Long-term lymphoma risk in thiopurine-treated inflammatory bowel disease: A 15-year propensity-matched cohort study

Table 1 Baseline characteristics of patients with inflammatory bowel disease taking thiopurines and patients with inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics, mean ± SD/n (%)

Characteristics	Before PSM			After PSM
	IBD with thiopurines (n = 42310)	IBD with 5-ASA (n = 84093)	SMD	IBD with thiopurines (n = 38781)	IBD with 5-ASA (n = 38781)	SMD
Age, years	41.6 ± 18.9	47.5 ± 19.0	0.311	42.6 ± 18.8	43.3 ± 18.6	0.038
Sex
Male	19675 (47.1)	38379 (46.3)	0.018	18277 (47.1)	18435 (47.5)	0.008
Female	22024 (52.8)	44512 (53.7)	0.008	20466 (52.8)	20305 (52.4)	0.008
Race
White	32869 (78.7)	62615 (75.5)	0.078	30306 (78.1)	30565 (78.8)	0.016
Black or African American	3749 (9.0)	7531 (9.1)	0.003	3490 (9.0)	3373 (8.7)	0.011
Asian	888 (2.1)	2327 (2.8)	0.044	872 (2.2)	789 (2.0)	0.015
American Indian or Alaska native	168 (0.4)	285 (0.3)	0.010	153 (0.4)	131 (0.3)	0.009
Native Hawaiian or other Pacific Islander	60 (0.1)	143 (0.2)	0.007	60 (0.2)	59 (0.2)	0.001
Unknown race	3041 (7.3)	7638 (9.2)	0.070	2964 (7.6)	2988 (7.7)	0.002
Ethnicity
Hispanic or Latino	1862 (4.5)	4370 (5.3)	0.037	1789 (4.6)	1613 (4.2)	0.022
Not Hispanic or Latino	31775 (76.1)	60134 (72.5)	0.083	29271 (75.5)	29640 (76.4)	0.022
Unknown ethnicity	8105 (19.4)	18463 (22.3)	0.070	7721 (19.9)	7528 (19.4)	0.013
Comorbidities
Essential hypertension	7153 (17.1)	17234 (20.8)	0.093	6769 (17.5)	6717 (17.3)	0.004
Type 2 diabetes mellitus	2711 (6.5)	6427 (7.7)	0.049	2558 (6.6)	2492 (6.4)	0.007
Rheumatoid arthritis	633 (1.5)	808 (1.0)	0.049	512 (1.3)	508 (1.3)	0.001
Psoriasis	593 (1.4)	769 (0.9)	0.046	489 (1.3)	446 (1.2)	0.010
Alcohol abuse	410 (1.0)	1102 (1.3)	0.032	401 (1.0)	375 (1.0)	0.007
Systemic lupus erythematosus	502 (1.2)	362 (0.4)	0.085	289 (0.7)	318 (0.8)	0.008
Nicotine dependence	2832 (6.8)	5215 (6.3)	0.020	2614 (6.7)	2578 (6.6)	0.004

Baseline demographic and clinical characteristics of patients with inflammatory bowel disease taking thiopurines and patients with inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics before and after propensity score matching. Standardized mean differences quantify covariable imbalance with values > 0.1 indicating clinically meaningful differences. 5-ASA: 5-aminosalicylates; IBD: Inflammatory bowel disease; PSM: Propensity score matching; SMD: Standardized mean difference.

Table 2 Odds ratio for lymphoma outcomes for patients with inflammatory bowel disease taking thiopurines vs inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics

