Xie XJ, Yu T, et al. Classification of inflammation activity in ulcerative colitis by confocal laser endomicroscopy. Am J Gastroenterol 2010; 105:1391–1396.
56▪. Kiesslich R, Duckworth CA, Moussata D, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 2012; 61:1146–1153.

An important study evaluating the use of this new technology in clinical practice.

57. Neumann H, Langner C, Grauer M, et al. Confocal laser endomicroscopy (CLE) enables accurate in vivo differentiation between microscopic colitis and quiescent ulcerative colitis – a longitudinal case study. DDW. San Diego, 2012.

Crohn's disease; idiopathic colitis; indeterminate colitis; microscopic colitis; ulcerative colitis

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