Abstract

Background: Refractory microscopic colitis is a rare condition with an unknown rate of occurrence. The efficacy of anti-tumor necrosis factor (TNF) therapy for microscopic colitis has never been reported.

Aims: 1) To report the frequency of refractory microscopic colitis in the database of the participant hospitals. 2) To describe the therapeutic response to anti-TNF therapy among the refractory cases.

Methods: Patients with a histological diagnosis of collagenous colitis and lymphocytic colitis were identified through the Department of Pathology database and the IBD practice database. Patients refractory to medical treatment and with severe symptoms were offered anti-TNF therapy.

Results: Five of 372 MC patients (1.3%; 95% CI, 0.6 to 3.1) presented with severe symptoms refractory to standard medical therapies. One patient was denied therapy from her insurance carrier. The other 4 received infliximab therapy. The response was excellent after one dose experiencing a 60–90% decrease in bowel movements. Three patients were switched to adalimumab (2 allergic reactions and 1 early loss of response to infliximab). Long-term clinical remission ( more than 1 year) was achieved in three cases (2 with adalimumab and 1 with infliximab). One patient on adalimumab had an early loss of response and was referred for colectomy.

Conclusions: Microscopic colitis with severe symptoms refractory to standard medical therapy including immunosuppressives is uncommon. In this setting, anti-TNF therapies may be a good option to avoid colectomy.

Introduction

Microscopic colitis (MC) is an inflammatory disorder of the colonic mucosa with normal or near-normal (mild erythema or edema) endoscopic appearance. The two entities included under the term MC, collagenous colitis (CC) and lymphocytic colitis (LC), are considered uncommon diseases. 1 CC differs from LC by a specific histopathological feature consisting of the presence of a subepithelial collagen band (10 μm or more) adjacent to the basal membrane, whereas the hallmark of LC is lymphocytic infiltration of the epithelium. The clinical features of CC and LC have been well described. 2 Most cases respond to symptomatic management; however, occasional cases refractory to standard medical therapy (anti-diarrheals, budesonide, and salicylates) have been reported. In those cases, benefit has been reported anecdotally from thiopurines or methotrexate. 35 A colectomy may be necessary in medically refractory cases when the quality of life is severely impaired. 2 The frequency of refractory microscopic colitis is unknown. In addition, to our knowledge, the efficacy of anti-TNF therapy has never been reported in microscopic colitis. The aim of the present study was: 1) To report the frequency of refractory MC obtained from the database of the participant hospitals 2) To describe the therapeutic response to anti-TNF therapy among the refractory cases.

Patients and methods

All patients evaluated at the Hospital Universitari Mutua Terrassa (HUMT, Barcelona, Spain) between January 1993 and September 2010 with a histological diagnosis of CC or LC were identified through the Department of Pathology database. Two out of 322 patients with microscopic colitis (168 CC and 154 LC) were refractory to medical treatment and the severity of their symptoms prompted us to administer anti-TNF therapy.

Additionally, all patients with a diagnosis of microscopic colitis in the UCSF Center for Colitis and Crohn's disease (San Francisco, California, USA) IBD database from January 2002 to December 2010 were evaluated. Three of 50 patients were found to require anti-TNF therapy. One patient was denied therapy from her insurance carrier. The other two received therapy.

The diagnosis of both CC and LC was based on both clinical and histological criteria, as previously defined. 1 The response to anti-TNF therapy was prospectively recorded.

Results

Among a total of 372 MC patients, 5 were refractory to conventional therapy giving a frequency of this condition of 1.3% (95% CI, 0.6 to 3.1) (0.6% at the HUMT and 6% at the UCSF). Cases 1 and 2 were treated at HUMT and cases 3 and 4 at UCSF. No patient was either current smoker or user of drugs suggested to induce MC. 6 Key results of the patients reported are described in Table 1 .

