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Originalarbeit
Microscopic Colitis: Clinical Presentation, Treatment and Outcome of 494 Patients Mikroskopische Kolitis: klinische Manifestation, Therapie und Outcome in 494 Patienten Authors
A. Madisch1, S. Miehlke2, F. Bartosch3, B. Bethke4, M. Stolte4
Affiliations
1
3 4
Department of Internal Medicine, Siloah Hospital, Hannover Facharztzentrum Eppendorf, Magen-Darm-Zentrum, Hamburg Universitätsklinikum Dresden, Medizinische Klinik I, Dresden Klinikum Kulmbach, Pathologisches Institut, Kulmbach
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Die kollagene und lymphozytäre Kolitis zählt zu den chronisch-entzündlichen Darmerkrankungen mit dem Leitsymptom chronische wässrige Diarrhö. Ziel: Wir untersuchten prospektiv klinische Parameter, Ansprechen auf medikamentöse Therapien und den klinischen Verlauf eines großen Patientenkollektivs mit kollagener (CC) und lymphozytärer (LC) Kolitis. Patienten und Methoden: Bei Patienten mit histologisch nachgewiesener kollagener und lymphozytärer Kolitis wurden prospektiv anhand standardisierter Fragebögen folgende Parameter erfasst: Symptombeginn und Zeitpunkt der Diagnosestellung, Krankheitsdauer, Stuhlfrequenz und -konsistenz, andere gastrointestinale Symptome einschließlich Gewichtsverlust, Medikamenten-anamnese und Begleiterkrankungen sowie Ansprechen auf die Therapie. Ergebnisse: Insgesamt 494 Patienten (CC, n = 287; LC, n = 207) waren für die Analyse auswertbar. Das mittlere Alter lag bei 65 in der CC- und 61 Jahren in der LC-Gruppe mit einem Anteil von 76 % Frauen in beiden Gruppen. Die Dauer der Symptomatik betrug vor Diagnosestellung durchschnittlich 37 (CC-Gruppe) und 23 Monate (LC-Gruppe). Die gastrointestinale Symptomatik von Patienten mit CC war der mit LC ähnlich. Begleitende Autoimmunerkrankungen wurden häufiger in der Gruppe mit CC (48,4 %) als mit LC (29,6 %) angegeben. Eine anhaltende klinische Remission wurde von 35,5 % in der CC und 38,6 % in der LC-Gruppe berichtet, aber Patienten mit CC (47,7 %) erhielten häufiger Medikamente wie z.B. Kortikosteroide, Antibiotika, Wismutsalicylat oder 5-Aminosalicylsäure (47,7 %) als Patienten mit LC (16,9 %). 18,6 % der CC- und 17,6 % der LC-Patienten wurden regelmäßig mit nichtsteroidalen Antirheumatika behandelt.
Background: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic disorders characterized by watery diarrhea. Aim: To evaluate prospectively the clinical features, response to treatment and outcomes in a large group of patients with CC and LC. Patients and Methods: Patients with histologically confirmed CC and LC were prospectively enrolled to complete a questionnaire on onset and duration of diarrhea, stool frequency and consistency, other gastrointestinal symptoms including weight loss, drug history, treatment success and concomitant diseases. Results: A total of 494 patients (CC, n = 287, LC, n = 207) were available for analysis. The mean age at diagnosis was 65 in CC and 61 years in LC with a identically female predominance (76 % of patients) in both groups. Prior to diagnosis the mean duration of symptoms was 37 in CC and 23 months in LC. CC and LC patients share similar pattern of clinical symptoms. Concomitant autoimmune disorders were more common in CC patients (48.4 %) than in LC patients (29.6 %). Sustained clinical remission was reported by 35.5 % of CC and 38,6 % of LC, but more CC patients (47.7 %) received medication such as corticosteroids, antibiotics, bismuth or 5-aminosalicyclic than LC patients (16.9 %). 18.6 % of CC patients and 17.6 % of LC were regularly using NSAIDs. Conclusion: Collagenous and lymphocytic colitis are frequently diagnosed in elderly female patients. CC and LC share similar symptom pattern, but concomitant autoimmune disease were more common in CC than in LC patients.
● Darm ● kollagene Kolitis ● chronisch entzündliche " "
Darmerkrankung
Key words
● intestine ● collagenous colitis ● chronic inflammatory " " "
bowel disease
received accepted
11.8.2013 8.3.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366281 Z Gastroenterol 2014; 52: 1062–1065 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Dr. Ahmed Madisch Department of Internal Medicine, Siloah Hospital Roesebeckstraße 15 30449 Hannover Germany Tel.: +49/5 11/9 27 22 31 Fax: +49/5 11/9 27 22 69 [email protected]
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
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2
Introduction
Results
!
!
