Clinical predictors of thiopurine-related adverse events in Crohn's disease

Table 1 Cohort demographics n (%)

Variables	Total(n = 351)	Discontinued due to adverse event(n = 110)	Continued therapy(n = 241)	P value
Gender				0.36
Female	185 (52.7)	62 (56.3)	123 (51.1)
Male	166 (47.3)	48 (43.6)	118 (48.9)
Age at diagnosis (A) (yr)				0.05
< 17	56 (16.0)	13 (11.8)	43 (17.8)
17-40	233 (66.4)	70 (63.3)	163 (67.6)
> 40	62 (17.7)	27 (24.5)	35 (14.5)
Age at thiopurine (yr)				0.007
< 17	21 (6.5)	5 (4.5)	16 (6.6)
17-40	195 (60.0)	44 (40.0)	151 (62.7)
> 40	109 (33.5)	43 (39.1)	66 (27.4)
L4 (upper gastrointestinal disease)				0.52
Yes	27 (7.7)	10 (9.1)	17 (7.1)
No	324 (92.3)	100 (90.1)	224 (92.9)
Behaviour (B) (%)				0.91
B1 (inflammatory)	183 (56.0)	55 (50.0)	128 (53.1)
B2 (fibrostenotic)	62 (19.0)	20 (18.2)	42 (17.4)
B3 (penetrating)	82 (25.1)	26 (23.6)	56 (23.2)
Perianal disease before thiopurine				0.69
Yes	82 (23.4)	24 (21.8)	58 (24.1)
No	269 (76.6)	86 (78.2)	183 (75.9)
Corticosteroid at diagnosis				0.35
Yes	142 (52.8)	39 (35.5)	103 (42.7)
No	127 (47.2)	42 (38.2)	85 (35.3)
Pre-thiopurine intestinal resection				0.81
Yes	140 (39.9)	45 (40.9)	95 (39.4)
No	211 (60.1)	65 (59.1)	146 (60.6)
Disease duration before thiopurines (yr)				0.22
< 1	100 (30.8)	22 (20.0)	78 (32.4)
1-5	81 (24.9)	22 (20.0)	59 (24.5)
5-10	63 (19.4)	23 (20.9)	40 (16.6)
> 10	81 (24.9)	25 (22.7)	56 (23.2)
5-ASA exposure before thiopurine	66 (24.8)	18 (16.4)	48 (19.9)	0.47
Anti-TNFα exposure1				< 0.0001
Thiopurine monotherapy	234 (66.7)	97 (88.2)	137 (56.9)
Non-con. Comb. therapy	79 (22.5)	5 (4.5)	74 (30.7)
Con. Comb therapy	38 (10.8)	8 (7.3)	30 (12.4)
Smoking history				0.12
Never	180 (51.3)	48 (43.6)	132 (54.8)
History of smoking	126 (35.9)	49 (44.5)	77 (32.0)
Unknown	45 (12.8)	13 (11.8)	32 (13.2)

¹Thiopurine monotherapy, defined as patients naive to anti-TNF therapy or suffering an adverse event that led to discontinuation of the thiopurine prior to exposure to anti-TNF therapy; non-concomitant onset combination therapy defined as anti-TNF therapy started more than 3 mo after thiopurine onset; concomitant onset combination therapy defined as concomitant prescription of thiopurine and anti-TNF within 3 mo. Clinical characteristics of the 351 CD patients treated with a thiopurine stratified by an adverse event requiring withdrawal of thiopurines. Anti-TNF: Anti-tumour necrosis factor; ASA: Aminosalicylic acid; CD: Crohn's disease.