Case 1

A 60-year-old woman was diagnosed with CC in 1987, after presenting with watery diarrhea and abdominal pain. She reported 4 to 6 watery, non-bloody bowel movements per day, with urge to defecate and occasional fecal incontinence. Full colonoscopy was macroscopically normal and multiple colonic biopsies showed CC. Laboratory assessment showed low increases in ESR and C-reactive protein (CRP) and small-bowel explorations to rule out Crohn's disease, including capsule endoscopy, were normal. She tried the following medications without success: cholestyramine, mesalazine, prednisone, budesonide, antibiotics, and azathioprine. Associated thyroiditis and celiac disease were ruled out. In the last few years, she was on loperamide 12 mg/day with partial response. At March 2009, she presented with rectal bleeding and diarrhea. Physical examination was normal. Laboratory assessment showed hemoglobin 10 g/dL, hematocrit 32%, MCV 87 fL, ESR 50 mm/h, CRP 7.3 mg/L (normal, 0–5), and ferritin 25 ng/mL. The remainder of the routine biochemical and hematological blood parameters was normal. Stool culture and parasites were negative.

On colonoscopy, the mucosa of all colonic segments showed mild inflammatory changes with loss of the normal submucosal vascular pattern. In the ascending colon, there was a circumferential ulceration with partial stricture of the colonic lumen ( Fig. 1 a). Also there were some small ulceration over the ileo-cecal valve. Terminal ileum could not be explored. Multiple biopsies were obtained.

Colonic biopsies showed marked thickening of the subepithelial collagen band with entrapped capillaries ( Fig. 2 ). A moderate mixed lymphoplasmacytic infiltrate was present in the lamina propria, occasional polymorphonuclear leukocytes entering the crypt epithelium were observed in some areas, and increased intraepithelial lymphocytes were present. There were some areas of ulceration and granulation tissue. Of note, there was amyloid deposition in the submucosal vessels with amyloid PP and type AA protein seen on immunohistochemistry ( Fig. 3 ). Mucosal architecture was normal. Colonic biopsies from a follow-up examination three years before were revised and there was no amyloid deposition.

The patient was not taking non-steroidal anti-inflammatory drugs, and the colonic ulcers were attributed to the colonic amyloidosis. Explorations to rule-out small bowel involvement by Crohn's disease as well as systemic amyloidosis were normal. She was started on infliximab (dose, 5 mg/kg/day at 0, 2 and 6 weeks) and had a partial response and early loss of response. She was switched to adalimumab (dose, 160–80-40 mg) with maintenance treatment every 2 weeks. Clinical remission was obtained with a 90% reduction in bowel movements from 20 liquid to 2 formed stools a day, with resolution of abdominal pain, which was maintained for more than 14 months. Acute phase reactants in blood analysis normalized. Full colonoscopy at 8 months of follow-up revealed healing of colonic mucosal ulcers, persistence of a partial colonic stricture in the ascending colon without inflammatory changes ( Fig. 1 b). Histological response was partial, with persisting mild amyloid AA deposition in submucosal small vessels and occasional thickened subepithelial band.

Case 2

A 58 year old woman developed a chronic diarrhea in 2002. She was diagnosed with gluten sensitive enteropathy with preserved villous architecture (35 intraepithelial lymphocytes per 100 epithelial cells). The HLA-DQ2 was positive and celiac serology was negative (IgA anti-tranglutaminase and anti-endomisium antibodies; IgA levels were normal). She adhered to a gluten free diet and experienced a partial clinical improvement but without histological response. A colonoscopy with multiple biopsies was performed showing a LC. Clinically, she presented with 10 liquid stools per day, rectal tenesmus and daily anal incontinence. Blood analysis was in the normal range. Various treatments were tried (cholestyramine, mesalazine, budesonide, antidiarrheal drugs), but symptomatic control was not achieved. In September 2007 she was reevaluated, as she was refractory to all treatments. A colonoscopy was performed showing an erythematous, friable mucosa and multiple biopsies showed a progression from LC to CC. Azathioprine was started but was unsuccessful. Due to the severe impairment of her quality of life, a biological therapy was proposed as a rescue therapy before colectomy. Infliximab (5 mg/kg at 0, 2, 6 weeks followed by re-treatment every 2 months) was started in June 2009. The patient experienced an improvement in clinical symptoms with a 70% decrease in bowel movements, passing 3 formed stools per day with disappearance of incontinence and tenesmus. After 5 months of treatment, infliximab was replaced by adalimumab, due to the appearance of intense pruritus as a side effect. A sustained clinical response was maintained with adalimumab 40 mg Q2weeks for more than 1 year. Repeat biopsies performed 9 months after the start of biological treatment showed similar histopathological findings.