Microscopic colitis (MC) with the two entities collagenous (CC) and lymphocytic colitis (LC) defines two distinct inflammatory diseases of the colon characterized by chronic watery diarrhea and normal radiological and endoscopical appearances [1 – 3]. Diagnosis is established by histological examination, which shows a diffuse inflammatory infiltrate in the lamina propria and epithelium of the colonic mucosa with signs of epithelial damage [3, 4]. CC differs from LC by the presence of a subepithelial collagen band (> 10 µm) adjacent to the basal membrane. In LC, the histomorphological landmark is an increase of intraepithelial lymphocytes of > 20 per 100 epithelial cells [2]. Based on epidemiological studies, MC is diagnosed in 4 to 13 % of patients with chronic watery diarrhea [3, 5, 7]. The reported incidence rate of CC in Europe ranges from 0.6 to 5.2 per 100 000 with a prevalence of 10.0 to 15.7 per 100 000, for LC the reported incidence rate is 3.7 to 4.0 per 100 000 with a prevalence of 8 to 14.2 per 100 000 per year [8, 9, 11 – 13]. Hence, MC is a disease affecting as many patients as Crohn’s disease or ulcerative colitis. The cause of MC is unknown, but it appears to be due to mucosal injury inducing a pathological immunological response to an unknown toxin in the fecal stream. Several large case series showed that chronic or intermittent watery diarrhea is the most common presenting symptom of patients with microscopic colitis [14 – 19]. Most of the large case series focusing on the clinical presentation of patients with microscopic colitis are retrospective analysed. In contrast the following study prospectively assessed the clinical presentation, treatment and outcome of 494 patients with microscopic colitis.
Clinical characteristics A total of 494 patients (CC, n = 287; LC, n = 207) were available for analysis. The demographic and clinical features are summarized " Table 1. CC and LC patients share similar pattern of sympin ● toms. Patients with CC and LC are at older age with a mean age at diagnosis of 65 (range 35 – 92) in CC and 61 years in LC (range 22 – 89). The female predominance (76 % of patients) was identically in both groups. Prior to diagnosis the mean duration of symptoms was 37 ± 8 in CC and 23 ± 6 months in LC. At diagnosis the daily mean stool frequency was 6 in both groups with a range between 1 to 42 in the CC and 1 to 20 in the LC population. Diarrhea was intermittent in 26.2 % of CC and 31.3 % of LC patients. Only a minority of CC and LC patients reported rectal bleeding. Abdominal pain was reported by 55 patients (22 %), weight loss (mean 6 kg) by 100 patients (49 %), and nocturnal stools by 126 patients (64 %) of the CC group. The corresponding rates in the LC group were 26.5 %, 48 % and 60.8 %, respectively " Table 1). (● Concomitant autoimmune disorders such as thyroid dysfunction, rheumatoid diseases and diabetes mellitus were more common in CC patients (48.4 %) than in LC patients (29.6 %). The most common autoimmune disease in LC patients was thyroid dysfunction " Table 1). (21.87 %), rheumatoid arthritis in CC patients (28.2 %) (●
Drug History !
Thirty-eight patients (18.4 %) of LC and of CC fourty-nine patients (17.1 %) were regularly using ASS or NSAIDs. The use of ß-blockers, Statins, ACE-inhibitors, Calcium antagonists and Proton
Patients and Methods !
Between 1998 and 2004 patients with histologically confirmed CC and LC were identified consecutively at the Institute of Pathology. After confirming the diagnosis of microscopic colitis the patients were asked to participate in the study and to complete a questionnaire including following parameters: onset and duration of diarrhea, stool frequency and consistency, other gastrointestinal symptoms including weight loss, drug history, concomitant diseases and treatment success. All patients underwent colonoscopy due to diarrheal symptoms. The returned questionnaires were consecutively collected and analyses without recording the return rate and time between diagnosis and the questionnaire completion. The histological assessment was reviewed by one experienced GI pathologist (M.S.) who confirmed the diagnosis of collagenous and lymphocytic colitis based on accepted histopathological criteria. These criteria included an increased mixed inflammatory infiltrate in the lamina propria, increased number of intraepithelial lymphocytes (> 20 per 100 epithelial cells) in LC, a surface epithelial damage, and the presence of an abnormal subepithelial collagen band (> 10 µm) adjacent to the basal membrane required for the histological diagnosis of CC. Diarrhea was defined as ≥ 3 bowel movements per day with a soft or liquid stool consistency.
Table 1
Clinical characteristics and symptoms in 287 CC and 207 LC patients
clinical characteristics
CC (n = 287)
LC (n = 207)
and symptoms age (years), median (range) gender female, n (%)
66 (35 – 92) 220 (76.9 %)
61 (22 – 89) 158 (76)
stool frequency, median (range)
6 (3 – 42)
6 (3 – 20)
stool consistency – watery (%)
85
78.5
stool components (%) – blood
5.6
6.8
– mucus
29.0
39.5
sustained diarrhea (%)
63.6
58.7
intermittent diarrhea (%)
26,2
31.3
nocturnal stools (%)
64
60.8
abdominal pain (%)
22.0
26.5
weight loss – % of patients
49
48
– mean of weight loss (kg)
3
6
general fatigue (%)
5
5
associated disorders (%) – thyroid dysfunction
20.3
– rheumatoid arthritis
28.2
9.2
– diabetes mellitus
11.2
7.2
21.87
– psoriasis
3.8
3.4
– neurodermitis
3.9
3.9
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
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Originalarbeit
Table 2 Concomitant Drugs potentially related to the development of microscopic colitis.
drugs
ß-Blocker ASS/NSAIDs
CC (n = 287)
LC (n = 207)
%
%
7.7
21.7
17.1
18.4
calcium antagonists
2.4
12.6
ACE Inhibitors
4.2
14.5
statins
1.0
10.6
antidpressive therapy
0.01
0
proton pump inhibitors
9.2
9.2
pump inhibitors were higher in the LC than in the CC group " Table 2). (●
Treatment and Outcome !
