Twenty-five MC-related hospitalizations were observed in 20 patients (15%), including 9 patients (36%) at diagnosis (Table 2). The cumulative probability of hospitalization was 7.7% (3.0%–12.2%) at 1 year, 10.2% (4.8%–15.3%) at 5 years, and 14.7% (8.2%–20.8%) at 7 years, with no significant difference between CC and LC (P = 0.6) (see Fig. 1, Supplementary Digital Content 1, http://links.lww.com/CTG/A91). The reasons for hospitalization were diarrhea (100%) with nocturnal stools (12%), hypokalemia (32%), abdominal pain (16%), rectal bleeding (8%), dehydration (8%), and anal incontinence (4%). The median duration of hospitalization was 10 days (6,14).
Associated autoimmune diseases
At diagnosis, 18 patients (15%) had AI disease. At the end of follow-up, 32 patients (25%; CC, 25%; LC, 23.2) presented 38 associated autoimmune diseases. The most frequent were thyroid disorders (24%), rheumatoid arthritis (16%), celiac disease (15.8%), and giant-cell arteritis (10.5%) (Table 3).
Dysplasia and cancer
Twelve patients (9%) had one or more colonic adenomas detected during the follow-up, 4 of them (33%) with high-grade dysplasia. No case of colorectal cancer was observed (SIR: 0; 95% CI: 0–0.28). Twenty neoplasias were observed in 17 patients (11%). Fifteen of them were diagnosed after MC diagnosis. No increased risk of overall cancer was observed compared with the general population (SIR: 0.83; 95% CI: 0.44–1.27). (see Tables 2 and 3, Supplementary Digital Content 1, http://links.lww.com/CTG/A91).
At diagnosis, colonoscopy was performed for 121 patients (94%) and rectosigmoidoscopy for 9 patients (6%). During a median follow-up of 9.6 years (7.6–10.6), 70 colonoscopies and 40 rectosigmoidoscopy were performed again. Erythema was observed in 17 patients (13.0%) and in 23 endoscopies (9.5%) with no significant difference between CC (14.9%, n = 13) and LC (8.3%, n = 4) (P = 0.42). Superficial ulcerations were observed in 2 patients and in 0.4% (n = 2) of endoscopies, with no difference between LC (n = 1) and CC (n = 1). These lesions were located in the sigmoid (61.1%), left colon (44.4%), transverse colon (33.3%), rectum (27.8%), and right colon (27.8%). No cases of perforation have been reported.
Treatment of MC
At diagnosis, 70 patients (55.6%) were initially treated with budesonide, 29 (23%) with 5-ASA, 32 (25.4%) with antidiarrheal drugs, 5 (4%) by antibiotics, and 1 (0.8%) by cholestyramine. Only 1 patient (0.8%) was treated with systemic corticosteroids. Of the 85 patients who had a medication at risk of MC, it was stopped in 22 patients (26%). It was the only intervention in 9 patients (7%). Sixteen patients (13%) received no treatment. The efficacy of first-stage treatment was 99% (Table 4).
Among the 37 patients who relapsed, the distribution of treatments was similar. Two patients (5%) had no treatment, and 1 patient had only stopped a potential medication at risk. Twenty-two (60%) patients were treated by budesonide with a median duration of 145 days (interquartile range, 90–270) and 8 (21.6%) by 5-ASA. The initial efficacy of treatment for the first relapse was 97%.
Overall, the cumulative probability of exposure to budesonide was 55.6% (46.0%–63.5%) at 1 year, 57.3% (47.7%–65.1%) at 5 years, and 58.2% (48.6%–66.0%) at 7 years. The median duration of initial treatment with budesonide was 92 days (70; 168). Thirty patients (40.5% of patients treated with budesonide) required more than one course of budesonide and 4 (5.4%) had budesonide resistance. One patient was effectively treated with azathioprine for 2.5 years for resistance to budesonide. Three patients (2.4%) were exposed to systemic corticosteroids. Symptomatic treatment (antimotility, antisecretory, or other antidiarrheal drugs) was initiated in 39% of patients. It was effective in 69% of cases (Table 4).
No side effects have been reported with budesonide. Five patients (16%) had to stop mesalazine for adverse effects (acute pancreatitis, hepatic and hematologic toxicity, allergic reaction, digestive intolerance). The only patient treated with azathioprine developed an ENT squamous cell carcinoma.