Case 3

A 63 year old woman was diagnosed with CC in 2007 after symptoms of profuse watery diarrhea occurring up to 20 times a day for seventeen years. She had occasional cramping abdominal pain but never noted any blood. She was diagnosed with irritable bowel syndrome and was followed over time. The patient had her first colonoscopy in 1996 which was endoscopically normal; however, on biopsy she did have chronic non-specific inflammatory changes in the right colon and cecum. Five years later, a repeat colonoscopy demonstrated normal mucosa grossly with histologic evidence of CC. Upon presentation to UCSF, she had already failed therapy with diphenoxylate, loperamide, bismuth subsalicylate, prednisone, 6-mercaptopurine, tincture of opium, and alosetron. Physical examination was unremarkable. Laboratory assessment was normal except for WBC 12.9 and ESR 28; IgA anti-tranglutaminase antibodies were negative. The remainder of the lab work and stool studies was negative. She was then started on infliximab 5 mg/kg at 0, 2, 6 weeks and continued a maintenance dose every 8 weeks. She had a dramatic response after one dose, experiencing an 86% decrease in bowel movements from 10–15 liquid stools a day to 1–2 formed stools a day. She continued maintenance therapy with positive response for one year and then returned on therapy to her referring physician.

Case 4

A 56 year old woman was initially diagnosed with LC in 2006 when presented with high-volume, watery diarrhea with occasional blood with up to 30 bowel movements per day. The patient underwent subsequent evaluation including upper endoscopy and colonoscopy which were reportedly normal, and duodenal biopsies without evidence of celiac disease. Right colonic biopsies revealed evidence of CC. She initially tried, without success, diphenoxylate, loperamide and mesalazine. She was then started on budesonide, which provided some relief, but she subsequently developed side effects including insomnia and migraine exacerbation leading to discontinuation of this medication. Upon presentation to UCSF, she continued to have as many as 8 loose, watery bowel movements per day. Physical examination was unremarkable. Laboratory studies were notable for a WBC 10.4. The remainder of lab and stool studies was negative. She responded positively to infliximab after one dose, reporting over a 60% decrease in bowel movements from 7–10 liquid to 2–4 formed stools a day. Unfortunately, she had an allergic reaction to a sulfa medication for hypertension, while taking infliximab, causing a Stevens Johnson syndrome. This led to extended suspension of infliximab. Subsequently, she experienced positive response on adalimumab after two doses (160 mg, 80 mg), with an 80% decrease in bowel movements from 15–20 liquid to 2–4 formed stool a day. Adalimumab was continued 40 mg Q2weeks, but after 3 months symptoms returned and colectomy was recommended.

Discussion

Results of the present study show that MC with severe symptoms refractory to medical therapy including immunosuppressives is uncommon. Frequency of this condition differs between the two participant centers, ranging from 0.6% to 6%. Differences in the selection of patients may explain this discrepancy. In HUMT there is a prospective program searching for microscopic colitis in the catchment area since 1993, with the result that since that time there has been a high degree of motivation for involved physicians to diagnose microscopic colitis. This program lets us diagnose most patients with mild to moderate symptoms. On the other hand, the UCSF Center for Colitis and Crohn's disease is a referral unit, and MC represents a selected group of patients with more severe symptoms. Regardless, the frequency of refractory disease to standard medical therapy in MC was low, less than that described for IBD. 7

Some aspects of the clinical picture of the patients described merit special comment. First, the clinical picture of microscopic colitis may be easily confused with irritable bowel syndrome (see case 3) if multiple biopsy samples of the colon are not routinely taken in all patients with watery chronic diarrhea when the colon looks macroscopically normal. In fact, a high percentage of these patients fulfill the Rome II criteria of functional bowel disease. 8 Likewise, the pathologist must use objective histological criteria for the diagnosis of both CC and LC, to avoid providing a diagnosis of non-specific chronic inflammation for these patients. 9 A prompt from the gastroenterologist requesting that CC and LC be ruled out may be helpful.