35.5 % of CC and 38.6 % of LC patients reported sustained clinical remission. More CC patients (47.7 %) received medication such as antidiarrheals, corticosteroids, antibiotics, bismuth, 5-aminosalicyclic or probiotics than LC patients (16.9 %). The highest remission rates were reported under budesonide with 44.8 % in collagenous colitis and 47.8 % in lymphocytic colitis. The other remission rates ranged between 2.9 % and 14.7 % without any differences between both groups.
Discussion !
In the last decades microscopic colitis has been recognized as a chronic inflammatory bowel disease with a high impact on quality of life [3, 5, 22, 29]. The clinical characteristics and association to other disease and drugs are mostly reported in retrospective case series. To our knowledge, the present study is the largest cohort of patients with MC assessing prospectively the clinical features and treatment outcome. The clinical features in our cohort are in line with those reported retrospectively in larger series [14, 15, 18 – 22]. CC and LC patients of our cohort shared a similar clinical picture with chronic or intermittent watery diarrhea as the most common presenting symptom. In contrast to other case series more than a half had sustained diarrhea, only a minority of patients suffered from intermittent diarrhea (20). Further clinical characteristics include nocturnal stools in more than 60 % of MC patients and mild weight loss in more than 40 % of MC patients. Recent epidemiological studies suggest that the incidence of microscopic colitis is higher than previously considered with a strong female predominance [8, 9]. These studies also demonstrate that those at highest risk of developing microscopic colitis are women in their eighties [23]. In a Swedish epidemiological study Olesen and co-workers showed that microscopic colitis was diagnosed in almost 20 % of those older than 70 years presenting with chronic diarrhea [10]. In the present cohort the median age was more than 60 in both groups with a female predominance of 76 %. Thus, in older female patients with chronic or intermittent diarrhea diagnostic work-up should focus on microscopic colitis as a main differential diagnosis that only can be established or ruled out by colonoscopy with multiple biopsies [6, 7].
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
The face of microscopic colitis resembles the subgroups of irritable bowel syndrome (IBS). Since symptoms of microscopic colitis and both diarrhea predominant irritable bowel syndrome or functional diarrhea are similar, a considerable number of patients with microscopic colitis may be misdiagnosed as IBS or a disease overlap could be present in a subgroup of patients. In the present study abdominal pain as a leading symptom of IBS was present in more than 20 % of CC and LC patients. Two studies could show that up to 50 % of patients with established microscopic colitis met the Rome- or Manning criteria for diarrhea-predominant IBS or functional diarrhea and most of them were treated as IBS patients before the correct diagnosis of microscopic colitis was performed [24, 25]. This might be the reason why the diagnosis of MC in our cohort population was also performed after 37 (CC) and 23 (LC) months after the first onset of symptoms. Since clinical symptom-based criteria of IBS are not specific enough to rule out the diagnosis of microscopic colitis, patients with diarrheapredominance of IBS-like symptoms should undergo matrix biopsies from the entire colon to investigate for possible microscopic colitis [6, 7]. There is an ongoing debate about drug consumption as a risk factor for microscopic colitis. Two case-control studies suggested that the use of NSAIDs is associated with microscopic colitis [26, 28]. In our cohort drug intake of NSAIDs were also frequently reported in both CC (17.1 %) and LC (18.4 %) patients. Other suspected drug of the case-control studies such as ß-Blockers, calcium antagonists, ACE inhibitors and statins were only frequently used by LC patients. Hence, many case reports showed a clear relationship to PPI, especially Lansoprazole [27], in our population PPI treatment was only reported by 9.2 % in both groups. In contrast to the case-control-study of Fernandez-Banares and coworkers, who found a significant association between the intake of the antidepressant sertraline and microscopic colitis, no antidepressants were reported by any patient of the present study [28]. Although a significant association of microscopic colitis with drug consumption was observed, a cause-effect relationship has not been established yet. Nevertheless drug-induced microscopic colitis should be considered in clinical practice at least as an exacerbate factor of an existing idiopathic microscopic colitis. The association between microscopic colitis and autoimmune diseases is well described. Patients with MC more often have concomitant autoimmune diseases such as rheumatic disease, celiac disease, thyroid disease and diabetes with an odds ratio of 11.0 (5.1 – 23.8, p < 0.001) in CC patients and of 16.6 (6.4 – 43.1, P< 0.001) in LC patients [29]. In our cohort the most common reported autoimmune disease was a