Factors associated with relapse
In the multivariable analysis, the age at diagnosis (HR, 1.03; 95% CI, 1.00–1.06; P = 0.02) and treatment with budesonide at diagnosis (HR, 2.50; 95% CI, 1.11–5.55; P = 0.03) were associated with the risk of relapse. Gender, smoking at diagnosis, discontinuation of medication at risk of MC, or delay in the diagnosis were not associated with relapse (see Table 1, Supplementary Digital Content 1, http://links.lww.com/CTG/A91).
In this large French population-based study of MC, with a median follow-up of nearly 10 years, we report a relapse rate of 30% and a hospitalization rate of 15%. A quarter of patients had an associated AI disease. Budesonide was prescribed in 60% of patients and was effective in 95% of them. Twenty percent of patients treated with budesonide developed steroid dependence and 5% steroid resistance.
Herein, the association of MC with autoimmune diseases is described. However, we found a less frequent association than previously reported (28%–43%) (3,24,25). These associations were mainly reported by studies of expert centers exposed to important selection bias. Moreover, unlike these studies, we excluded type 2 diabetes from the autoimmune diseases spectrum. Few studies have reported diagnosis change between CL and CC over time. In our study, 8 patients changed their diagnosis during follow-up, 6 (13%) from CC to LC and 2 (5%) from LC to CC. However, only half of the patients had a second endoscopy with new biopsies during follow-up. For these reasons, we may have underestimated the rate of change in diagnosis over time. A recent Danish cohort reports similar trends, with a changed to a different MC subgroup in, respectively, 6% and 9% of CC and LC after 2 years of follow-up. One objective of our study was to assess the risk of colorectal cancer in patients with MC. Chronic inflammation is responsible for colonic neoplasia in Crohn's disease or ulcerative colitis (26). During the 10 years of follow-up, no colorectal cancer has been detected. Two studies have reported a decreased risk of colorectal cancer in patients with MC (27,28). One of the hypotheses mentioned was the more frequent colonoscopy in these patients, allowing earlier diagnosis and treatment of preneoplastic lesions. We used data of the Somme cancer registry and observed no increased or decreased risk of digestive or extradigestive cancer in patients with MC.
Budesonide was the most used treatment in our cohort. Its high efficacy is comparable with data from the literature (clinical remission: 80%–86%) (14,29,30). We observed a high rate of steroid dependence (22%), which is similar to that reported in Crohn's disease and ulcerative colitis (31). By contrast, a population-based study of MC conducted by Gentile et al. (19) reported a 64% dependence on corticosteroids. However, the study included smaller patient population, and more than 20% of patients were treated with systemic corticosteroids. The same study found a rate of steroid resistance for budesonide of 3.5%.
In our study, more than 1 in 4 patients experienced a relapse. This relapse rate is consistent with data from several prospective studies (25%–61%) (17,21,29,32). These results may support the interest of maintenance treatment with budesonide (14). As demonstrated by a randomized controlled clinical trial, a 12-month treatment with budesonide is effective and well tolerated. Identifying factors predicting relapse would identify patients who could benefit from such treatment. In our study, older age at diagnosis and budesonide exposure at diagnosis were associated with relapse. A post-hoc analysis of 4 randomized studies conducted in 2013 (32) identified the following risk factors of disease relapse: number of stools at diagnosis above 5, a delay at diagnosis of more than 1 year, and the absence of maintenance treatment by budesonide. In our study, the association between budesonide treatment at first flare and risk of relapse was observed. Comparable results have been observed in Crohn's disease or ulcerative colitis where the first course of corticosteroid could be a surrogate marker of disease severity. New prospective studies will be needed to assess the risk of relapse.
Our study has several strengths. First, histologic confirmation by a group of 4 pathologists was systematically blinded to initial results. Second, our cohort is the largest among the population-based cohorts (15,16,19,20), except for the study by Fernández-Bañares (21) which followed 184 patients with MC but only over a period of 28 months. The duration of follow-up of our study is so far the longest reported in the literature. The number of variables identified, the cross-referencing of data through several sources (university hospital, private gastroenterologists, general practitioner), and the methodology of data collection validated by the EPIMAD register reinforce the validity of the collected data. One of the limitations of our study is the retrospective data collection. Furthermore, it was demonstrated in previous studies that there is a similarity between symptoms of MC and irritable bowel syndrome (IBS), with 38%–58% of patients with MC fulfilling IBS criteria (33,34). This leads to difficulty in individualizing an authentic flare of MC from IBS symptoms.
