Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website http://www.gastrores.org

Review

Volume 11, Number 3, June 2018, pages 174-188

Anti-Inflammatory Biologics and Anti-Tumoral Immune Therapies-Associated Colitis: A Focused Review of Literature

Figure 1. Biopsy from the colon revealed extensive large epithelioid granulomas with central necrosis. Acid-fast mycobacteria were identified by Ziehl-Neelsen stain in colon biopsies (picture not shown).

Figure 2. Colonic biopsy from one patient receiving etanercept for rheumatoid arthritis showed a non-caseating granuloma in the colonic mucosa without epithelial injury.

Figure 3. One example of anti-PD-1 monoclonal antibody-associated colitis by colonoscopy. There was a diffuse area of severely erythematous mucosa with friability and adherent exudates in the entire colon: (a) Sigmoid colon; (b) Rectum. The terminal ileum was normal.

Figure 4. One example of anti-PD-1 monoclonal antibody-associated colitis. The biopsy from the colon revealed similar features including cryptitis, crypt abscess (a), mixed lymphoplasmacytic inflammation with erosion (b), cryptal apoptosis (c), and mild crypt distortion (d). The biopsy did not show surface intraepithelial lymphocytosis or granuloma.

Figure 5. Biopsy from the terminal ileum from one patient treated with rituximab revealed mild surface intraepithelial lymphocytosis and a poorly formed non-caseating granuloma (a) ( H&E stain), and a lack of CD20+ lymphocytes (b) (immunoperoxidase stain).

**Table 1.** Grading Colitis-Associated With Medication/Drug
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Colitis	Asymptomatic, pathologic or radiographic findings only	Abdominal pain; mucus or blood in stool	Abdominal pain; fever; change in bowel habits with ileum; peritoneal signs	Life-threatening consequences (e.g. perforation, bleeding, ischemia, necrosis, toxic megacolon)	Death

Table 1. Grading Colitis-Associated With Medication/Drug

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Colitis

Asymptomatic, pathologic or radiographic findings only

Abdominal pain; mucus or blood in stool

Abdominal pain; fever; change in bowel habits with ileum; peritoneal signs

Life-threatening consequences (e.g. perforation, bleeding, ischemia, necrosis, toxic megacolon)

Death

**Table 2.** Anti-TNF-α Agents
Drug name	Registration name	Structure	Ligands	Molecular weight (kDa)	Half-life (days)	Clinical use	Other features
AS: ankylosing spondylitis; CD: Crohn’s disease; IBD: inflammatory bowel disease; JIA: juvenile idiopathic arthritis; PA: psoriatic arthritis; PP: plaque psoriasis; RA: rheumatoid arthritis; TNF: tumor necrosis factor; UC: ulcerative colitis.
Infliximab	Remicade	Chimeric monoclonal antibody	Soluble and transmembrane TNF-α	150	8 - 10	CD, UC, RA, AS, PA, PP
Adalimumab	Humira	Human monoclonal antibody	Soluble and transmembrane TNF-α	150	10 - 20	CD, RA, AS, PA, PP, JIA
Golimumab	Simponi	Human monoclonal antibody	Soluble and transmembrane TNF-α	150	7 - 20	RA, AS, PA
Certolizumab pegol	Cimzia	TNF-specific, PEGylated Fab’ antibody fragment	Soluble and transmembrane TNF-α	About 95	- 14	RA, PA, AS, CD
Etanercept	Enbrel	A fusion protein of two TNFR2 receptor extracellular domains and the Fc portion of human IgG	Soluble and transmembrane TNF-α	150	4	RA, JIA, PA, AS, PP	No efficacy in IBD

Table 2. Anti-TNF-α Agents

Drug name

Registration name

Structure

Ligands

Molecular weight (kDa)

Half-life (days)

Clinical use

Other features

AS: ankylosing spondylitis; CD: Crohn’s disease; IBD: inflammatory bowel disease; JIA: juvenile idiopathic arthritis; PA: psoriatic arthritis; PP: plaque psoriasis; RA: rheumatoid arthritis; TNF: tumor necrosis factor; UC: ulcerative colitis.

