Microscopic Colitis: Treatment - Falk Aktuell · 2017-10-13 · Microscopic Colitis – Clinical...

Microscopic Colitis:

Treatment

Andreas TrommKlinik für Innere Medizin

Evangelisches Krankenhaus Hattingen gGmbHAkademisches Lehrkrankenhaus, Ruhr-Universität Bochum (Germany)

Microscopic Colitis – Definition

Collagenous and lymphocytic colitis

MicroscopicColitis

Collagenous Colitis Lymphocytic Colitis(Lindström et al..1976) (Lazenby et al..1989)(Freeman et al..1976)

“The watery diarrheacolitis syndrome”

(Sylwestrowicz et al..1989)

Microscopic Colitis – Symptoms

Symptoms of collagenous colitis

n = 163 patients

100 %

27 %

42 %

41 %

21 %

12 %

Watery diarrhea

Nocturnal diarrhea

Weight loss

Abdominal pain

Fatigue

Meteorism

Bohr et al., Gut 1996; 39: 846 - 851

Microscopic Colitis – Clinical course

Clinical course and prognosis in collagenous colitis

n=24 patients (Bonderup et al., 1999)

No increased risk of colon neoplasms(follow up over 2 – 12 years)

Study with 117 patients (Chan et al., 1999)

Generally benign course

Good general and nutritional condition

10 / 24 patients (42 %) with chronic orintermittent diarrhea

4 / 24 patients (17 %) in remission over 2 – 10 years

Cause of death unrelated to collagenous colitis: 6 / 24 patients (Age 20 – 82 years) after 5 – 16 yearsduration

Bonderup et al., Eur. J. Gastroenterol. Hepatol. 1999; 11: 493-495; Chan et al., IBD 1999; 5: 40-43

Genetics(HLA)

Drugs Infection(NSAID) (Yersinia antibodies)

Bile acids Altered(Malabsorption) immune response

(associatedautoimmune disease)

Altered inflammation markers(NO, TGF-beta, VEGF etc.)

Microscopic Colitis – Pathogenesis

Pathogenetic factors

?

Microscopic Colitis – Therapy

Recommendations for therapy of microscopic colitis

Symptomatic

• Loperamide

• Colestyramine

• Octreotide

• Bismuth

Anti-inflammatory

• Systemic steroids

• Topical steroids

• Salicylates

• Anti- / Probiotics

• Immunosuppressants

Microscopic Colitis – History

Collagenous and lymphocytic colitis in the literature

Lindström, Freeman et al.

Eckstein et al.

Lindström et al.

Bohr et al.

Fine et al.

Chande et al.

1976 First descriptions

1988 First case of duodenalinvolvement

1990 268 published cases

1996 > 500 published cases

1999 First published controlled study

2003 First published meta-analysis


Controlled studies of collagenous colitis (2005)

Budesonide3 studies, 1 metaanalysis Positive effectn = 94 patients Evidence level Iawith collagenous colitis

Prednisolone1 small study Slight effectn = 12 patients (Evidence level Ib)with collagenous colitis

Bismuth1 small study (abstract) Positive effectn = 14 patients (Evidence level Ib)with collagenousand lymphocytic colitis


Non-controlled study with bismuthin microscopic colitis

Patients

Therapy

Results

n = 13 (1 drop out) 7 patients with collagenous colitis6 patients with lymphocytic colitis

9 tablets = 262 mg bismuth-subsalicylate/day over 8 weeks

• 11 / 12 no diarrhea, stool weight

• Response within 2 weeks

• Histology: 9 / 12 without signs of inflammation7 / 7 without collagen layer

Fine & Lee, Gastroenterology 1998; 114: 29-36

Patients

Therapy

Results

Cross-Over

Fine et al., Gastroenterology 1999; 116: A880


Bismuth in microscopic colitis: Randomized placebo-controlled study

n = 149 patients with collagenous colitis5 patients with lymphocytic colitis

3 x 3 tablets = 262 mg bismuth-subsalicylate/day or placebo for 8 weeks

Bismuth (n = 7) Placebo (n = 7)

Stool frequencyand stool weight

Bismuth in 5 / 6 patients effective, in 1 / 6 patients withdrawal due to nausea

7 / 7 0 / 7


Systemic vs. topical steroid therapyin collagenous colitis

Prednisolone Budesonide

Möllmann et al. (1996)

Hard gelatine capsule(soluble in gastric juice)


Budenofalk® 3mg capsuleswith pH modified drug release

Eudragite coatingresistant to pH < 6.4

Budesonide layer

Matrix: sugar core

Patients(n)

