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Report From the Falk Workshop on Microscopic Colitis: Creating Awareness for an Underappreciated Disease

2012; Elsevier BV; Volume: 143; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2012.09.014

1528-0012

Elisabeth R. Corti–Hoekstra, Jan M. H. van den Brande, Maikel P. Peppelenbosch,

Inflammatory Bowel Disease

Microscopic colitis (MC) attracts relatively little attention, but nevertheless represents a highly relevant clinical problem known to all practicing physicians. The reason for its relative obscurity has always been the lack of insight into its pathogenesis, resulting in blanket treatments with topical steroids. These, however, fail in a substantial proportion of patients and have required life-long maintenance with budesonide. Furthermore, incidence is rising. As became evident at the recent workshop on MC held May 3, 2012, in Basel, Switzerland, the underlying pathogenic mechanisms are progressively being uncovered and more rational targeted treatment will be the future of care. In particular it became clear that the disease is largely mediated through intra-epithelial CD8+ T cells and various subtypes may require personalized medicine. In this meeting report, we critically summarize these novel insights and suggest the lines future research in this important affliction should follow. The meeting was attended by approximately 1000 leading clinicians and scientists from all over the world. MC is characterized by chronic, nonbloody diarrhea. Other symptoms include abdominal pain, fecal incontinence, and weight loss. The clinical course is chronic relapsing. The symptoms can seriously affect quality of life.1Hjortswang H. Tysk C. Bohr J. et al.Health-related quality of life is impaired in active collagenous colitis.Dig Liver Dis. 2011; 43: 102-109Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The incidence of MC has risen in recent years, from 7/100,000 in 1993 up to a current incidence of 12–19/100,000 per year, comparable with inflammatory bowel disease (IBD; Lectures of D. S. Pardi, The Mayo Clinic, Rochester, MN; and J. Bohr, Örebro University Hospital, Örebro, Sweden). However, whereas IBD is subject to intense research effort and basic and clinical experimentation, MC attracts less attention and clinicians resort to treating this disease with budesonide, often life-long, because of recurring disease. The presentations at this workshop underscored the variability in the disease pathogenesis, and the need for more personalized approaches in therapy. Typically, the diagnosis of MC is made by its highly specific histologic features that set it apart from Crohn's disease, ulcerative colitis, infectious colitis, and irritable bowel syndrome. Although at present most physicians treat all MC in a similar fashion, 2 subtypes are distinguished based on histopathologic features: Lymphocytic colitis (LC) and collagenous colitis (CC). Present consensus in the field is that these are different representations of the same disease. In LC an increased number of surface intra-epithelial lymphocytes is typical, usually >20/100 epithelial cells. In CC, a continuous subepithelial fibrous band underneath the surface epithelium is found. But in both LC as well as CC, increased densities of lymphocytes in the epithelium and lamina propria are found. A Th1 cytokine profile has previously been reported in both LC and CC with increased interferon-γ, tumor necrosis factor (TNF), and interleukin-15. Immunologic studies at Örebro University in Sweden aimed to characterize the intestinal mucosal lymphocytes in MC patients. Data were presented demonstrating increased frequencies of CD8+ T cells in both the epithelium and lamina propria of both LC and CC patients, whereas the frequencies of CD4+ T cells were decreased (lecture of E. H. Hörnquist, Örebro University School of Health and Medical Sciences, Örebro, Sweden). This suggests a different etiology compared with IBD, particularly one that is mediated by these intra-epithelial CD8+ T lymphocytes. In this sense, the disease is reminiscent of the small intestinal representation of celiac disease and indeed genetic factors predisposing to celiac disease also predispose to MC. Patients with anti-gliadin antibodies benefit from a gluten-free diet. Thus, this subgroup of patients should first be treated by dietary intervention before topical steroids are employed. The relationship between celiac disease and MC in general is underexplored. Although the incidence of MC already approaches that of IBD, it is felt that current epidemiologic figures may well understate true incidence. In part, this is explained by the diagnostic methods. Recently, it became evident that by taking biopsies from the left colon only, the diagnosis can be missed. In the cecum there are naturally more intra-epithelial lymphocytes than in the rectum,2Machado C.S. Rodrigues M.A. Maffei H.V. Gut intraepithelial lymphocyte counts in neonates, infants and children.Acta Paediatr. 1994; 8312: 1264-1267Crossref Scopus (14) Google Scholar so that it is important for the pathologist to know where the biopsies were taken (lecture of D. E. Aust, Universitätsklinikum Carl Gustav Carus, Dresden, Germany). Indeed, with the increase in aging populations in developed countries, it is to be expected that incidence will further increase because it is typically a disease of the elderly, with the peak diagnosis generally occurring in the 6th decade of life. The increasing incidence of MC together with its autoimmune-like features fits well with the general trend of increasing prevalence of autoimmune disease. Strikingly, this increase is mainly in older patients and not in those of younger age, setting it apart from other gastrointestinal autoimmune disorders, but similar to rheumatoid arthritis. Consistent with a different status of MC is the observation that infliximab tends to be ineffective in this disease (in contrast with Crohn's disease or ulcerative colitis). Initial responses to adalimumab in CC have been described in a case report of 3 patients. Treatment with adalimumab failed to maintain remission in 2 patients3Münch A. Ignatova S. Ström M. Adalimumab in budesonide and methotrexate refractory collagenous colitis.Scand J Gastroenterol. 