Infliximab

Remicade

Chimeric monoclonal antibody

Soluble and transmembrane TNF-α

150

8 - 10

CD, UC, RA, AS, PA, PP

Adalimumab

Humira

Human monoclonal antibody

Soluble and transmembrane TNF-α

150

10 - 20

CD, RA, AS, PA, PP, JIA

Golimumab

Simponi

Human monoclonal antibody

Soluble and transmembrane TNF-α

150

7 - 20

RA, AS, PA

Certolizumab pegol

Cimzia

TNF-specific, PEGylated Fab’ antibody fragment

Soluble and transmembrane TNF-α

About 95

- 14

RA, PA, AS, CD

Etanercept

Enbrel

A fusion protein of two TNFR2 receptor extracellular domains and the Fc portion of human IgG

Soluble and transmembrane TNF-α

150

RA, JIA, PA, AS, PP

No efficacy in IBD

**Table 3.** TNF-α Blockade-Associated Colitis
Agent	Colitis	Histology features	Clinical presentation	Treatment	Clinical outcome	References
CD: Crohn’s disease; JRA: Juvenile rheumatoid arthritis; N/A: information not available; RA: rheumatoid arthritis; TB: tuberculosis; TNF: tumor necrosis factor; UC: ulcerative colitis.
Infliximab	UC (n = 1)	Chronic active colitis with cryptitis, crypt abscesses, architectural distortion, dense lymphoplasmacytic infiltrate	Bloody diarrhea 2 weeks after his fourth infliximab inclusion	Cessation of infliximab; Parental steroids; Mesalamine	Resolved	[6]
	Apoptotic enteropathy (n = 1)	Architectural distortion, empty appearing lamina propria, cystically dilated crypts with atrophic epithelial lining, scattered apoptosis of basal crypt epithelium	Watery diarrhea	Cessation of infliximab	Diarrhea improved at 1 month following the last dose of infliximab	[8]
	Ischemic colitis (n = 13)	N/A	N/A	N/A	3 died; 9 recovered; 1 without follow-up data	[9]
	Intestinal TB	Intestinal and pulmonary TB (n = 1)	N/A	N/A	N/A	[12]
		Intestinal, pulmonary, brain TB (n = 1)	Worsening diarrhea	Anti-TB treatment	Died 8 months after diagnosis of TB	[13]
	CMV colitis (n = 1)	Features not well depicted in the text; No pictures from H&E stained sections presented; Pictures from immunostain equivocal for CMV at the most	Developed abdominal discomfort, anorexia, epigastric pain, watery diarrhea at 10 days after the third dose of infliximab	Cessation of infliximab and starting ganciclovir	No recurrence of diarrhea at 30 months of follow-up	[15]
Adalimumab	Ischemic colitis (n = 13)	Ischemic colitis without vasculitis on right hemicolectomy specimen (n = 1)	Developed post-prandial bilious vomiting, right flank and upper quadrant cramping pain and diarrhea 1 week after initiating adalimumab for RA	Right hemicolectomy	Alive after right hemicolectomy	[16]
		N/A (n = 12)	N/A	N/A	1 died; 10 recovered; 1 without follow-up data	[9]
	Apoptotic enteropathy (n = 2)	Increase in apoptotic bodies in the duodenum and mild increase in apoptotic bodies in the colon	Diarrhea or abdominal pain	N/A	N/A	[17]
	Disseminated TB with mycobacteria detected in feces (n = 1)	N/A	N/A	N/A	N/A	[12]
	Indolent T-cell lymphoproliferative disease of the gastrointestinal tract (n = 1)	Active chronic colitis and multiple foci of small lymphocyte infiltrates expanding the lamina propria of the inflamed mucosa without crypt destruction. The T cells are CD8+, TIA-1+, TCRβ-F1+ with TCRG and TCRB gene rearrangement by PCR study	Not mentioned	Cessation of adalimumab	Monoclonal T-cell infiltrate reappeared at the only site of active inflammation	[18]
Certolizumab pegol	Ischemic colitis (n = 3)	N/A	N/A	N/A	1 recovered; 1 without follow-up data	[9]
Etanercept	UC	N/A	Developed diarrhea; No resolution of UC after cessation of etanercept, need anti-IBD standard therapy and/or other anti-TNF-α agent	N/A	N/A	[19]
		Histology of UC (n = 1)	Developed bloody diarrhea after 28 months on etanercept for JRA	Flaring on adalimumab and infliximab, resolution only after cessation of all anti-TNF agents	Healing UC confirmed by colonoscopy 10 months after cessation of infliximab	[6]
		Histology of UC (n = 3) and one with microgranuloma	N/A	Cessation of etanercept and need anti-IBD with anti-TNF-α agents in two patients	Resolution in 2; 1 without follow-up data	[27]
	CD (n = 9)	Epithelioid granuloma present; Also with upper gastrointestinal tract involvement	N/A	Cessation of etanercept in most cases, need anti-IBD standard therapy and/or other anti-TNF-α agent	4 with remission; 5 without remission	[26, 27]
	Ischemic colitis (n = 7)	N/A	N/A	N/A	1 died; 6 recovered	[9]
	Apoptotic enteropathy (n = 1)	Prominent apoptotic bodies in the duodenum and mild increase in apoptotic bodies in the colon	Diarrhea	N/A	N/A	[17]
	Sarcoid-like lesions	N/A	N/A	N/A	N/A	[28]