Delarive et al. (1998); Bohr et al. (1998); Janetscheck et al. (1998); Lanyi et al. (1999); Tromm et al. (1999)


Budesonide in collagenous colitis: Pilot studies

Histologicaleffects

7 positive 3 / 3 positive

Delarive 1998 5 notstudied

Bohr 1998 2 positive

Janetscheck 1998 3 positive 1 / 1 positive

Lanyi 1999 3 positive

Clinicaleffects

Tromm 1999

notstudied

notstudied

3 complete2 partial


Budesonide in collagenous colitis: Stool frequency

0

5

10

15

20

25

Before therapy

After 10 weeks of therapy

Stool frequency/day

(n = 7)

p < 0.001

After 10 days of therapy

Tromm et al., Am. J. Gastroenterol. 1999: 94; 1871-1875


Budesonide in collagenous colitis: Effects on the collagen layer

Patients Number ofmeasurements

Thickness of collagen layer Paired Student'st-Test

Before Budesonide After Budesonide

1 16 16.47 ± 4.9 5.57 ± 0.97 p < 0.0005

2 7 12.85 ± 2.7 4.95 ± 0.88 p < 0.0005

3 21 21.14 ± 9.3 9.28 ± 3.77 p = 0.003

(n = 3) (µm; average ± standard deviation)

Tromm et al., Am. J. Gastroenterol. 1999: 94; 1871-1875


Budesonide in collagenous colitis: 1. randomized placebo-controlled study

Patients n = 28

Therapy 9 mg Budesonide-PMR*/day or Placebo for 8 weeks

Results Budesonide-PMR*(n = 14)

8 / 14p = 0.05

9 / 144 / 140 / 14

p < 0.001

*PMR: pH-modified release

Clinicalresponse

Histologicalresponse• complete• partial• none

Placebo(n = 14)

3 / 14

4 / 14 0 / 14 8 / 14

Baert et al., Gastroenterology 2002; 122: 20-25

*CIR: controlled ileal release

Clinicalresponse

Histologicalresponse

Patients n = 43

Therapy 9 mg Budesonide-CIR*/day or placebo for 6 weeks

Results

Time to response: 13 days



Budesonide-CIR*(n = 23)

20 / 23p < 0.001

18 / 23p < 0.001

Placebo(n = 20)

1 / 20

1 / 20

Miehlke et al., Gastroenterology 2002; 123: 978-984

*CIR: controlled ileal release

week 1-4: 9 mg/dweek 5-6: 6 mg/dweek 7-8: 3 mg/d

Clinicalresponse

Patients n = 20

Therapy initially 9 mg Budesonide-CIR*/day or placebo for 8 weeks

Results



Budesonide-CIR*(n = 10)

10 / 10p < 0.001

Placebo(n = 10)

2 / 10

Bonderup et al., Gut 2003; 52: 248-251

Total

Baert et al. 2002


Budesonide in collagenous colitis: Cochrane Metaanalysis 2004 – Clinical features

Placebo

Clinical improvement

3 / 12

8 / 47(17.02 %)

Odds-Ratio

25.0

100.0

Weight

6.3 (1.26; 30.92)

Bonderupet al. 2 / 10 21.2 3.73 (4.15; 135.72)

2002 3 / 25 53.8 13.08 (4.39; 38.99)

12.32 (5.53; 27.46)

8 / 11

38 / 47(80.85 %)

Budesonide

10 / 10

20 / 26

2003

Miehlkeet al.

Chande et al., The Cochrane Library 2004; Baert et al., Gastroenterology 2002; 122: 20-25;Miehlke et al., Gastroenterology 2002; 123: 978-984; Bonderup et al., Gut 2003; 52: 248-251

Total


Budesonide in collagenous colitis: Metaanalysis II – Clinical features

Clinical improvement

Relative risk for response

(clinical improvement = reduction of stool frequency)

= 4.9 (2.67 – 6.38)

NNT = 1.58 (95% CI: ± 1.86)

100.0 12.32 (5.53; 27.46)Feyen et al., Aliment. Pharmacol. Ther. 2004; 20: 745–749

Baert et al., Gastroenterology 2002; 122: 20-25 Miehlke et al., Gastroenterology 2002; 123: 978-984Bonderup et al., Gut 2003; 52: 248-251


Budesonide in collagenous colitis: Cochrane Metaanalysis 2004 – Histology

Total

10 / 11

34 / 47(72.34 %)

Placebo Budesonide

Histological improvement

4 / 12

8 / 47(17.02 %)

Odds-Ratio

20.20 (1.85; 216.19)

14 / 26 1 / 25 28.00 (3.28; 238.91)

10 / 10 3 / 10 45.00 (2.01; 100.80)

Baert et al. 2002

Bonderupet al.