2012; 47: 59-63Crossref PubMed Scopus (57) Google Scholar (patients quickly developed vomiting and abdominal pain) and was not effective in a third. Thus, early indications are that anti-TNF therapy does not seem to be as effective in MC as in IBD. This fits well with the notion that infliximab acts by provoking apoptosis in the CD4+ compartment thus counteracting chronic inflammation.4ten Hove T. van Montfrans C. Peppelenbosch M.P. et al.Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease.Gut. 2002; 50: 206-211Crossref PubMed Scopus (519) Google Scholar CD4+ cells are not markedly increased in this disease in contrast to the CD8+-positive compartment; thus, there is no rationale for using anti-TNF antibodies in MC. However, some patients that fail first-line treatment with topical steroids do react to immunomodulators such as methotrexate. Indeed, efficacy of this type of medication on CD8+ T cells has been well documented in other diseases. Their relative efficacy in microscopic colitis compared with anti-TNF antibodies highlight how knowledge on the pathogenic mechanisms mediating MC (over-reactivity of the intra-epithelial CD8+ compartment) can aid in designing rational treatment. Especially in patients with low expression of the glucocorticoid receptor in the mucosal lymphocytes, such immunomodulators are the first treatment of choice.5Löwenberg M. Verhaar A.P. Bilderbeek J. et al.Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN.EMBO Rep. 2006; 7: 1023-1029Crossref PubMed Scopus (122) Google Scholar Although the notion that the disease is mediated through intra-epithelial infiltration of CD8+ T cells is thus important for devising treatment strategy, an equally important notion is the growing realization that the etiology of MC is multifactorial. A genetic predisposition for MC was suggested by studies that found a human leukocyte antigen association. In addition, an accumulation of MC in families was reported (Lecture of A. Madisch, Klinikum Siloah, Hannover, Germany). Therefore, patients with afflicted family members have to be monitored carefully, even after initial colonic biopsies yielded negative or inconclusive results. Microscopic colitis is clearly triggered by luminal factors as supported by a report of clinical and pathologic improvement after fecal stream diversion via an ileostomy and relapse of disease after restoring continuity. The nature of luminal triggers is unclear, prompting investigations into the microbiome of MC, but may well depend on noxious stimuli such as high intestinal bile acid levels. In support of this notion, MC is reduced by fasting (lecture of A. Münch, Linköping University Hospital, Linköping, Sweden) and positively correlated with drug use (aspirin, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and sertraline).6Fernández-Bañares F. Esteve M. Espinós J.C. et al.Drug consumption and the risk of microscopic colitis.Am J Gastroenterol. 2007; 102: 324-330Crossref PubMed Scopus (167) Google Scholar Indeed, cigarette smoking has shown to be a clear risk factor for both collagenous as well as LC.7Vigren L. Sjöberg K. Benoni C. et al.Is smoking a risk factor for collagenous colitis?.Scand J Gastroenterol. 2011; 46: 1334-1339Crossref PubMed Scopus (74) Google Scholar Furthermore, there is a strong association with autoimmune diseases like rheumatic disease, thyroid disease, and diabetes. Thus, very different from IBD, an increased response to bacterial elements does not seem to be involved and MC is thus to be set apart from conditions like Crohn's disease, ulcerative colitis, and infectious colitis. This has significant consequences for therapy. Multiple randomized, controlled trials have demonstrated the effectiveness of budesonide treatment in collagenous and LC. After a short-term treatment with 9 mg/d, remission rates are as high as 76% and response rates up to 96%; however, relapses are common. In case of relapse after withdrawal a repeated treatment with budesonide or low-dose maintenance therapy are treatment options. Alternative drugs, such as loperamide, cholestyramine, and aminosalicylates, may be considered. Bismuth salicylate is occasionally used, mainly in the United States, but data are limited (lecture of S. Miehlke, Magen-Darm-Zentrum IKE, Hamburg, Germany). The exact role of mesalamine remains unclear. Immunosuppressive agents are considered in patients refractory to other medical treatments. Data are, however, limited to case reports, some with positive results. As mentioned, celiac disease and MC can coincide and then a gluten-free diet should be tried as a first treatment. A possible future therapy could be an intervention in the microbiome through oral macrobiotics, because probiotic treatment of CC with Lactobacillus acidophilus did show some amelioration of disease with respect to stool frequency and the number of liquid stools,8Wildt S. Munck L.K. Vinter-Jensen L. et al.Probiotic treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis.Inflamm Bowel Dis. 2006; 12: 395-401Crossref PubMed Scopus (75) Google Scholar but the absence of a bacterial component in the disease argues against such a therapy. Certainly, more personalized treatments are needed. The Falk Symposium on Microscopic Colitis was successful in creating awareness for an underestimated disease and contributed to the progress of research in the field. MC is common, especially in elderly women and the incidence is rising. MC seems to be mediated by intra-epithelial CD8+ T-cell infiltration, setting it clearly apart from IBD and infectious colitis. Treatment with budesonide remains the main therapeutic strategy, but other treatments are being studied. Further studies are needed to explore the exact pathophysiology as well as new treatment options.