Table 3. TNF-α Blockade-Associated Colitis

Agent

Colitis

Histology features

Clinical presentation

Treatment

Clinical outcome

References

CD: Crohn’s disease; JRA: Juvenile rheumatoid arthritis; N/A: information not available; RA: rheumatoid arthritis; TB: tuberculosis; TNF: tumor necrosis factor; UC: ulcerative colitis.

Infliximab

UC (n = 1)

Chronic active colitis with cryptitis, crypt abscesses, architectural distortion, dense lymphoplasmacytic infiltrate

Bloody diarrhea 2 weeks after his fourth infliximab inclusion

Cessation of infliximab; Parental steroids; Mesalamine

Resolved

[6]

Apoptotic enteropathy (n = 1)

Architectural distortion, empty appearing lamina propria, cystically dilated crypts with atrophic epithelial lining, scattered apoptosis of basal crypt epithelium

Watery diarrhea

Cessation of infliximab

Diarrhea improved at 1 month following the last dose of infliximab

[8]

Ischemic colitis (n = 13)

N/A

3 died; 9 recovered; 1 without follow-up data

[9]

Intestinal TB

Intestinal and pulmonary TB (n = 1)

N/A

[12]

Intestinal, pulmonary, brain TB (n = 1)

Worsening diarrhea

Anti-TB treatment

Died 8 months after diagnosis of TB

[13]

CMV colitis (n = 1)

Features not well depicted in the text; No pictures from H&E stained sections presented; Pictures from immunostain equivocal for CMV at the most

Developed abdominal discomfort, anorexia, epigastric pain, watery diarrhea at 10 days after the third dose of infliximab

Cessation of infliximab and starting ganciclovir

No recurrence of diarrhea at 30 months of follow-up

[15]

Adalimumab

Ischemic colitis (n = 13)

Ischemic colitis without vasculitis on right hemicolectomy specimen (n = 1)

Developed post-prandial bilious vomiting, right flank and upper quadrant cramping pain and diarrhea 1 week after initiating adalimumab for RA

Right hemicolectomy

Alive after right hemicolectomy

[16]

N/A (n = 12)

N/A

1 died; 10 recovered; 1 without follow-up data

[9]

Apoptotic enteropathy (n = 2)

Increase in apoptotic bodies in the duodenum and mild increase in apoptotic bodies in the colon

Diarrhea or abdominal pain

N/A

[17]

Disseminated TB with mycobacteria detected in feces (n = 1)

N/A

[12]

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract (n = 1)

Active chronic colitis and multiple foci of small lymphocyte infiltrates expanding the lamina propria of the inflamed mucosa without crypt destruction. The T cells are CD8+, TIA-1+, TCRβ-F1+ with TCRG and TCRB gene rearrangement by PCR study

Not mentioned

Cessation of adalimumab

Monoclonal T-cell infiltrate reappeared at the only site of active inflammation

[18]

Certolizumab pegol

Ischemic colitis (n = 3)

N/A

1 recovered; 1 without follow-up data

[9]

Etanercept

N/A

Developed diarrhea; No resolution of UC after cessation of etanercept, need anti-IBD standard therapy and/or other anti-TNF-α agent

N/A

[19]

Histology of UC (n = 1)

Developed bloody diarrhea after 28 months on etanercept for JRA

Flaring on adalimumab and infliximab, resolution only after cessation of all anti-TNF agents

Healing UC confirmed by colonoscopy 10 months after cessation of infliximab

[6]

Histology of UC (n = 3) and one with microgranuloma

N/A

Cessation of etanercept and need anti-IBD with anti-TNF-α agents in two patients

Resolution in 2; 1 without follow-up data

[27]