thyroid dysfunction in LC and CC patients, followed by rheumatoid arthritis and diabetes mellitus, especially in LC patients. Diabetes was found in 11.2 % of CC and 7.2 % in LC patients with a similar frequency to retrospective studies (18 – 20). MC is a chronic disorder with a variable course of symptoms during a long-term follow-up. In a long-term follow-up study of our group 30 % of patients may experience persistent diarrhea even 10 years after diagnosis, 50 % showed sustained remission mostly under anti-inflammatory drugs [21]. In the present study spontaneous sustained remission of diarrhea was seen in near 35 % of patients on both groups. Information on treatment and response was available of 68 % CC and 71 % LC patients. More CC (47.7 %) than LC (16.9 %) patients were under treatment supporting the observation in literature that LC often showed a spontaneous resolution of symptoms. The reported response rates of treatment were very low and are not in line with
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the remission rates published in literature [32, 33]. The highest treatment success was observed with budesonide, but the success rates of 44 or 47 % is much lower than the reported at least 80 % in the placebo-controlled trials [30 – 33]. The reason for this result is unclear, but one possible explanation includes the bias, that the majority of the patients who respond to the questionnaires might be those with persisting symptoms. Furthermore the data were patient-based without any medical records from the general practitioners and gastroenterologists. Another possible explanation is the minor knowledge of the disease and treatment options within general practitioners and gastroenterologists during the time period of the study. In conclusion, the present study represents one of the largest prospectively assessed cohort of MC patients and confirms previous retrospective reports regarding clinical features, female predominance and onset of the disease in later age. Nevertheless the present study has several limitations. The data were consecutively collected, but we have no return rate of the questionnaires. Thus, not all patients diagnosed and contacted were included in the study and the time between diagnosis and questionnaire completion was not recorded resulting in a possible bias especially regarding the spontaneous high clinical remission rate. The low remission rate and outcome under empirical treatment should be also interpreted with caution. As explained above, a possible reason for this result is that the data were only the patient perspective without any information from the general practitioner. Another weakness of the study is the missing control group, but despite the only descriptive character of the study the large patient population can help to increase the awareness for MC among general practitioners and gastroenterologists.
References 01 Read NW, Krejs GJ, Read MG et al. Chronic diarrhea of unknown origin. Gastroenterology 1980; 76: 264 – 271 02 Lazenby AJ, Yardley JH, GiardielloI FM et al. Lymphocytic (microscopic) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989; 20: 18 – 28 03 Münch A, Aust D, Bohr J et al. Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohns Colitis 2012; 6: 932 – 945 04 Lindstrom CG. Collagenous colitis with watery diarrhoea a new entity? Pathol. Eur 1976; 11: 87 – 93 05 Bogomoletz WV. Collagenous, microscopic and lymphocytic colitis. An evolving concept. Virchows Arch 1994; 6: 573 – 579 06 Pardi DS, Kelly CP. Microscopic colitis. Gastroenterology 2011; 140: 1155 – 1165 07 Fine KD, Seidel RH, Do K. The prevalence, anatomic distrubution and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endos 2000; 51: 318 – 326 08 Shah RJ, Bleau B, Gianelle RA. Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea. Am J Gastroenterol 2001; 96: 1091 – 1095 09 Fernandez-Banares F, Salas A, Forne M et al. Incidence of collagenous and lymphocytic colitis: a 5-year population-based study. Am J Gastroenterol 1999; 94: 418 – 423 10 Bohr J, Tysk C, Eriksson S et al. Collagenous colitis in Orebro, Sweden, an epidemiological study 1984–1993. Gut 1995; 37: 394 – 397 11 Olesen M, Eriksson S, Bohr J et al. Microscopic colitis: a common diarrhoeal disease. An epidemiological study in Orebro, Sweden, 19931998. Gut 2004; 53: 346 – 350 12 Raclot G, Queneau PE, Ottignon Y. Incidence of collagenous colitis. a retrospective study in the east of France. Gastroenterology 1994; 106: A23