In our large population-based cohort with a median follow-up of 10 years, two-third of patients with MC observed long-term clinical remission after diagnosis. A high prevalence of autoimmune disease has been observed, but no increased risk of cancer was observed. Fifteen percent of patients were hospitalized due to MC. Budesonide was the most used and most effective treatment.
CONFLICTS OF INTEREST
Guarantor of the article: Mathurin Fumery, MD.
Specific author contributions: J.L. and M.F.: Study concept and design. J.L.: Acquisition of data. D.D., H.S., J.L., M.F., H.B.K., and O.G.: Analysis and interpretation of data. J.L. and M.F.: Drafting of the manuscript. C.G.R., G.S., H.S., D.D., E.N.K., J.L.D., F.B., C.Y., D.C., H.B.K., O.G.: Critical revision of the manuscript for important intellectual content. M.F., J.L.: Approval of the final manuscript.
Financial support: None.
Potential competing interests: None.
WHAT IS KNOWN
- ✓ MC is now recognized as one of the most common causes of chronic diarrhea, but long-term natural history of MC is unknown.
WHAT IS NEW HERE
- ✓ About one-third of patients will relapse, and 15% will be hospitalized.
- ✓ Twenty-five percent of patients will present an associated autoimmune disease.
- ✓ MC did not increase risk of digestive and extradigestive cancer.
- ✓ About one-quarter will present corticodependency.
- ✓ MC is a global disease associated with a systemic disease and risk of flare-related hospitalization.
- ✓ No increased risk of cancer is associated with MC.
Collaborators: Fadi Assi, Abselam Bental, Sylvie Dautreme, Mathieu Eoche, Denis Laude, Jean Christophe Prevost, Francois Sevenet, Arsene Papazian, Hubert Mancheron, Alain Rudelli, Bruno Heyman, Michel Wantiez, Gil Cohen, Marine Lagarde, Nicole Reix, Marion Groux, Marthe Chavance-thelu, Morgane Bourgeois Fumery, Richard Delcenserie, Jean-Paul Joly, Vincent Hautefeuille, Justine Thomas, Sami Hakim, Charles Sabbagh.
1. Lindström CG. “Collagenous colitis” with watery diarrhoea—A new entity? Pathol Eur 1976;11:87–9.
2. Fumery M, Kohut M, Gower-Rousseau C, et al. Incidence, clinical presentation, and associated factors of microscopic colitis in northern France: A population-based study. Dig Dis Sci 2016.
3. O'Toole A, Coss A, Holleran G, et al. Microscopic colitis: Clinical characteristics, treatment and outcomes in an Irish population. Int J Colorectal Dis 2014;29:799–803.
4. Bjørnbak C, Engel PJH, Nielsen PL, et al. Microscopic colitis: Clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther 2011;34:1225–34.
5. Tong J, Zheng Q, Zhang C, et al. Incidence, prevalence, and temporal trends of microscopic colitis: A systematic review and meta-analysis. Am J Gastroenterol 2015;110:265–76.
6. Järnerot G, Tysk C, Bohr J, et al. Collagenous colitis and fecal stream diversion. Gastroenterology 1995;109:449–55.
7. Austin LL, Dobbins WO. Studies of the rectal mucosa in coeliac sprue: The intraepithelial lymphocyte. Gut 1988;29:200–5.
8. Fischer H, Holst E, Karlsson F, et al. Altered microbiota in microscopic colitis. Gut 2015;64:1185–6.
9. Fine KD, Do K, Schulte K, et al. High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. Am J Gastroenterol 2000;95:1974–82.
10. Järnerot G, Hertervig E, Grännö C, et al. Familial occurrence of microscopic colitis: A report on five families. Scand J Gastroenterol 2001;36:959–62.
11. Roth B, Manjer J, Ohlsson B. Microscopic colitis and reproductive factors related to exposure to estrogens and progesterone. Drug Target Insights 2013;7:53–62.