CD (n = 9)

Epithelioid granuloma present; Also with upper gastrointestinal tract involvement

N/A

Cessation of etanercept in most cases, need anti-IBD standard therapy and/or other anti-TNF-α agent

4 with remission; 5 without remission

[26, 27]

Ischemic colitis (n = 7)

N/A

1 died; 6 recovered

[9]

Apoptotic enteropathy (n = 1)

Prominent apoptotic bodies in the duodenum and mild increase in apoptotic bodies in the colon

Diarrhea

N/A

[17]

Sarcoid-like lesions

N/A

[28]

**Table 4.** Anti-CD20 (Rituximab)-Associated Colitis
Case	Age (years)	Gender	Underlying disease	Rituximab dose and duration	Other treatment	Interval between completion to symptoms of colitis	Diagnosis	Histology confirmation	Follow-up	Reference
N/A: information not available; R-CHOP: rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, prednisolone; R-CVP: rituximab, cyclophosphamide, vincristine, and prednisolone; RTX: rituximab; SLE: systemic lupus erythematosus.
1	62	Female	Marginal zone B cell lymphoma	Several cycles of RTX (2002 - 2005) and four doses in 2005	None	Not mention (short)	Diffuse colitis with pneumatosis	Fulminant colitis on subcolectomy specimen	Symptom recurred 5 years later after receiving a second course of four cycles of RTX, developed biopsy proven colitis.	[63]
2	67	Male	Relapse of follicular lymphoma	Four cycles of fludarabine, cyclophosphamide with rituximab and then maintenance therapy with RTX at a dose of 375 mg/m² every 3 months for a total of six cycles	None	2 months after his sixth cycle of RTX	Diffuse pancolitis	Confirmed by histology on subtotal colectomy	Patient died of recurrence of bacterial pneumonia 4 months after surgery.	[68]
3	26	Female	Non-Hodgkin lymphoma	N/A	N/A	N/A	Fulminant colitis	Confirmed by histology on colectomy	N/A	[69]
4	45	Female	Grave’s disease (clinical trial)	After the second infusion with weekly dose of 375 mg/m²	None	During treatment	Ulcerative colitis	Confirmed by sigmoidoscopy and biopsy	Mesalamine induced remission on day 650.	[67]
5	4	Male	Refractory nephrotic syndrome	4-week course of rituximab at a dose of 375 mg/m²	FK-506	6 weeks after RTX therapy	Severe ulcerative colitis	Confirmed by colonoscopy and biopsy	Corticosteroid induced remission with endoscopic and histologic healing.	[66]
6	34	Unknown	Bullous SLE	After three infusions at a dose of 375 mg/m²	N/A	During treatment	Ulcerative colitis	Confirmed by colonoscopy and biopsy	Episode of acute appendicitis with appendectomy. Later developed UC. Symptoms resolved upon RTX discontinuation.	[70]
7	38	Female	Refractory seronegative rheumatoid arthritis	N/A	None	13 weeks	Ulcerative colitis	Confirmed by colonoscopy and biopsy	Corticosteroid and 5-ASA induced remission; follow-up biopsy one year after RTX cessation showed restoration of B cells in the colonic mucosa and resolution of colitis.	[64]
8	80	Female	Small lymphocytic lymphoma	RTX 3-month maintenance	R-CVP	3 months	Crohn’s disease	Confirmed by colonoscopy/biopsy and resection histology	Surgical resection	[62]
9	74	Male	Grade 2 follicular lymphoma	RTX 3-month maintenance	R-CHOP	22 months	Crohn’s disease	Confirmed by colonoscopy and biopsy inflammation and small granulomata	Treated with hydrocortisone	[62]

Table 4. Anti-CD20 (Rituximab)-Associated Colitis

Case

Age (years)

Gender

Underlying disease

Rituximab dose and duration

Other treatment

Interval between completion to symptoms of colitis

Diagnosis

Histology confirmation

Follow-up

Reference

N/A: information not available; R-CHOP: rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, prednisolone; R-CVP: rituximab, cyclophosphamide, vincristine, and prednisolone; RTX: rituximab; SLE: systemic lupus erythematosus.

Female

Marginal zone B cell lymphoma

Several cycles of RTX (2002 - 2005) and four doses in 2005

None

Not mention (short)

Diffuse colitis with pneumatosis

Fulminant colitis on subcolectomy specimen

Symptom recurred 5 years later after receiving a second course of four cycles of RTX, developed biopsy proven colitis.