13 Pardi DS, Smyrk TC, Kammer P. The epidemiology of microscopic colitis: a population-based study in Olmsted County. Gastroenterology 2004; 126: A124 14 Agnarsdottir M, Gunnlaugsson O, Orvar KB et al. Collagenous and lymphocytic colitis in Iceland. Dig Dis Sci 2002; 47: 1122 – 1128 15 Fernandez-Banares F, Salas A, Esteve M et al. Collagenous colitis and lymphocytic colitis: evaluation of clinical and histological features, response to treatment and long-term follow up. Am J Gastroenterol 2003; 98: 340 – 347 16 Bohr J, Tysk C, Eriksson S et al. Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut 1996; 39: 846 – 851 17 Wang KK, Perrault J, Carpenter HA et al. Collagenous colitis: a clinicopathologic correlation. Mayo Clin Proc 1987; 62: 665 – 671 18 Sylwestrovicz T, Kelly JK, Hwang WS et al. Collagenous colitis and microscopic colitis: the watery diarrhea-colitis syndrome. Am J Gastroenterol 1989; 84: 763 – 768 19 Baert F, Wouters K, Haens GD et al. Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis. Gut 1999; 45: 375 – 381 20 Mullhaupt B, Guller U, AnabitarteN M et al. Lymphocytic colitis: clinical presentation in long term course. Gut 1998; 43: 629 – 633 21 Pardi DS, Ramnath VR, Loftus EV et al. Lymphocytic colitis: clinical features, treatment, and outcomes. Am J Gastroenterol 2002; 97: 2829 – 2833 22 Bjørnbak C, Engel PJ, Nielsen PL et al. Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther 2011; 34: 1225 – 1234 23 Park YS, Baek DH, Kim WH et al. Clinical Characteristics of Microscopic Colitis in Korea: Prospective Multicenter Study by KASID. Gut Liver 2011; 5: 181 – 186 24 Madisch A, Miehlke S, Lindner M et al. Clinical course ofcollagenous colitis over a period of 10 years. Z Gastroenterol 2006; 44: 971 – 974 25 Madisch A, Heymer P, Voss C et al. Oral budesonide therapy improves quality of life in patients with collagenous colitis. Int J Colorectal Dis 2005; 20: 312 – 316 26 Williams JJ, Beck PL, Andrews CN et al. Microscopic colitis – a common cause of diarrhoea in older adults. Age Ageing 2010; 39: 162 – 168 27 Madisch A, Bethke B, Stolte M et al. Is there an association of microscopic colitis and irritable bowel syndrome–a subgroup analysis of placebo-controlled trials. World J Gastroenterol 2005; 11: 6409 28 Limsui D, Pardi DS, Camilleri M et al. Symptomatic overlap between irritable bowel syndrome and microscopic colitis. Inflamm Bowel Dis 2007; 13: 175 – 181 29 Riddell RH, Tanaka M, Mazzoleni G. Non-steroidal anti-inflammatory drugs as a possible cause of collagenous colitis: a case-control study. Gut 1992; 33: 683 – 686 30 Keszthelyi D, Jansen SV, Schouten GA et al. Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 2010; 32: 1124 – 1128 31 Fernandez-Banares F, Esteve M, Espinos JC et al. Drug consumption and the risk of microscopic colitis. Am J Gastroenterol 2007; 102: 324 – 330 32 Nyhlin N, Montgomery SM, Wickbom A et al. Symptom burden in collagenous and lymphocytic colitis compared to a matched control group. Gut 2009; 58 (Suppl 2): A309 33 Miehlke S, Heymer P, Bethke B et al. Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial. Gastroenterology 2002; 123: 978 – 984 34 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 – 2100 35 Chande N, MacDonald JK, McDonald JW. Interventions for treating microscopic colitis: a Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group systematic review of randomized trials. Am J Gastroenterol 2009; 104: 235 – 241 36 Madisch A, Morgner A, Stolte M et al. Investigational treatment options in microscopic colitis. Expert Opin Investig Drugs 2008; 17: 1829 – 1837
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Originalarbeit
Originalarbeit
Microscopic Colitis: Clinical Presentation, Treatment and Outcome of 494 Patients Mikroskopische Kolitis: klinische Manifestation, Therapie und Outcome in 494 Patienten Authors
A. Madisch1, S. Miehlke2, F. Bartosch3, B. Bethke4, M. Stolte4
Affiliations
1
3 4
Department of Internal Medicine, Siloah Hospital, Hannover Facharztzentrum Eppendorf, Magen-Darm-Zentrum, Hamburg Universitätsklinikum Dresden, Medizinische Klinik I, Dresden Klinikum Kulmbach, Pathologisches Institut, Kulmbach
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Die kollagene und lymphozytäre Kolitis zählt zu den chronisch-entzündlichen Darmerkrankungen mit dem Leitsymptom chronische wässrige Diarrhö. Ziel: Wir untersuchten prospektiv klinische Parameter, Ansprechen auf medikamentöse Therapien und den klinischen Verlauf eines großen Patientenkollektivs mit kollagener (CC) und lymphozytärer (LC) Kolitis. Patienten und Methoden: Bei Patienten mit histologisch nachgewiesener kollagener und lymphozytärer Kolitis wurden prospektiv anhand standardisierter Fragebögen folgende Parameter erfasst: Symptombeginn und Zeitpunkt der Diagnosestellung, Krankheitsdauer, Stuhlfrequenz und -konsistenz, andere gastrointestinale Symptome einschließlich Gewichtsverlust, Medikamenten-anamnese und Begleiterkrankungen sowie Ansprechen auf die Therapie. Ergebnisse: Insgesamt 494 Patienten (CC, n = 287; LC, n = 207) waren für die Analyse auswertbar. Das mittlere Alter lag bei 65 in der CC- und 61 Jahren in der LC-Gruppe mit einem Anteil von 76 % Frauen in beiden Gruppen. Die Dauer der Symptomatik betrug vor Diagnosestellung durchschnittlich 37 (CC-Gruppe) und 23 Monate (LC-Gruppe). Die gastrointestinale Symptomatik von Patienten mit CC war der mit LC ähnlich. Begleitende Autoimmunerkrankungen wurden häufiger in der Gruppe mit CC (48,4 %) als mit LC (29,6 %) angegeben. Eine anhaltende klinische Remission wurde von 35,5 % in der CC und 38,6 % in der LC-Gruppe berichtet, aber Patienten mit CC (47,7 %) erhielten häufiger Medikamente wie z.B. Kortikosteroide, Antibiotika, Wismutsalicylat oder 5-Aminosalicylsäure (47,7 %) als Patienten mit LC (16,9 %). 18,6 % der CC- und 17,6 % der LC-Patienten wurden regelmäßig mit nichtsteroidalen Antirheumatika behandelt.