On the other hand, colonic amyloidosis complicating CC has not been previously reported (see case 1). Only a single-case report of primary AL amyloidosis developing CC during the follow-up has been described. 10 Conversely, secondary (AA) amyloidosis is associated with persistent chronic inflammation and has been described with several chronic intestinal inflammatory conditions, mainly IBD. Systemic amyloidosis among IBD patients is a rare but serious complication that may lead to death, most cases being reported among Crohn's disease patients. 11 The present patient with CC and colonic AA-amyloidosis was refractory to medical therapy (including prednisone, budesonide, and azathioprine) and over the years was only treated with anti-diarrheals with a partial improvement in clinical symptoms, but persisting low-grade inflammation (small increase of both ESR and CRP). Colonic amyloidosis was diagnosed more than 20 years from CC diagnosis, and systemic involvement was excluded. The presence of a stricture and ulcerations in ascending colon, which is not a typical finding in MC, was attributed to the colonic amyloidosis. 11 Anti-TNF therapy was useful to achieve clinical remission and also to improve the colonic amyloidosis (healing of colonic ulcers and decrease of the colonic amyloid deposit). Improvement with anti-TNF therapies of systemic amyloidosis complicating IBD has also been described. 12 , 13

Treatment with anti-TNF agents, at the same dose regimen used in IBD patients, was successful in all four treated patients. However, in one of them a severe allergic reaction from an unrelated sulfa therapy interrupting infliximab therapy and an early loss of response to adalimumab prompted a recommendation of colectomy (see case 4). It is important to take into account that, in the same way as IBD, restorative proctocolectomy with ileo-anal anastomosis may not be considered curative for CC, since in some patients collagenous pouchitis may develop. 14

Histological remission was not achieved in the two patients in whom it was evaluated, but in one of them there was a partial response. This observation agrees with that described in randomized clinical trials of budesonide vs placebo in which clinical remission was not always associated with histological remission, with persistence of some degree of histological damage. 15 , 16 In our experience this is a frequent finding when follow-up histological studies are performed. 17

In conclusion, MC with severe symptoms refractory to standard medical therapy including immunosupressants is uncommon. Secondary amyloidosis may complicate CC with uncontrolled inflammatory activity. In these subsets of patients, anti-TNF therapy may be a good option to avoid colectomy. To our knowledge, this is a novel finding, not previously described.

Conflict of interest

Dr Mahadevan is Consultant of UCB, Centocor, and Abbott.

Aknowledgments

Esteve, Mahadevan, Sainz, Rodriguez, Salas and Fernández-Bañares have contributed to the design of the study, data recompilation and writing of the paper. This study was partly supported by a Research Grant from the ‘Fondo de Investigaciones Sanitarias’ (PI06/1577), Spanish Ministry of Health (Instituto de Salud Carlos III). This sponsor played no role in the study design, data collection, analysis and interpretation of data, or writing of the paper. All authors have approved the final draft submitted.

  • CC

    collagenous colitis

  • LC

    lymphocytic colitis

  • MC

    microscopic colitis

References

1
Fernández-Bañares
F.
Salas
A.
Esteve
M.
Pardo
L.
Casalots
J.
Forné
M.
Espinós
J.C.
Loras
C.
Rosinach
M.
Viver
J.M.
Evolution of the incidence of collagenous colitis and lymphocytic colitis in Terrassa, Spain: a population-based study
Inflamm Bowel Dis
 
Sep. 27 2010
Pubmed PMID: 20878755
2
Tysk
C.
Bohr
J.
Nyhlin
N.
Wickbom
A.
Eriksson
S.
Diagnosis and management of microscopic colitis
World J Gastroenterol
 
14
48
2008
7280
7288
3
Pardi
D.S.
Loftus
E.V.
Jr.
Tremaine
W.J.
Sandborn
W.J.
Treatment of refractory microscopic colitis with azathioprine and 6-mercaptopurine
Gastroenterology
 