[63]

Male

Relapse of follicular lymphoma

Four cycles of fludarabine, cyclophosphamide with rituximab and then maintenance therapy with RTX at a dose of 375 mg/m² every 3 months for a total of six cycles

None

2 months after his sixth cycle of RTX

Diffuse pancolitis

Confirmed by histology on subtotal colectomy

Patient died of recurrence of bacterial pneumonia 4 months after surgery.

[68]

Female

Non-Hodgkin lymphoma

N/A

Fulminant colitis

Confirmed by histology on colectomy

N/A

[69]

Female

Grave’s disease (clinical trial)

After the second infusion with weekly dose of 375 mg/m²

None

During treatment

Ulcerative colitis

Confirmed by sigmoidoscopy and biopsy

Mesalamine induced remission on day 650.

[67]

Male

Refractory nephrotic syndrome

4-week course of rituximab at a dose of 375 mg/m²

FK-506

6 weeks after RTX therapy

Severe ulcerative colitis

Confirmed by colonoscopy and biopsy

Corticosteroid induced remission with endoscopic and histologic healing.

[66]

Unknown

Bullous SLE

After three infusions at a dose of 375 mg/m²

N/A

During treatment

Ulcerative colitis

Confirmed by colonoscopy and biopsy

Episode of acute appendicitis with appendectomy. Later developed UC. Symptoms resolved upon RTX discontinuation.

[70]

Female

Refractory seronegative rheumatoid arthritis

N/A

None

13 weeks

Ulcerative colitis

Confirmed by colonoscopy and biopsy

Corticosteroid and 5-ASA induced remission; follow-up biopsy one year after RTX cessation showed restoration of B cells in the colonic mucosa and resolution of colitis.

[64]

Female

Small lymphocytic lymphoma

RTX 3-month maintenance

R-CVP

3 months

Crohn’s disease

Confirmed by colonoscopy/biopsy and resection histology

Surgical resection

[62]

Male

Grade 2 follicular lymphoma

RTX 3-month maintenance

R-CHOP

22 months

Crohn’s disease

Confirmed by colonoscopy and biopsy inflammation and small granulomata

Treated with hydrocortisone

[62]