Background: Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic disorders characterized by watery diarrhea. Aim: To evaluate prospectively the clinical features, response to treatment and outcomes in a large group of patients with CC and LC. Patients and Methods: Patients with histologically confirmed CC and LC were prospectively enrolled to complete a questionnaire on onset and duration of diarrhea, stool frequency and consistency, other gastrointestinal symptoms including weight loss, drug history, treatment success and concomitant diseases. Results: A total of 494 patients (CC, n = 287, LC, n = 207) were available for analysis. The mean age at diagnosis was 65 in CC and 61 years in LC with a identically female predominance (76 % of patients) in both groups. Prior to diagnosis the mean duration of symptoms was 37 in CC and 23 months in LC. CC and LC patients share similar pattern of clinical symptoms. Concomitant autoimmune disorders were more common in CC patients (48.4 %) than in LC patients (29.6 %). Sustained clinical remission was reported by 35.5 % of CC and 38,6 % of LC, but more CC patients (47.7 %) received medication such as corticosteroids, antibiotics, bismuth or 5-aminosalicyclic than LC patients (16.9 %). 18.6 % of CC patients and 17.6 % of LC were regularly using NSAIDs. Conclusion: Collagenous and lymphocytic colitis are frequently diagnosed in elderly female patients. CC and LC share similar symptom pattern, but concomitant autoimmune disease were more common in CC than in LC patients.
● Darm ● kollagene Kolitis ● chronisch entzündliche " "
Darmerkrankung
Key words
● intestine ● collagenous colitis ● chronic inflammatory " " "
bowel disease
received accepted
11.8.2013 8.3.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1366281 Z Gastroenterol 2014; 52: 1062–1065 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Dr. Ahmed Madisch Department of Internal Medicine, Siloah Hospital Roesebeckstraße 15 30449 Hannover Germany Tel.: +49/5 11/9 27 22 31 Fax: +49/5 11/9 27 22 69 [email protected]
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
Downloaded by: Rutgers University. Copyrighted material.
2
Introduction
Results
!
!
Microscopic colitis (MC) with the two entities collagenous (CC) and lymphocytic colitis (LC) defines two distinct inflammatory diseases of the colon characterized by chronic watery diarrhea and normal radiological and endoscopical appearances [1 – 3]. Diagnosis is established by histological examination, which shows a diffuse inflammatory infiltrate in the lamina propria and epithelium of the colonic mucosa with signs of epithelial damage [3, 4]. CC differs from LC by the presence of a subepithelial collagen band (> 10 µm) adjacent to the basal membrane. In LC, the histomorphological landmark is an increase of intraepithelial lymphocytes of > 20 per 100 epithelial cells [2]. Based on epidemiological studies, MC is diagnosed in 4 to 13 % of patients with chronic watery diarrhea [3, 5, 7]. The reported incidence rate of CC in Europe ranges from 0.6 to 5.2 per 100 000 with a prevalence of 10.0 to 15.7 per 100 000, for LC the reported incidence rate is 3.7 to 4.0 per 100 000 with a prevalence of 8 to 14.2 per 100 000 per year [8, 9, 11 – 13]. Hence, MC is a disease affecting as many patients as Crohn’s disease or ulcerative colitis. The cause of MC is unknown, but it appears to be due to mucosal injury inducing a pathological immunological response to an unknown toxin in the fecal stream. Several large case series showed that chronic or intermittent watery diarrhea is the most common presenting symptom of patients with microscopic colitis [14 – 19]. Most of the large case series focusing on the clinical presentation of patients with microscopic colitis are retrospective analysed. In contrast the following study prospectively assessed the clinical presentation, treatment and outcome of 494 patients with microscopic colitis.
Clinical characteristics A total of 494 patients (CC, n = 287; LC, n = 207) were available for analysis. The demographic and clinical features are summarized " Table 1. CC and LC patients share similar pattern of sympin ● toms. Patients with CC and LC are at older age with a mean age at diagnosis of 65 (range 35 – 92) in CC and 61 years in LC (range 22 – 89). The female predominance (76 % of patients) was identically in both groups. Prior to diagnosis the mean duration of symptoms was 37 ± 8 in CC and 23 ± 6 months in LC. At diagnosis the daily mean stool frequency was 6 in both groups with a range between 1 to 42 in the CC and 1 to 20 in the LC population. Diarrhea was intermittent in 26.2 % of CC and 31.3 % of LC patients. Only a minority of CC and LC patients reported rectal bleeding. Abdominal pain was reported by 55 patients (22 %), weight loss (mean 6 kg) by 100 patients (49 %), and nocturnal stools by 126 patients (64 %) of the CC group. The corresponding rates in the LC group were 26.5 %, 48 % and 60.8 %, respectively " Table 1). (● Concomitant autoimmune disorders such as thyroid dysfunction, rheumatoid diseases and diabetes mellitus were more common in CC patients (48.4 %) than in LC patients (29.6 %). The most common autoimmune disease in LC patients was thyroid dysfunction " Table 1). (21.87 %), rheumatoid arthritis in CC patients (28.2 %) (●
Drug History !