Table 2 Adverse events n (%)

Variables	Hypersensitivity	Pancreatitis	GI	Leucopenia	Hepatotoxicity	Infection
patients	25 (7.1)	22 (6.2)	19 (5.4)	13 (3.7)	12 (3.4)	4 (1.1)
Gender
Males	16 (64.0)	9 (40.9)	7 (36.8)	4 (30.8)	4 (33.3)	2 (50.0)
Females	9 (36.0)	13 (59.1)	12 (63.2)	9 (69.2)	8 (66.7)	2 (50.0)
Age at thiopurine (yr)	37.6 (32.3, 47.9)	43.9 (32.2, 48.8)	26.5 (22.8, 47.1)	29.6 (23.6, 47.7)	49 (41.8, 57.9)	24.3 (19.3, 27.1)
Time from prescription to withdrawal of thiopurine (d)	31 (29.0, 65.0)	29 (14.5, 30.0)	17 (7.0, 26.0)	347.5 (159.0, 866.0)	51 (30.0, 70,0)	1907 (603.0, 2718.0)
AZA dose (mg/kg)	2.2 (1.6, 2.4)	2.3 (2.0, 2.4)	2 (1.7, 2.2)	1.6 (0.8, 2.3)	1.3 (0.8, 2.0)	2.1 (2.0, 3.1)

Main reasons leading to discontinuation of thiopurine therapy in 351 patients due to an adverse event. No multiple reasons were recorded. Data are given as median and IQR unless otherwise stated. Other (n = 15, 13.6%) causes for discontinuation were alopecia (n = 3), photosensitivity (n = 1), basal cell carcinoma (n = 2), mood disturbance (n = 1), syncopal episodes (n = 1), fatigue (n = 1), headache (n = 1), eye problems (n = 1) and unknown (n = 4). AZA: Azathioprine; IQR: Interquartile range; GI: Gastrointestinal intolerance.

Table 3 Multivariate analysis

Adjust variables	Crude analysis	Adjusted analysis
Total (n = 351)
Age starting thiopurine older than 40 vs 40 or younger	OR (95%CI)
Female	3.6 (1.9-7.1)	4.0 (1.9-8.3)
Male	1.2 (0.6-2.6)	1.3 (0.6-3.0)

Predictors of thiopurine-related adverse events as determined by multivariate analysis. A significant age-by-gender interaction was observed in both crude and adjusted analyses, P-value = 0.03 and 0.04 respectively.

Table 4 Stratified multivariate analysis

Adjusted variables		Adjusted OR (95%CI)
	All cohort (n = 351)	Female (n = 185)	Male (n = 166)
Age at Thiopurine prescription > 40 (sex-by-age interaction, P = 0.04)	2.4 (1.4-4.2)	2.8 (1.4-5.6)	0.9 (0.4-2.1)
Female vs male (referent)	1.2 (0.7-2.0)	NA	NA
Smoking history (current/past)	1.5 (0.9-2.5)	1.5 (0.8-3.1)	1.6 (0.8-3.6)
Pre-thiopurine intestinal resection vs no resection (referent)	0.86 (0.43-1.71)	0.7 (0.3-1.8)	1.0 (0.4-2.8)
L1 vs L2 (referent)	1.4 (0.6-3.2)	1.2 (0.4-3.6)	3.1 (0.9-10.4)
L3 vs L2 (referent)	1.5 (0.7-3.0)	1.1 (0.4-2.7)	2.1 (0.7-6.3)
B2 vs B1 (referent)	1 (0.5-2.2)	1.0 (0.3-2.8)	0.7 (0.2-2.4)
B3 vs B1 (referent)	1.1 (0.5-2.5)	1.0 (0.3-2.8)	0.8 (0.3-2.5)
Pre-thiopurine perianal disease vs no perianal disease (referent)	0.7 (0.4-1.3)	1.1 (0.5-2.7)	0.7 (0.3-1.8)
5-ASA at time of thiopurine vs past or never (referent)	0.8 (0.4-1.5)	0.7 (0.3-1.8)	1.0 (0.4-2.4)
Corticosteroid at diagnosis vs no exposure at diagnosis (referent)	0.9 (0.5-1.6)	0.7 (0.3-1.5)	0.9 (0.4-2.2)
L4 vs L2 (referent)	1.8 (0.7-4.3)	3.4 (0.9-12.2)	0.9 (0.3-3.1)

Predictors of thiopurine discontinuation in all cohort and as determined by this stratified multivariate analysis by sex. Demographic data suggests a higher incidence of adverse events in female patients over the age of 40 years. An age-by-gender interaction is seen as described in this multivariate analysis of thiopurine-exposed patients in female subjects over the age of 40 years. ASA: Aminosalicylic acid; NA: Not available.