2002

2003

Miehlkeet al.

Chande et al., The Cochrane Library 2004; Baert et al., Gastroenterology 2002; 122: 20-25;Miehlke et al., Gastroenterology 2002; 123: 978-984; Bonderup et al., Gut 2003; 52: 248-251

1009080706050403020100


Budesonide in collagenous colitis:Improvement in quality of life

Madisch et al., Int. J. Colorectal. Dis. 2004; 11 (Epub)

Before therapy After 6 weeks

Budesonide

Placebo

p < 0.001

GastrointestinalQuality of Life Index (GIQLI)

Patientsn = 29 patients

n = 17 budesoniden = 12 placebo

Therapy9 mg Budesonide/dayfor 6 weeks


Effect of budesonideon bile acid uptake in collagenous colitis

Mean 75SeHCAT values increase from 23 ± 9.9 % to 40 ± 14.7 %

Bile acid uptake75SeHCAT(75Selenium homotaurocholic acid) test[%]

0

10

40

20

70

Before therapy After 8 weeks therapy

30

50

60(n = 15)

Bajor et al., Gastroenterology 2003; 124: A-146

Affected bowel surface area (n = 6 patients)


Effect of budesonide on vascular endothelial growth factor (VEGF) in collagenous colitis

[%][%]

2

4

10

12

0

8

6

0Before After

TherapyControls

10

20

30

VEGF-stained epithelium VEGF-stained lamina propria

ControlsBefore After Therapy

p = 0.04 p = 0.01

p = 0.03

p = 0.04

Griga et al., Eur. J. Gastroenterol. Hepatol. 2004; 16: 397-402

Stool weight

Stool frequency

RemissionStool weight ≤ 200 g/dayand frequency ≤ 2/day

Prednisolone(n = 9)

7 / 9

5 / 9

2 / 9

Placebo(n = 3)

1 / 3

0 / 3

0 / 3


Prednisolone in collagenous colitis:First randomized placebo-controlled study

Patients n = 12

Therapy 50 mg Prednisolone/day or placebo for 2 weeks

Results

Munck et al., Scand. J. Gastroenterol. 2003; 38: 606-610


Pilot study:E. coli Nissle 1917 in collagenous colitis

0

5

10

15

20

Therapy start Therapy end ≥ 4 weeks

Stool frequency/day (n = 14)

7.6 ± 4.8/day p = 0.034 3.7 ± 5.8/day

Non-Responders21.4 %

Responders78.6 %

Tromm et al., Z. Gastroenterol. 2004; 42: 365-368

Patients

Therapy

Results

Madisch et al., Poster #W1037 DDW 2005

n = 31 randomised; n = 25 per protocolStool frequency > 5/d

3 x 400 mg BSE vs placebo for 6 weeks

BSE Placebo

Stool frequency 58,3 % 30,8 %(< 3/d)

Microscopic Colitis

Latest news: DDW 2005 in Chicago (USA):Boswellia serrata extract (BSE) in collagenouscolitis – A randomized, double-blind, placebocontrolled, multicentre trial.


Collagenous Colitis: Evidence-based therapy 2005

Exclude use of NSAIDs

With respect to With respect topathophysiology controlled studies

Budesonide Budesonide(Colestyramine) (Bismuth)

(Prednisolone)

Microscopic Colitis

Collagenous and lymphocytic colitis: Open questions on therapy in 2005

Spontaneous remission rate

Duration of acute phase therapy (6 – 8 weeks)

Therapy in non-responders tobudesonide or bismuth

Maintenance therapy:

- Which drug?- At what dose and for which period?

?

Microscopic Colitis

Ongoing studies in 2005

Budesonide for maintenance therapy of collagenous colitis*

E. coli Nissle 1917 vs. Budesonide in collagenouscolitis (acute phase)**

Budesonide in lymphocytic colitis (acute phase)*

………….

?