120
2001
1483
1484
4
Vennamaneni
S.R.
Bonner
G.F.
Use of azathioprine or 6-mercaptopurine for treatment of steroid-dependent lymphocytic and collagenous colitis
Am J Gastroenterol
 
96
2001
2798
2799
5
Riddell
J.
Hillman
L.
Chiragakis
L.
Clarke
A.
Collagenous colitis: oral low-dose methotrexate for patients with difficult symptoms: long-term outcomes
J Gastroenterol Hepatol
 
22
2007
1589
1593
6
Fernández-Bañares
F.
Esteve
M.
Espinós
J.C.
Rosinach
M.
Forné
M.
Salas
A.
Viver
J.M.
Drug consumption and the risk of microscopic colitis
Am J Gastroenterol
 
102
2007
324
330
7
Faubion
W.A.
Jr.
Loftus
E.V.
Jr.
Harmsen
W.S.
Zinsmeister
A.R.
Sandborn
W.J.
The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study
Gastroenterology
 
121
2001
255
260
8
Limsui
D.
Pardi
D.S.
Camilleri
M.
Loftus
E.V.
Jr.
Kammer
P.P.
Tremaine
W.J.
Sandborn
W.J.
Symptomatic overlap between irritable bowel syndrome and microscopic colitis
Inflamm Bowel Dis
 
13
2007
175
181
9
Fernández-Bañares
F.
Salas
A.
Esteve
M.
Pitfalls and errors in the diagnosis of collagenous and lymphocytic colitis
J Crohns Colitis
 
2
2008
343
347
10
Janczewska
I.
Mejhert
M.
Hast
R.
Runarsson
G.
Sandstedt
B.
Primary AL-amyloidosis, ulcerative colitis and collagenous colitis in a 57-year-old woman: a case study
Scand J Gastroenterol
 
39
2004
1306
1309
11
Ebert
E.C.
Nagar
M.
Gastrointestinal manifestations of amyloidosis
Am J Gastroenterol
 
103
2008
776
787
12
Serra
I.
Oller
B.
Mañosa
M.
Naves
J.E.
Zabana
Y.
Cabré
E.
Domènech
E.
Systemic amyloidosis in inflammatory bowel disease: retrospective study on its prevalence, clinical presentation, and outcome
J Crohns Colitis
 
4
2010
269
274
13
Park
Y.K.
Han
D.S.
Eun
C.S.
Systemic amyloidosis with Crohn's disease treated with infliximab
Inflamm Bowel Dis
 
14
2008
431
432
14
Shen
B.
Bennett
A.E.
Fazio
V.W.
Sherman
K.K.
Sun
J.
Remzi
F.H.
Lashner
B.A.
Collagenous pouchitis
Dig Liver Dis
 
38
2006
704
709
15
Miehlke
S.
Heymer
P.
Bethke
B.
Bästlein
E.
Meier
E.
Bartram
H.P.
Wilhelms
G.
Lehn
N.
Dorta
G.
DeLarive
J.
Tromm
A.
Bayerdörffer
E.
Stolte
M.
Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial
Gastroenterology
 
123
2002
978
984
16
Baert
F.
Schmit
A.
D'Haens
G.
Dedeurwaerdere
F.
Louis
E.
Cabooter
M.
De Vos
M.
Fontaine
F.
Naegels
S.
Schurmans
P.
Stals
H.
Geboes
K.
Rutgeerts
P.
Belgian IBD Research Group
Codali Brussels
Budesonide in collagenous colitis: a double-blind placebo-controlled trial with histologic follow-up
Gastroenterology
 
122
2002
20
25
17
Fernández-Bañares
F.
Salas
A.
Esteve
M.
Espinós
J.
Forné
M.
Viver
J.M.
Collagenous and lymphocytic colitis: evaluation of clinical and histological features, response to treatment, and long-term follow-up
Am J Gastroenterol
 
98
2003
340
347

Figures

Figure 1

(a) Circumferential ulceration with partial stricture of the right colon in a collagenous colitis patient with secondary amyloidosis. (b) Follow-up colonoscopy showing persisting partial colonic stricture in ascending colon without inflammatory changes.