Thirty-eight patients (18.4 %) of LC and of CC fourty-nine patients (17.1 %) were regularly using ASS or NSAIDs. The use of ß-blockers, Statins, ACE-inhibitors, Calcium antagonists and Proton
Patients and Methods !
Between 1998 and 2004 patients with histologically confirmed CC and LC were identified consecutively at the Institute of Pathology. After confirming the diagnosis of microscopic colitis the patients were asked to participate in the study and to complete a questionnaire including following parameters: onset and duration of diarrhea, stool frequency and consistency, other gastrointestinal symptoms including weight loss, drug history, concomitant diseases and treatment success. All patients underwent colonoscopy due to diarrheal symptoms. The returned questionnaires were consecutively collected and analyses without recording the return rate and time between diagnosis and the questionnaire completion. The histological assessment was reviewed by one experienced GI pathologist (M.S.) who confirmed the diagnosis of collagenous and lymphocytic colitis based on accepted histopathological criteria. These criteria included an increased mixed inflammatory infiltrate in the lamina propria, increased number of intraepithelial lymphocytes (> 20 per 100 epithelial cells) in LC, a surface epithelial damage, and the presence of an abnormal subepithelial collagen band (> 10 µm) adjacent to the basal membrane required for the histological diagnosis of CC. Diarrhea was defined as ≥ 3 bowel movements per day with a soft or liquid stool consistency.
Table 1
Clinical characteristics and symptoms in 287 CC and 207 LC patients
clinical characteristics
CC (n = 287)
LC (n = 207)
and symptoms age (years), median (range) gender female, n (%)
66 (35 – 92) 220 (76.9 %)
61 (22 – 89) 158 (76)
stool frequency, median (range)
6 (3 – 42)
6 (3 – 20)
stool consistency – watery (%)
85
78.5
stool components (%) – blood
5.6
6.8
– mucus
29.0
39.5
sustained diarrhea (%)
63.6
58.7
intermittent diarrhea (%)
26,2
31.3
nocturnal stools (%)
64
60.8
abdominal pain (%)
22.0
26.5
weight loss – % of patients
49
48
– mean of weight loss (kg)
3
6
general fatigue (%)
5
5
associated disorders (%) – thyroid dysfunction
20.3
– rheumatoid arthritis
28.2
9.2
– diabetes mellitus
11.2
7.2
21.87
– psoriasis
3.8
3.4
– neurodermitis
3.9
3.9
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
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Table 2 Concomitant Drugs potentially related to the development of microscopic colitis.
drugs
ß-Blocker ASS/NSAIDs
CC (n = 287)
LC (n = 207)
%
%
7.7
21.7
17.1
18.4
calcium antagonists
2.4
12.6
ACE Inhibitors
4.2
14.5
statins
1.0
10.6
antidpressive therapy
0.01
0
proton pump inhibitors
9.2
9.2
pump inhibitors were higher in the LC than in the CC group " Table 2). (●
Treatment and Outcome !
35.5 % of CC and 38.6 % of LC patients reported sustained clinical remission. More CC patients (47.7 %) received medication such as antidiarrheals, corticosteroids, antibiotics, bismuth, 5-aminosalicyclic or probiotics than LC patients (16.9 %). The highest remission rates were reported under budesonide with 44.8 % in collagenous colitis and 47.8 % in lymphocytic colitis. The other remission rates ranged between 2.9 % and 14.7 % without any differences between both groups.
Discussion !
In the last decades microscopic colitis has been recognized as a chronic inflammatory bowel disease with a high impact on quality of life [3, 5, 22, 29]. The clinical characteristics and association to other disease and drugs are mostly reported in retrospective case series. To our knowledge, the present study is the largest cohort of patients with MC assessing prospectively the clinical features and treatment outcome. The clinical features in our cohort are in line with those reported retrospectively in larger series [14, 15, 18 – 22]. CC and LC patients of our cohort shared a similar clinical picture with chronic or intermittent watery diarrhea as the most common presenting symptom. In contrast to other case series more than a half had sustained diarrhea, only a minority of patients suffered from intermittent diarrhea (20). Further clinical characteristics include nocturnal stools in more than 60 % of MC patients and mild weight loss in more than 40 % of MC patients. Recent epidemiological studies suggest that the incidence of microscopic colitis is higher than previously considered with a strong female predominance [8, 9]. These studies also demonstrate that those at highest risk of developing microscopic colitis are women in their eighties [23]. In a Swedish epidemiological study Olesen and co-workers showed that microscopic colitis was diagnosed in almost 20 % of those older than 70 years presenting with chronic diarrhea [10]. In the present cohort the median age was more than 60 in both groups with a female predominance of 76 %. Thus, in older female patients with chronic or intermittent diarrhea diagnostic work-up should focus on microscopic colitis as a main differential diagnosis that only can be established or ruled out by colonoscopy with multiple biopsies [6, 7].