* A. Madisch, Dresden (Germany): personal communication;** A. Tromm, Hattingen (Germany)

Microscopic Colitis – Therapy: latest news DDW 2005 in Chicago (USA)

Non-controlled study with boswellia serratain collagenous colitis

Patients

Therapy

Results

n = # # patients with collagenous colitis

Bosweelia serrata/day for # weeks

• 11 / 12 no diarrhea, stool weight

• Response within 2 weeks

• Histology: 9 / 12 without signs of inflammation7 / 7 wthout collagen layer

*A. Madisch, Dresden (Germany): personal communication

Contents

Microscopic Colitis – Diagnosis

Clinical diagnosisin collagenous and lymphocytic colitis

ESR

Stool frequency

Stool volume

Steatorrhea

Leukocyte excretionin stool

Blood and mucusadmixture in stool

Extraintestinalmanifestations

Frequently elevated

Up to 20 / day

Up to 5 liters / day

In over 50 % of patients

In over 50 % of patients

Infrequent

Arthritis in 5 – 10 %


Pathogenesis of collagenous colitis: Pathological bowel flora

Costridium difficile / pseudomembranous colitis

2000200020012003

Yersinia antibodies in collagenous colitis vs. controls:9 / 32 vs. 1 / 17 (p = 0.0078)

1998

Yersinia-IgA antibodies: 82.3%Yersinia-IgG antibodies: 73.4%

2003

Contents

Khan et al. (2000)

Vesouliset al. (2000)

Treanor et al. (2001)

Yuan et al. (2003)

Mäkinenet al. (1998)

Miehlkeet al. (2003)

Khan et al.Vesoulis et al. Treanor et al. Yuan et al.

Mäkinen et al.

Miehlke et al.

(H.E. stain)

Contents


Histology of collagenous colitis

Contents

Microscopic Colitis – Symptoms

Diseases associated with collagenous colitis

Sjögren’s SyndromeHyper-. Hypothyroidism

Sprue

Raynaud’sSyndrome

Psoriasis

RheumatoidArthritis(RF+/-)

(H.E. stain)

Contents


Histology of lymphocytic colitis


Pathogenesis of diarrhea in collagenous colitis

Contents

Lee et al. (1992)

Jackson et al. (1995)

Tremaineet al. (1999)

Burgel et al. (2002)

The frequency of diarrhea is correlatedwith in inflammatory changes in thelamina proprianot with the thickness of the collagen layer

(Lee et al., 1992; Jackson et al., 1995; Tremaine et al., 1999)

Active chloride secretion and chloride resorption

(Lee et al., 1992; Burgel et al., 2002)

Microscopic Colitis – Differential diagnosis

CIBD vs. microscopic colitis:Histological differential diagnosis

Contents

Lazenbyet al. (1989)

Normal CIBD Collagenouscolitis

Lymphocyticcolitis

Epithelial flattening 7.3 8.2 35.4 35.2

Intraepitheliallymphocytes 4.6 4.4 21.1 24.6

Cryptlymphocytes 1.1 1.2 1.6 2.0

Collagen layer – – 100 –

Mononuclearcells 1.1 1.8 1.9 1.6

Neutrophilicgranulocytes 0.1 0.6 0.1 0.2

Crypt distortion 0.3 1.9 0.5 0.8

All data in [%]

Contents


Collagen metabolism in the intestinal mucosa

Subepithelialcollagen

layer

?

Collagen synthesis Collagen breakdown

?

Microscopic Colitis – PathogenesisCollagen metabolism in collagenous colitis

Contents

Aigner et al. (1997)

Günther et al. (1999)

Normal architecture and extracellular matrixoutside the collagen layer(Aigner et al., 1997)

No increase of collagen type VI mRNA(Aigner et al., 1997)

MMP-1 (Matrix Metallo-Proteinase-1)

TIMP-1 (Tissue Inhibitor Metallo-Proteinase-1)(Günther et al., 1999)

Reduced collagen breakdown

Contents

Järnerot et al.(1995)


Collagenous Colitis: Effect of intestinal contents(“fecal stream diversion”)

Patients

Stoma

Results

n = 9 Patients with severe diarrhea in collagenouscolitis refractory to therapy

Primary Primary Secondaryileostomy sigmoidostomy placement of an(n = 8) (Hartmann) (n = 1) Ileostoma

• Postoperative, no diarrhea• Histological reduction of collagen layer:20 µm (10 – 40 µm) 2 µm (0 – 10 µm)

Importance of luminal agencies

30 µm

o.B. Ileostoma

o.B.


