Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy

Table 1 Baseline demographics and inflammatory bowel disease characteristics stratified by inflammatory bowel disease diagnosis

	Crohn's disease	Ulcerative colitis	Indeterminate IBD
	n = 4	n = 14	n = 1
Demographics
Age at first ICI use, yr, median, IQR	63, 4	69, 12.5	60, 0
Female sex, n (%)	2 (50.0)	2 (14.3)	0 (0)
White race, n (%)	3 (75.0)	11 (78.6)	1 (100)
Black race, n (%)	1 (25.0)	1 (7.1)	0 (0)
Asian race, n (%)	0 (0)	1 (7.1)	0 (0)
Other race, n (%)	0 (0)	1 (7.1)	0 (0)
Non-Hispanic ethnicity, n (%)	4 (100)	12 (85.7)	1 (100)
Hispanic/Latino ethnicity, n (%)	0 (0)	2 (14.3)	0 (0)
Never smoker, n (%)	2 (50.0)	5 (35.7)	0 (0)
Former smoker, n (%)	2 (50.0)	9 (64.3)	1 (100)
Body mass index, median, IQR	21.6, 1.7	25.5, 6.1	24.1, 0
IBD characteristics
Age at IBD onset, yr, median, IQR1	56, 0	39.5, 32.8	54, 0
IBD duration, yr, median, IQR1	7, 1	20, 29.25	6, 0
Disease location, n (%)	L1: 1 (25.0)	E1: 1 (7.1)	-
	L2: 1 (25.0)	E2: 4 (28.6)	-
	L3: 2 (50.0)	E3: 7 (50.0)	-
	-	Unknown: 2 (14.3)	-
Disease behavior, n (%)	B1: 2 (50.0)	-	-
	B2: 1 (25.0)	-	-
	B3: 0 (0)	-	-
	Unknown: 1 (25.0)	-	-
Perianal disease, n (%)	0 (0)	-	-
Extra-intestinal manifestations, n (%)	0 (0)	0 (0)	0 (0)

¹Unknown for 2 CD and 4 UC patients because date of IBD onset was not available.

Disease location and behavior were categorized using the Montreal classification: Location (L): L1, ileal disease; L2, colonic disease; L3, ileocolonic disease; Behavior (B): B1, inflammatory phenotype; B2, obstructive/stricturing phenotype; B3, penetrating/fistulizing phenotype; Extent (E): E1, proctitis; E2, left-sided colitis; E3, extensive/pan colitis. IQR: Interquartile range; IBD: Inflammatory bowel disease; ICI: Immune checkpoint inhibitor.

Table 2 All baseline clinical characteristics stratified by prevalence of inflammatory bowel disease exacerbation