Outcomes	Events in IBD with thiopurines	Events in IBD with 5-ASA	OR (95%CI)	P value
Overall lymphoma
1 year	36	26	1.39 (0.84-2.29)	0.1907
3 years	71	30	2.37 (1.54-3.64)	< 0.001
5 years	91	50	1.82 (1.29-2.57)	< 0.001
10 years	136	70	1.95 (1.46-2.60)	< 0.001
15 years	148	77	1.93 (1.46-2.54)	< 0.001
Hodgkin lymphoma
1 year	≤ 10	≤ 10
3 years	≤ 10	≤ 10
5 years	≤ 10	≤ 10
10 years	≤ 10	≤ 10
15 years	26	10	2.60 (1.25-5.40)	0.008
Non-Hodgkin lymphoma
1 year	33	24	1.38 (0.81-2.33)	0.2383
3 years	68	28	2.43 (1.57-3.78)	< 0.001
5 years	85	47	1.81 (1.26-2.58)	0.0009
10 years	125	66	1.90 (1.41-2.56)	< 0.001
15 years	136	70	1.95 (1.46-2.60)	< 0.001
B-cell lymphoma
1 year	33	26	1.27 (0.76-2.13)	0.3153
3 years	63	26	2.43 (1.54-3.83)	< 0.001
5 years	82	49	1.68 (1.17-2.39)	0.0039
10 years	120	65	1.85 (1.36-2.51)	< 0.001
15 years	129	70	1.85 (1.38-2.47)	< 0.001
T-cell/natural killer cell lymphoma
1 year	≤ 10	≤ 10
3 years	≤ 10	≤ 10
5 years	≤ 10	≤ 10
10 years	23	13	1.77 (0.90-3.49)	0.0955
15 years	26	13	2.00 (1.03-3.89)	0.037

Odds ratios of lymphoma outcomes at the 1-year, 3-year, 5-year, 10-year, and 15-year follow-up among propensity score-matched cohorts of patients with inflammatory bowel disease taking thiopurines vs patients with inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics. Outcomes are presented as event counts with percentage and corresponding odds ratios with 95% confidence intervals. All analyses reflect matched sample sizes of 39618 per group. 5-ASA: 5-aminosalicylates; IBD: Inflammatory bowel disease; OR: Odds ratio; CI: Confidence interval.

Table 3 Odds ratio for lymphoma outcomes for patients with ulcerative colitis taking thiopurines vs ulcerative colitis taking 5-aminosalicylic acid and not taking thiopurines or biologics

Outcomes	Events in UC with thiopurines	Events in UC with 5-ASA	OR (95%CI)	P value
Overall lymphoma
1 year	≤ 10	≤ 10
3 years	29	15	1.94 (1.04-3.62)	0.037
5 years	38	19	2.01 (1.16-3.48)	0.016
10 years	54	26	2.08 (1.31-3.32)	0.0017
15 years	60	27	2.23 (1.41-3.50)	0.0004
Hodgkin lymphoma
1 year
3 years
5 years
10 years
15 years
Non-Hodgkin lymphoma
1 year	≤ 10	≤ 10
3 years	27	13	2.05 (1.07-3.90)	0.029
5 years	35	17	2.07 (1.16-3.69)	0.012
10 years	50	24	2.09 (1.28-3.40)	0.0024
15 years	55	25	2.20 (1.37-3.53)	0.0008
B-cell lymphoma
1 year	≤ 10	≤ 10
3 years	27	12	2.26 (1.14-4.46)	0.016
5 years	34	16	2.13 (1.18-3.86)	0.0107
10 years	50	24	2.09 (2.38-3.40)	0.0024
15 years	55	25	2.20 (1.37-3.53)	0.0008
T-cell/natural killer cell lymphoma
1 year	≤ 10	≤ 10
3 years	≤ 10	≤ 10
5 years	≤ 10	≤ 10
10 years	≤ 10	≤ 10
15 years	≤ 10	≤ 10

Odds ratios of lymphoma outcomes at the 1-year, 3-year, 5-year, 10-year, and 15-year follow-up among propensity score-matched cohorts of patients with ulcerative colitis taking thiopurines vs patients with ulcerative colitis taking 5-aminosalicylic acid and not taking thiopurines or biologics. Outcomes are presented as event counts with percentage and corresponding odds ratios with 95% confidence intervals. All analyses reflect matched sample sizes of 12334 per group. 5-ASA: 5-aminosalicylates; UC: Ulcerative colitis; OR: Odds ratio; CI: Confidence interval.