Madisch A et al. Microscopic Colitis: Clinical … Z Gastroenterol 2014; 52: 1062–1065
The face of microscopic colitis resembles the subgroups of irritable bowel syndrome (IBS). Since symptoms of microscopic colitis and both diarrhea predominant irritable bowel syndrome or functional diarrhea are similar, a considerable number of patients with microscopic colitis may be misdiagnosed as IBS or a disease overlap could be present in a subgroup of patients. In the present study abdominal pain as a leading symptom of IBS was present in more than 20 % of CC and LC patients. Two studies could show that up to 50 % of patients with established microscopic colitis met the Rome- or Manning criteria for diarrhea-predominant IBS or functional diarrhea and most of them were treated as IBS patients before the correct diagnosis of microscopic colitis was performed [24, 25]. This might be the reason why the diagnosis of MC in our cohort population was also performed after 37 (CC) and 23 (LC) months after the first onset of symptoms. Since clinical symptom-based criteria of IBS are not specific enough to rule out the diagnosis of microscopic colitis, patients with diarrheapredominance of IBS-like symptoms should undergo matrix biopsies from the entire colon to investigate for possible microscopic colitis [6, 7]. There is an ongoing debate about drug consumption as a risk factor for microscopic colitis. Two case-control studies suggested that the use of NSAIDs is associated with microscopic colitis [26, 28]. In our cohort drug intake of NSAIDs were also frequently reported in both CC (17.1 %) and LC (18.4 %) patients. Other suspected drug of the case-control studies such as ß-Blockers, calcium antagonists, ACE inhibitors and statins were only frequently used by LC patients. Hence, many case reports showed a clear relationship to PPI, especially Lansoprazole [27], in our population PPI treatment was only reported by 9.2 % in both groups. In contrast to the case-control-study of Fernandez-Banares and coworkers, who found a significant association between the intake of the antidepressant sertraline and microscopic colitis, no antidepressants were reported by any patient of the present study [28]. Although a significant association of microscopic colitis with drug consumption was observed, a cause-effect relationship has not been established yet. Nevertheless drug-induced microscopic colitis should be considered in clinical practice at least as an exacerbate factor of an existing idiopathic microscopic colitis. The association between microscopic colitis and autoimmune diseases is well described. Patients with MC more often have concomitant autoimmune diseases such as rheumatic disease, celiac disease, thyroid disease and diabetes with an odds ratio of 11.0 (5.1 – 23.8, p < 0.001) in CC patients and of 16.6 (6.4 – 43.1, P< 0.001) in LC patients [29]. In our cohort the most common reported autoimmune disease was a thyroid dysfunction in LC and CC patients, followed by rheumatoid arthritis and diabetes mellitus, especially in LC patients. Diabetes was found in 11.2 % of CC and 7.2 % in LC patients with a similar frequency to retrospective studies (18 – 20). MC is a chronic disorder with a variable course of symptoms during a long-term follow-up. In a long-term follow-up study of our group 30 % of patients may experience persistent diarrhea even 10 years after diagnosis, 50 % showed sustained remission mostly under anti-inflammatory drugs [21]. In the present study spontaneous sustained remission of diarrhea was seen in near 35 % of patients on both groups. Information on treatment and response was available of 68 % CC and 71 % LC patients. More CC (47.7 %) than LC (16.9 %) patients were under treatment supporting the observation in literature that LC often showed a spontaneous resolution of symptoms. The reported response rates of treatment were very low and are not in line with
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the remission rates published in literature [32, 33]. The highest treatment success was observed with budesonide, but the success rates of 44 or 47 % is much lower than the reported at least 80 % in the placebo-controlled trials [30 – 33]. The reason for this result is unclear, but one possible explanation includes the bias, that the majority of the patients who respond to the questionnaires might be those with persisting symptoms. Furthermore the data were patient-based without any medical records from the general practitioners and gastroenterologists. Another possible explanation is the minor knowledge of the disease and treatment options within general practitioners and gastroenterologists during the time period of the study. In conclusion, the present study represents one of the largest prospectively assessed cohort of MC patients and confirms previous retrospective reports regarding clinical features, female predominance and onset of the disease in later age. Nevertheless the present study has several limitations. The data were consecutively collected, but we have no return rate of the questionnaires. Thus, not all patients diagnosed and contacted were included in the study and the time between diagnosis and questionnaire completion was not recorded resulting in a possible bias especially regarding the spontaneous high clinical remission rate. The low remission rate and outcome under empirical treatment should be also interpreted with caution. As explained above, a possible reason for this result is that the data were only the patient perspective without any information from the general practitioner. Another weakness of the study is the missing control group, but despite the only descriptive character of the study the large patient population can help to increase the awareness for MC among general practitioners and gastroenterologists.
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