**Table 5.** Clinical, Endoscopic Finding, and Histology of Anti-CD20 (Rituximab, RTX)-Associated Colitis
Case	Clinical	Imaging study	Colonoscopy	Lab	Biopsy finding	Histology on colectomy	IHC	Final diagnosis	Reference
CMV: cytomegalovirus; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; FGD: fluorodeoxyglucose; Hb: hemoglobin; N/A: information not available; N/D: not done; PET-CT: positron emission tomography/computed tomography; RA: rheumatoid arthritis; RTX: rituximab; SLE: systemic lupus erythematosus.
1	Severe abdominal pain and diarrhea	N/A	Diffuse severe colitis on sigmoidoscopy	N/D	N/A	Diffuse colitis with pneumatosis in colectomy specimen	N/D	Fulminant colitis	[63]
2	2-week history of fever, cough, shortness of breath, and watery diarrhea. On the sixth day of admission the patient developed severe bloody diarrhea (6 - 7 bowel movements/day)	A CT scan revealed diffuse thickening of the entire colon with pericolic stranding adjacent to cecum and ascending colon.	Flexible sigmoidoscopy revealed severe confluent inflammation extending from the anorectal junction to the proximal limit of viewing at 30 cm	CBC neutrophils was 4.9 × 10⁹/L; Stool specimens were negative for Salmonella, Shigella, Campylobacter, parasites, and Clostridium difficile toxin A and B	Biopsies from the rectal and colonic mucosa revealed almost complete dropout of tubules and almost complete loss of surface epithelium without any pseudomembranes. The few residual crypts showed marked depletion of mucin and extensive apoptosis. Immunohistochemistry for CMV was negative.	Total colectomy 2 weeks after the initial onset of bloody diarrhea because of failure to respond to hydrocortisone therapy. Histology of colectomy showed diffuse pancolitis and terminal ileitis.	Lack of CD20⁺ cells; Normal number to a moderate increase of CD3⁺ cells; Moderate excess of enlarged macrophages	Severe apoptotic enterocolopathy/RTX-induced immunodysregulatory ileocolitis	[68]
3	N/A	N/A	N/A	N/A	N/A	Fulminant colitis	N/A	Fulminant colitis	[69]
4	Developed bloody diarrhea up to 20 stools per day	N/D	Sigmoidoscopy revealed colitis	N/D	Colonic biopsy taken 67days after initiation of RTX: inflammation, irregular crypts, and crypt abscesses	N/D	Biopsy taken 67 days after initiation of RTX: absence of CD20⁺ cells	Ulcerative colitis	[67]
5	Developed crampy abdominal pain, bloody diarrhea with 20 stools per day, weight loss, intermittent fevers	Abdominal ultrasound revealed severe pancolitis with wall thickening up to 6 mm.	Severe pancolitis with deep ulcers	Blood, urine, stool cultures negative. Clostridium difficile assays negative. Torovirus detected in the stool by electron microscopy.	Cryptitis with mixed inflammation in the lamina propria. No granulomata were identified.	N/D	Biopsy: absence of CD20⁺ cells	Severe ulcerative colitis	[66]
6	Profuse watery diarrhea	N/A	Erythematous mucosa (colitis)	N/A	Important infiltrates composed of mainly CD8+ T lymphocytes	N/D	Biopsy: primarily CD8⁺ T lymphocytes	Ulcerative colitis developed after initial episode of acute appendicitis	[70]
7	Bloody diarrhea developed 7 weeks after completion of biweekly at a dose of 1 g/2 weeks	N/D	Moderately severe pancolitis	N/D	Biopsy at 13 weeks: Goblet cell depletion, active and chronic inflammation with crypt abscess	N/D	Biopsy at 13 weeks: absence of CD20⁺ cell in the colonic biopsies	Ulcerative colitis	[64]
8		Crohn’s disease	[62]
	Two episodes of fever and diarrhea	N/D	Non-specific transverse colon ulcer, normal ileum (at the first episode)	Clostridium difficile was positive for the first episode.	No viral inclusions, granulomas, or changes of chronicity	Treated with metronidazole but had ongoing exacerbations of abdominal pain and diarrhea.	N/D
	A few month later, patient presented with abdominal pain, rectal bleeding	PET-CT revealed FDG-avid disease in her ileum when the patient had abdominal pain.	Ulcer at ileocolic anastomosis and an ulcer at the hepatic flexure and left colon	Fecal calprotectin 5,403 mg/kg	Patchy active inflammation with ulceration and multiple small granuloma, some with multinucleated giant cells	Patient underwent resection 3 month later because of the development of inflammatory mass in the right colon despite budesonide therapy.	N/D
9								Crohn’s disease	[62]
	5-week history of diarrhea, abdominal pain, fevers, and 8 kg of weight loss	Distal ileal wall thickening	Ileal inflammation, linear ulceration, but normal colonic mucosa	Anemia (Hb at 116 g/L); ESR of 74 mm/h; CRP of 87 mg/L; Fecal calprotectin of 3,226 mg/kg	N/A	N/D	N/D
	Re-presented 3 weeks later with recurrent fevers and worsening abdominal pain despite budesonide therapy	PET-CT revealed transmural update and thickening in the mid to distal small bowel.	Ileal inflammation, linear ulceration for at least 15 cm very easy contact bleeding, but normal colonic mucosa	N/D	Active ileitis with ulceration; Focal active colitis with ulceration and a single poorly formed granuloma	N/D	N/D

Table 5. Clinical, Endoscopic Finding, and Histology of Anti-CD20 (Rituximab, RTX)-Associated Colitis

Case

Clinical

Imaging study

Colonoscopy

Lab

Biopsy finding

Histology on colectomy

IHC

Final diagnosis

Reference

CMV: cytomegalovirus; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; FGD: fluorodeoxyglucose; Hb: hemoglobin; N/A: information not available; N/D: not done; PET-CT: positron emission tomography/computed tomography; RA: rheumatoid arthritis; RTX: rituximab; SLE: systemic lupus erythematosus.

Severe abdominal pain and diarrhea

N/A

Diffuse severe colitis on sigmoidoscopy

N/D

N/A

Diffuse colitis with pneumatosis in colectomy specimen

N/D

Fulminant colitis

[63]

2-week history of fever, cough, shortness of breath, and watery diarrhea. On the sixth day of admission the patient developed severe bloody diarrhea (6 - 7 bowel movements/day)

A CT scan revealed diffuse thickening of the entire colon with pericolic stranding adjacent to cecum and ascending colon.