	Exacerbation	No exacerbation	P value1
	n = 7	n = 12
Demographics
Female sex, n (%)	0 (0)	4 (33.3)	0.2451
Age at first ICI use, yr, median, IQR	60, 12.5	66, 9.3	0.6055
White race, n (%)	4 (57.1)	11 (91.7)	0.1174
Black race, n (%)	1 (14.3)	1 (8.3)	1.0000
Asian race, n (%)	1 (14.3)	0 (0)	0.3684
Other race, n (%)	1 (14.3)	0 (0)	0.3684
Non-Hispanic ethnicity, n (%)	5 (71.4)	12 (100)	0.1228
Hispanic/Latino ethnicity, n (%)	2 (28.6)	0 (0)	0.1228
Former smoker, n (%)	3 (42.9)	9 (75.0)	0.3261
Body mass index, median, IQR	24.3, 1.8	25.2 (6.7)	0.9018
Co-morbidities
Hypertension, n (%)	1 (14.3)	6 (50.0)	0.1733
Hyperlipidemia, n (%)	3 (42.9)	6 (50.0)	1.0000
Heart failure, n (%)	0 (0)	3 (25.0)	0.2632
Coronary artery disease, n (%)	0 (0)	2 (16.7)	0.5088
Chronic kidney disease, n (%)	0 (0)	2 (16.7)	0.5088
Diabetes mellitus, n (%)	2 (28.6)	1 (8.3)	0.5232
Gastroesophageal reflux disease, n (%)	1 (14.3)	1 (8.3)	1.0000
Asthma, n (%)	0 (0)	2 (16.7)	0.5088
Chronic obstructive pulmonary disease, n (%)	1 (14.3)	1 (8.3)	1.0000
IBD characteristics
Crohn's disease, n (%)	0 (0)	4 (33.3)	0.2451
Ulcerative colitis, n (%)	6 (85.7)	8 (66.7)	0.6027
Indeterminate IBD, n (%)	1 (14.3)	0 (0)	0.3684
Age at IBD onset, yr, median, IQR2	47, 28.3	56, 24.5	0.9668
IBD duration, yr, median, IQR2	11.5, 19.75	20, 24	0.9184
History of GI surgery before ICI use, n (%)	2 (28.6)	5 (41.7)	0.6562
Latest known disease state before ICI use, n (%)	Active: 0 (0)	Active: 0 (0)	1.0000
	Inactive: 5 (71.4)	Inactive: 10 (83.3)	0.6027
	Unknown: 2 (28.6)	Unknown: 2 (16.7)	0.6027
Latest available 25 (OH) D before ICI use, ng/mL, median, IQR3	38.9, 11.2	29.0, 9.5	0.8857
GI medications at start of ICI use, n (%)
Aminosalicylate	3 (42.9)	3 (25.0)	0.6169
Glucocorticoid	1 (14.3)	2 (16.7)	1.0000
Cholecalciferol (vitamin D3)	3 (42.9)	3 (25.0)	0.6169
Laxative (PEG, senna glycoside, docusate)	3 (42.9)	3 (25.0)	0.6169
Anti-diarrheal (diphenoxylate-atropine, loperamide)	1 (14.3)	3 (25.0)	1.0000
TNF inhibitor	0 (0)	1 (8.3)	1.0000
Mercaptopurine	1 (14.3)	0 (0)	0.3684
Other medications at start of ICI use, n (%)
Oral antibiotics	0 (0)	2 (16.7)	0.5088
Proton pump inhibitor	3 (42.9)	2 (16.7)	0.3047
Famotidine	0 (0)	2 (16.7)	0.5088
Metformin	1 (14.3)	0 (0)	0.3684
Insulin secretagogue	0 (0)	1 (8.3)	1.0000
Insulin	1 (14.3)	1 (8.3)	1.0000
Benzodiazepine	2 (28.6)	4 (33.3)	1.0000
Selective serotonin reuptake inhibitors	1 (14.3)	2 (16.7)	1.0000
Diuretic	0 (0)	4 (33.3)	0.2451
ACE inhibitor or angiotensin receptor blocker	3 (42.9)	5 (41.7)	1.0000
HMA-CoA reductase inhibitor	4 (57.1)	6 (50.0)	1.0000
Anticoagulant or antiplatelet	1 (14.3)	4 (33.3)	0.6027
Nonsteroidal anti-inflammatory drug	3 (42.9)	3 (25.0)	0.6169
Donezepil	1 (14.3)	1 (8.3)	1.0000
Glucosamine	1 (14.3)	1 (8.3)	1.0000
Ondansetron	2 (28.6)	3 (25.0)	1.0000
Chemotherapeutic kinase inhibitor	1 (14.3)	0 (0)	0.3684
Cancer characteristics and management
Primary cancer origin, n (%)
Bladder	0 (0)	5 (41.7)	0.1060
Melanoma	3 (42.9)	2 (16.7)	0.3047
Lung	2 (28.6)	4 (33.3)	1.0000
GI	1 (14.3)	1 (8.3)	1.0000
Other	1 (14.3)	3 (25.0)	1.0000
Radiation therapy for cancer, n (%)	5 (71.4)	9 (75.0)	1.0000
Checkpoint inhibitor, n (%)
Ipilimumab	2 (28.6)	1 (8.3)	0.5232
Nivolumab	2 (28.6)	2 (16.7)	0.6027
Pembrolizumab	4 (57.1)	8 (66.7)	1.0000
Atezolizumab	0 (0)	1 (8.3)	1.0000
Avelumab	0 (0)	0 (0)	1.0000
Durvalumab	0 (0)	1 (8.3)	1.0000
Cemiplimab	0 (0)	0 (0)	1.0000
Any anti-PD-1 or -PD-L1	6 (85.7)	12 (100)	0.3684
Combination anti-CTLA-4 and -PD-1/PD-L1	1 (14.3)	1 (8.3)	1.0000

¹P-values from Fisher's exact test for categorical variables or Mann-Whitney U test for continuous variables.

²Unknown for 1 patient with and 5 patients without immune checkpoint inhibitor (ICI)-attributed inflammatory bowel disease (IBD) exacerbations because date of IBD onset was not available.

³Unknown for 3 patients with and 8 patients without ICI-attributed IBD exacerbations.

IQR: Interquartile range; IBD: Inflammatory bowel disease; ICI: Immune checkpoint inhibitor; GI: Gastrointestinal; PEG: Polyethylene glycol; ACE: Angiotensin converting enzyme; HMA-CoA: Hydroxymethylglutaryl-coenzyme A; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; CTLA-4: Cytotoxic T-lymphocyte antigen 4.

Table 3 Inflammatory bowel disease management and clinical outcomes following immune checkpoint inhibitor treatment stratified by prevalence of inflammatory bowel disease exacerbation

	Exacerbation	No exacerbation	P value1
	n = 7	n = 12
Follow up time, d, median, IQR	435, 306	572, 450	0.4824
Length of ICI use, mo, median, IQR	12, 10	6.5, 9.3	0.3685
Reason for ICI discontinuation, n (%)
Cancer remission	1 (14.3)	1 (8.3)	1.0000
Cancer non-response	0 (0)	2 (16.7)	0.5088
Side effect(s)	1 (14.3)	3 (25.0)	1.0000
Patient preference	0 (0)	1 (8.3)	1.0000
Deceased	1 (14.3)	2 (16.7)	1.0000
Unknown	0 (0)	1 (8.3)	1.0000
Not discontinued	4 (57.1)	2 (16.7)	0.1287
GI-related hospitalization, n (%)	4 (57.1)	0 (0)	0.0090
GI-related surgery, n (%)	2 (28.6)	0 (0)	0.1228
IBD medications used after ICI initiation, n (%)
Aminosalicylates	4 (57.1)	4 (33.3)	0.3765
Glucocorticoids	3 (42.9)	4 (33.3)	1.0000
TNF inhibitor	2 (28.6)	1 (8.3)	0.5232
Mercaptopurine	1 (14.3)	0 (0)	0.3684
None	2 (28.6)	5 (41.7)	0.6562
Deceased, n (%)	1 (14.3)	4 (33.3)	0.6027

¹P-values from Fisher's exact test.

IQR: Interquartile range; IBD: Inflammatory bowel disease; ICI: Immune checkpoint inhibitor; GI: Gastrointestinal; TNF: Tumor necrosis factor.