12. Fernandez-Bañares F, Esteve M, Salas A, et al. Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea. Dig Dis Sci 2001;46:2231–8.
13. Beaugerie L, Pardi DS. Review article: Drug-induced microscopic colitis—Proposal for a scoring system and review of the literature. Aliment Pharmacol Ther 2005;22:277–84.
14. Münch A, Bohr J, Miehlke S, et al. Low-dose budesonide for maintenance of clinical remission in collagenous colitis: A randomised, placebo-controlled, 12-month trial. Gut 2016;65:47–56.
15. Chan JL, Tersmette AC, Offerhaus GJ, et al. Cancer risk in collagenous colitis. Inflamm Bowel Dis 1999;5:40–3.
16. Bonner GF, Petras RE, Cheong DM, et al. Short- and long-term follow-up of treatment for lymphocytic and collagenous colitis. Inflamm Bowel Dis 2000;6:85–91.
17. Fernández-Bañares F, Salas A, Esteve M, et al. Collagenous and lymphocytic colitis. evaluation of clinical and histological features, response to treatment, and long-term follow-up. Am J Gastroenterol 2003;98:340–7.
18. Goff JS, Barnett JL, Pelke T, et al. Collagenous colitis: Histopathology and clinical course. Am J Gastroenterol 1997;92:57–60.
19. Gentile NM, Abdalla AA, Khanna S, et al. Outcomes of patients with microscopic colitis treated with corticosteroids: A population-based study. Am J Gastroenterol 2013;108:256–9.
20. Sveinsson OA, Orvar KB, Birgisson S, et al. Clinical features of microscopic colitis in a nation-wide follow-up study in Iceland. Scand J Gastroenterol 2008;43:955–60.
21. Fernández-Bañares F, de Sousa MR, Salas A, et al. Impact of current smoking on the clinical course of microscopic colitis. Inflamm Bowel Dis 2013;19:1470–6.
22. Schneider S, Rampal A, Hebuterne X, et al. Microscopic colitis. Gastroenterol Clin Biol 1998;22:431–41.
23. Gower-Rousseau C, Salomez JL, Dupas JL, et al. Incidence of inflammatory bowel disease in northern France (1988-1990). Gut 1994;35:1433–8.
24. Olesen M, Eriksson S, Bohr J, et al. Lymphocytic colitis: A retrospective clinical study of 199 Swedish patients. Gut 2004;53:536–41.
25. Pardi DS, Ramnath VR, Loftus EV, et al. Lymphocytic colitis: Clinical features, treatment, and outcomes. Am J Gastroenterol 2002;97:2829–33.
26. Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: The role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004;287:G7–17.
27. Tontini GE, Pastorelli L, Spina L, et al. Microscopic colitis and colorectal neoplastic lesion rate in chronic nonbloody diarrhea: A prospective, multicenter study. Inflamm Bowel Dis 2014;20:882–91.
28. Yen EF, Pokhrel B, Bianchi LK, et al. Decreased colorectal cancer and adenoma risk in patients with microscopic colitis. Dig Dis Sci 2012;57:161–9.
29. Miehlke S, Madisch A, Karimi D, et al. Budesonide is effective in treating lymphocytic colitis: A randomized double-blind placebo-controlled study. Gastroenterology 2009;136:2092–100.
30. Miehlke S, Madisch A, Kupcinskas L, et al. Double-blind, double-dummy, randomized, placebo-controlled, multicenter trial of budesonide and mesalamine in collagenous colitis. Gastroenterology 2012;142:S-211.
31. Faubion WA, Loftus EV, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: A population-based study. Gastroenterology 2001;121:255–60.
32. Miehlke S, Hansen JB, Madisch A, et al. Risk factors for symptom relapse in collagenous colitis after withdrawal of short-term budesonide therapy. Inflamm Bowel Dis 2013;19:2763–7.
33. Abboud R, Pardi DS, Tremaine WJ, et al. Symptomatic overlap between microscopic colitis and irritable bowel syndrome: A prospective study. Inflamm Bowel Dis 2013;19:550–3.
34. Limsui D, Pardi DS, Camilleri M, et al. Symptomatic overlap between irritable bowel syndrome and microscopic colitis. Inflamm Bowel Dis 2007;13:175–81.
Supplemental Digital Content
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology