Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review

Table 1 Nodular regenerative hyperplasia of the liver during thioguanine therapy

Dosage of thioguanine	6-TGN level	Observed NRH	Ref.
About 20 mg per day (18-24 mg)	278 (68-492)	0% (0/12)	[20]
20 mg per day	564 ± 278	0% (0/28)	[18]
20 mg per day	802 (106-1092)	0% (0/13)	[47]
About 21 mg per day (0.3 mg/kg)	464 (65-1199)	6% (7/111)	[48]
40 mg per day	807 (105-2545)	0% (0/11)	[16]
About 40 mg per day (estimated)	1230 (530-2310)	62% (16/26)	[15]
40-80 mg per day	Unknown	36% (16/45)	[45]

6-TGN concentrations were calculated using the method described by Lennard et al[27]. Modified from Seinen et al[49]. 6-TGN: 6-thioguanine nucleotides concentration (as pmol/8 × 10⁸ red blood cells), presented as medians with range or mean with standard deviation; NRH: Nodular regenerative hyperplasia.

Table 2 Other adverse events associated with thioguanine use

Adverse event	Prevalence	Ref.
GI complaints	1%-17%	[16,17,19,20,37,38]
Myelosuppression1	1%-15%	[17,20,36,38]
General malaise	4%-22%	[17,38]
Allergic reaction	1%-6%	[17,33]
Other AE (e.g., myalgia, alopecia)	1%-38%	[16,17,19,20,33,36-38]

¹Variable definitions of myelosuppression were applied.

Table 3 Summary of included articles with most important study characteristics

Author	Ref.	Year	Score1	Number of patients	Number of IBD (CD/UC/IBDu)	Dose (med)	Follow-up (M)	Effective n (%)	Non-effective n (%)	Discontinuation	6-TGN (med)
										n (%)
Dubinsky	17	2001	Very low	10	10/0/0	40	4	7 (70)	1 (10)	2 (20)	15482
Cheung	18	2003	Very low	15	13/1/1	40	3	12 (79)	1 (7)	2 (14)	N/A
Herrlinger	19	2003	Low	37	37/0/0	40	6	21 (57)	7 (19)	9 (24)	N/A
Bonaz	21	2003	Very low	49	49/0/0	20	12	38 (78)3	6 (12)	5 (10)	6484
Dubinsky	22	2003	Very low	21	14/7/0	20	9	14 (67)	3 (14)	4 (19)	13651
Teml	23	2005	Low	20	0/14/6	20	6	11 (55)	3 (15)	6 (30)	8164
Qasim	24	2007	Very low	40	28/10/2	40	6	19 (48)	8 (20)	13 (32)	N/A
Ansari	12	2008	Low	30	30/0/0	40	6	18 (60)	5 (17)	7 (23)	8074
Almer	25	2009	Low	23	23/0/0	40	9	5 (22)	5 (22)	13 (56)	11552
Asseldonk	16	2011	Low	46	0/46/0	20	22	37 (80)3	3 (7)	6 (13)	2784
Pavlidis	15	2014	Moderate	62	21/41/0	20	6	46 (78)	11 (14)	5 (8)	8114

¹Grading based on GRADE guidelines[50,51].

²Median value in subgroup with clinical response to 6-thioguanine treatment;

³Expected value;

⁴Median value in total group, regardless of clinical response to treatment. IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; IBDu: IBD unclassified; 6-TGN: 6-thioguanine nucleotides; N/A: Not applicable; Ref: Number in reference list; Dose: Median dosage of thioguanine therapy at initiation.

Table 4 Summary of results of included articles in the total group, as well as different disease groups n (%)

Total number of patients	CD	UC	IBDu	Daily dose (mg)1	Treatment years2	Benefit3	No benefit	Discontinuation
353	225 (64)	119 (34)	9 (2)	20	268	228 (65)	53 (15)	72 (20)
				[10-80]
								Discontinuation	Response unknown4
Crohn’s disease (n = 225)					141	118 (52)	25 (11)	40 (18)	42 (19)
Ulcerative colitis (n = 119)					122	73 (62)	16 (13)	11 (9)	19 (16)

¹Median start dose of thioguanine was 20 mg/d. This was adjusted based on symptoms and metabolite levels to doses of 10-80/d;

²Treatment years are calculated based on sample size and median follow-up;

³Defined as a clinically relevant decrease in disease activity scores by global physician assessment or when corticosteroids could be tapered or discontinued;

⁴When results are not subdivided in disease entities (i.e., total results are given, but not for CD/UC). CD: Crohn’s disease; UC: Ulcerative colitis; IBDu: Inflammatory bowel disease unclassified.