Flexible sigmoidoscopy revealed severe confluent inflammation extending from the anorectal junction to the proximal limit of viewing at 30 cm

CBC neutrophils was 4.9 × 10⁹/L; Stool specimens were negative for Salmonella, Shigella, Campylobacter, parasites, and Clostridium difficile toxin A and B

Biopsies from the rectal and colonic mucosa revealed almost complete dropout of tubules and almost complete loss of surface epithelium without any pseudomembranes. The few residual crypts showed marked depletion of mucin and extensive apoptosis. Immunohistochemistry for CMV was negative.

Total colectomy 2 weeks after the initial onset of bloody diarrhea because of failure to respond to hydrocortisone therapy. Histology of colectomy showed diffuse pancolitis and terminal ileitis.

Lack of CD20⁺ cells; Normal number to a moderate increase of CD3⁺ cells; Moderate excess of enlarged macrophages

Severe apoptotic enterocolopathy/RTX-induced immunodysregulatory ileocolitis

[68]

N/A

Fulminant colitis

N/A

Fulminant colitis

[69]

Developed bloody diarrhea up to 20 stools per day

N/D

Sigmoidoscopy revealed colitis

N/D

Colonic biopsy taken 67days after initiation of RTX: inflammation, irregular crypts, and crypt abscesses

N/D

Biopsy taken 67 days after initiation of RTX: absence of CD20⁺ cells

Ulcerative colitis

[67]

Developed crampy abdominal pain, bloody diarrhea with 20 stools per day, weight loss, intermittent fevers

Abdominal ultrasound revealed severe pancolitis with wall thickening up to 6 mm.

Severe pancolitis with deep ulcers

Blood, urine, stool cultures negative. Clostridium difficile assays negative. Torovirus detected in the stool by electron microscopy.

Cryptitis with mixed inflammation in the lamina propria. No granulomata were identified.

N/D

Biopsy: absence of CD20⁺ cells

Severe ulcerative colitis

[66]

Profuse watery diarrhea

N/A

Erythematous mucosa (colitis)

N/A

Important infiltrates composed of mainly CD8+ T lymphocytes

N/D

Biopsy: primarily CD8⁺ T lymphocytes

Ulcerative colitis developed after initial episode of acute appendicitis

[70]

Bloody diarrhea developed 7 weeks after completion of biweekly at a dose of 1 g/2 weeks

N/D

Moderately severe pancolitis

N/D

Biopsy at 13 weeks: Goblet cell depletion, active and chronic inflammation with crypt abscess

N/D

Biopsy at 13 weeks: absence of CD20⁺ cell in the colonic biopsies

Ulcerative colitis

[64]

Crohn’s disease

[62]

Two episodes of fever and diarrhea

N/D

Non-specific transverse colon ulcer, normal ileum (at the first episode)

Clostridium difficile was positive for the first episode.

No viral inclusions, granulomas, or changes of chronicity

Treated with metronidazole but had ongoing exacerbations of abdominal pain and diarrhea.

N/D

A few month later, patient presented with abdominal pain, rectal bleeding

PET-CT revealed FDG-avid disease in her ileum when the patient had abdominal pain.

Ulcer at ileocolic anastomosis and an ulcer at the hepatic flexure and left colon

Fecal calprotectin 5,403 mg/kg

Patchy active inflammation with ulceration and multiple small granuloma, some with multinucleated giant cells

Patient underwent resection 3 month later because of the development of inflammatory mass in the right colon despite budesonide therapy.

N/D

Crohn’s disease

[62]

5-week history of diarrhea, abdominal pain, fevers, and 8 kg of weight loss

Distal ileal wall thickening

Ileal inflammation, linear ulceration, but normal colonic mucosa

Anemia (Hb at 116 g/L); ESR of 74 mm/h; CRP of 87 mg/L; Fecal calprotectin of 3,226 mg/kg

N/A

N/D

Re-presented 3 weeks later with recurrent fevers and worsening abdominal pain despite budesonide therapy

PET-CT revealed transmural update and thickening in the mid to distal small bowel.

Ileal inflammation, linear ulceration for at least 15 cm very easy contact bleeding, but normal colonic mucosa

N/D

Active ileitis with ulceration; Focal active colitis with ulceration and a single poorly formed granuloma

N/D