Pathogenesis the collagenous colitis: NSAID

Contents

Riddell et al.(1992)

n = 31 with collagenous colitis vs. n = 31 matched controls with irritable bowel or diverticulosis

Patients

Symptoms

Duration greater than less thanNSAID use 6 months 6 months

Association with 19 / 31 4 / 31collagenous colitis Patients Patients

p < 0.02

Significantly more frequent with use over 6 months

Diarrhea begins after an average NSAIDuse of 5.5 (0.5 – 15) years

Association of NSAID use with collagenous colitis

1985 – 89 1990 – 93 1994 – 97 1998 – 2001

20

15

10

5

Microscopic Colitis – Epidemiology

Overview: Epidemiologyof lymphocytic and collagenous colitis

Contents

Pardi et al. (2004)

Per 100,000 persons Olmsted County, Minnesota, USA

Microscopic colitis Lymphocytic colitis Collagenous colitis

0

Biopsies of normal mucosa in 111 patientswith more than 4 weeks of persistent diarrhea

11.7 % (n = 13) Microscopic Colitis

4.5 % (n = 5) Melanosis coli

0.9 % (n = 1) Suspected collagenous colitis


Importance of biopsy in patientswith normal endoscopic findings

Contents

Marshallet al. (1995)


Microscopic colitis: Enhancing diagnostic reliability

Contents

Fraseret al. (2002)

Patients (n = 111) with a primary diagnosis of

microscopic colitis

Blinded re-evaluation

15 % with normal histology


Epidemiology of collagenous colitis

Contents

Fernandez-Banareset al. (1999)

Olesen et al. (2004)

Incidence

0.6 – 2.3 / 100,000 (Fernandez-Banares et al.,1999)

4.9 / 100,000(Olesen et al.. 2004)

Prevalence

10 – 15.7 / 100,000 (Fernandez-Banares et al.,1999)

Sex

: 4.75 : 1

Age

Average 53 years at time offirst diagnosis

Diagnosis

In 9.5 of 100 colonoscopieswith macroscopically normal findings and watery diarrhea

(Fernandez-Banares et al.,1999)

Patients

n = 199

Sex

: 2.4 : 1

Age

Average 59 (48 – 70) yearsat time of first diagnosis

Incidence

4.4 / 100,000 (Olesen et al., 2004)

Genetics

12 % with diagnosis of a chronic inflammatory boweldisease. Sprue orcollagenous colitis infirst or second-degreerelatives

Clinical course

30 % intermittent7 % continuous

63 % single event


Epidemiology of lymphocytic colitis

Contents

Olesen et al. (2004)


Pathogenesis of collagenous colitis: Bile acids

Contents

Ung et al. (2000)

n = 27 Patients with collagenous colitis12 / 27 (44 %) with pathological 75SeHCAT test

Patients

Treatment with colestyramine21 / 27 (78 %) with improvement:• 11 / 12 (92 %) with pathological 75SeHCAT test

• 10 / 15 (68 %) with normal 75SeHCAT test

75SeHCAT test = 75Selenium homotaurocholic acid test

(Griga et al., 2004)

(Taha et al., 2004)


Pathogenesis of collagenous colitis: Vascular endothelium growth factor (VEGF)Percent of bowel surface area affected (n = 21 patients)

Contents

Griga et al. (2004)

Taha et al. (2004)

VEGF expression in colon epithelial cells and lamina propria fibroblasts

VEGF in perfusate significantly higher than in controls

0Collagenous colitis Controls

15

10

5

20

25

p = 0.03

[%]

3

2

1

0Collagenous colitis Controls

4

5

p = 0.01

6

7

VEGF-stained epithelium VEGF-stained lamina propria

[%]

Contents

Schwab et al. (2000)


Pathogenesis of collagenous colitis: Histamine

Histamine secretion[ng/mg saturated weight]

15

10

5

0

Food allergens

Lipopoly-saccharides

Anti-IgEspontaneous

Anti-IgE

spontaneous

p < 0.001

Collagenous colitis Healthy controls

Stimulation with Stimulation with

Contents

Mostly younger patients

Males and females

Diarrhea: porridge-like.watery. bloody

Weight loss

Endoscopy: Signs of inflammation

Microscopic Colitis – Differential diagnosis

CIBD vs. microscopic colitis: Patient characteristics

Microscopic colitisChronic inflammatorybowel disease

Age usually > 50 years

Females predominate

Diarrhea: watery

Weight usually unchanged

Endoscopy: Normal findings

Microscopic Colitis: Treatment - Falk Aktuell · 2017-10-13 · Microscopic Colitis – Clinical...

Documents

Transcript of Microscopic Colitis: Treatment - Falk Aktuell · 2017-10-13 · Microscopic Colitis – Clinical...