Figure 1

(a) Circumferential ulceration with partial stricture of the right colon in a collagenous colitis patient with secondary amyloidosis. (b) Follow-up colonoscopy showing persisting partial colonic stricture in ascending colon without inflammatory changes.

Figure 2

Subepithelial collagen band entrapping capillary vessels (Trichromic stain).

Figure 2

Subepithelial collagen band entrapping capillary vessels (Trichromic stain).

Figure 3

Amyloid deposits in submucosal vessels. Congo red stain positivity (a) showing green birefringence visualized under polarized light (b); Immunohistochemical expression of amyloid AA in submucosal vessels (c).

Figure 3

Amyloid deposits in submucosal vessels. Congo red stain positivity (a) showing green birefringence visualized under polarized light (b); Immunohistochemical expression of amyloid AA in submucosal vessels (c).

Tables

Table 1

Key aspects of patients described.

Case Diagnosis (time of evolution) Main clinical symptoms Associated diseases Previous treatment failures Anti-TNF therapy Clinical response (follow-up) 
CC (20 years)  Diarrhea, 20 liquid dbm a , and rectal bleeding.  Secondary (AA) colonic amyloidosis Cholestyramine Mesalazine Prednisone Budesonide Antibiotics Azathioprine -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks. Early loss of response.-Adalimumab: Induction: 160–80–40 mg Maintenance: 40 mg Q2 weeks 90% reduction in dbm (14 months) 
LC (6 years) CC (present) Watery diarrhea, 10 dbm.  GSE b Loperamide Cholestyramine Mesalazine Budesonide Azathioprine -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks; retreatment Q2 months. Side effect at 5 months of starting. -Adalimumab: 40 mg Q2 weeks 70% reduction in dbm (12 months) 
CC (17 years with diarrhea) Watery diarrhea, 20 dbm. None Anti-diarrheals Bismuth subsalicylate Prednisone 6-mercaptopurine Tincture of opium Alosetron -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks; retreatment Q2 months. 86% reduction in dbm (12 months) 
LC (2 years) CC (present) Watery diarrhea, 8 dbm. None Anti-diarrheals Mesalazine Budesonide  -Infliximab: Induction: 5 mg/kg/day at 0 week. Allergic reaction c -Adalimumab: Induction: 160–80–40 mg Maintenance: 40 mg Q2 weeks.  80% reduction in dbm. Loss of response after 3 months. Colectomy recommended. 
Case Diagnosis (time of evolution) Main clinical symptoms Associated diseases Previous treatment failures Anti-TNF therapy Clinical response (follow-up) 
CC (20 years)  Diarrhea, 20 liquid dbm a , and rectal bleeding.  Secondary (AA) colonic amyloidosis Cholestyramine Mesalazine Prednisone Budesonide Antibiotics Azathioprine -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks. Early loss of response.-Adalimumab: Induction: 160–80–40 mg Maintenance: 40 mg Q2 weeks 90% reduction in dbm (14 months) 
LC (6 years) CC (present) Watery diarrhea, 10 dbm.  GSE b Loperamide Cholestyramine Mesalazine Budesonide Azathioprine -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks; retreatment Q2 months. Side effect at 5 months of starting. -Adalimumab: 40 mg Q2 weeks 70% reduction in dbm (12 months) 
CC (17 years with diarrhea) Watery diarrhea, 20 dbm. None Anti-diarrheals Bismuth subsalicylate Prednisone 6-mercaptopurine Tincture of opium Alosetron -Infliximab: Induction: 5 mg/kg/day at 0, 2 & 6 weeks; retreatment Q2 months. 86% reduction in dbm (12 months) 
LC (2 years) CC (present) Watery diarrhea, 8 dbm. None Anti-diarrheals Mesalazine Budesonide  -Infliximab: Induction: 5 mg/kg/day at 0 week. Allergic reaction c -Adalimumab: Induction: 160–80–40 mg Maintenance: 40 mg Q2 weeks.  80% reduction in dbm. Loss of response after 3 months. Colectomy recommended. 
a

Dbm, daily bowel movements.

b

Gluten-sensitive enteropathy (lymphocytic enteropathy).

c

Allergic reaction to a sulfa medication that led to extended suspension of infliximab.