Table 4 Odds ratio for lymphoma outcomes for patients with Crohn’s disease taking thiopurines vs Crohn’s disease taking 5-aminosalicylic acid and not taking thiopurines or biologics

Outcomes	Events in CD with thiopurines	Events in CD with 5-ASA	OR (95%CI)	P value
Overall lymphoma
1 year	11	11	1.00 (0.43-2.30)	09985
3 years	21	17	1.24 (0.65-2.34)	0.5168
5 years	29	21	1.36 (0.77-2.41)	0.253
10 years	45	25	1.80 (1.10-2.94)	0.0169
15 years	45	31	1.39 (0.87-2.10)	0.1626
Hodgkin lymphoma
1 year
3 years
5 years
10 years
15 years
Non-Hodgkin lymphoma
1 year	≤ 10	11	0.91 (0.39-2.14)	0.8359
3 years	19	17	1.12 (0.58-2.15)	0.739
5 years	27	21	1.29 (0.73-2.28)	0.386
10 years	40	25	1.60 (0.97-2.64)	0.063
15 years	37	27	1.37 (0.83-2.25)	0.211
B-cell lymphoma
1 year	≤ 10	≤ 10
3 years	15	18	0.83 (0.42-1.65)	0.406
5 years	24	22	1.09 (0.61-1.95)	0.769
10 years	36	27	1.33 (0.81-2.20)	0.257
15 years	34	27	1.26 (0.76-2.08)	0.370
T-cell/natural killer cell lymphoma
1 year	≤ 10	≤ 10
3 years	≤ 10	≤ 10
5 years	≤ 10	≤ 10
10 years	≤ 10	≤ 10
15 years	≤ 10	≤ 10

Odds ratios of lymphoma outcomes at the 1-year, 3-year, 5-year, 10-year, and 15-year follow-up among propensity score-matched cohorts of patients with Crohn’s disease taking thiopurines vs patients with Crohn’s disease taking 5-aminosalicylic acid and not taking thiopurines or biologics. Outcomes are presented as event counts with percentage and corresponding odds ratios with 95% confidence intervals. All analyses reflect matched sample sizes of 18111 per group. CD: Crohn’s disease; 5-ASA: 5-aminosalicylates; OR: Odds ratio; CI: Confidence interval.

Table 5 Multivariate Cox proportional hazards model for patients with inflammatory bowel disease taking thiopurines and patients with inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics assessing predictors for lymphoma

Covariate	Hazard ratio (95%CI)	P value
Male	1.59 (1.33-1.90)	< 0.0001
Age at index
≥ 50 years	1.90 (0.99-3.62)	0.0527
18-50 years	5.59 (2.94-10.63)	< 0.0001
Race
Asian	1.88 (0.99-3.57)	0.0558
Black or African American	1.13 (0.67-1.94)	0.6445
Native Hawaiian or Other Pacific Islander	1.52 (0.20-11.31)	0.6840
White	1.21 (0.78-1.89)	0.3998
Other race	2.00 (1.00-4.01)	0.0502
Ethnicity
Hispanic or Latino	0.75 (0.39-1.43)	0.3772
Not Hispanic or Latino	1.31 (1.02-1.68)	0.0330
Comorbidities
Essential hypertension	1.19 (0.94-1.50)	0.1445
Type 2 diabetes mellitus	0.97 (0.72-1.30)	0.8143
Hyperlipidemia	0.95 (0.73-1.23)	0.6989
Tobacco use	0.82 (0.35-1.90)	0.6395
Alcohol use disorders	1.26 (0.66-2.38)	0.4868
Nicotine dependence	0.95 (0.65-1.40)	0.8014
Laboratory values
Total cholesterol (mg/dL)
≥ 200	1.09 (0.64-1.85)	0.7540
Cholesterol in LDL (mg/dL)
≥ 150	1.08 (0.58-2.03)	0.8031
Cholesterol in HDL (mg/dL)
≥ 50	0.98 (0.72-1.34)	0.9204
Glycosylated hemoglobin (%)
> 6.50	1.95 (1.36-2.78)	0.0003

Hazard ratios with 95% confidence intervals from a multivariable Cox proportional hazards model evaluating demographic factors, race/ethnicity, and comorbidities associated with lymphoma outcomes in patients with inflammatory bowel disease taking thiopurines and patients with inflammatory bowel disease taking 5-aminosalicylic acid and not taking thiopurines or biologics. Covariables include age, sex, race/ethnicity categories, cardiometabolic conditions, and substance use. A hazard ratio > 1 indicates increased risk while a hazard ratio < 1 indicates reduced risk. All variables were included in the fully adjusted model. Hazard ratios for categorical variables reflect comparisons against an implicit reference group as defined by TriNetX variable encoding. CI: Confidence interval; HDL: High density lipoprotein; LDL: Low density lipoprotein.