Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease

Table 1 Characteristics of excluded studies

Author	Location	Study design	Participants	TPMT genotypes was determined	Dose of thiopurine	Reason for exclusion
Cao et al[6], 2009	China	Cross-sectional	43 treated IBD patients	TPMT*2, TPMT*3A	AZA 1.35 mg/kg per day	Incomplete data
				TPMT*3B, TPMT*3C
Takatsu et al[7], 2009	Japan	Cross-sectional	147 treated IBD patients	TPMT*2, TPMT*3B	AZA 25 mg/d	Incomplete data
				TPMT*3C, TPMT*8	or 75 mg/d
					or 100 mg/d
Uchiyama et al[8], 2009	Japan	Cross-sectional	16 treated IBD patients with ADRs	TPMT*2, *3A, *3B	AZA < 50 mg/d	Incomparable control group
				TPMT*3C, *3D, *4	or 6-MP < 30 mg/d	No definition of ADRs
				TPMT*5, *6, *7, *8		Pediatric patients included
Ban et al[9], 2008	Japan	Case-control	70 treated IBD patients	TPMT*2, TPMT*3A	Not mentioned	Dose of thiopurine not mentioned
			41 healthy controls	TPMT*3B, TPMT*3C
Gearry et al[10], 2003	New Zealand	Case-control	56 treated IBD patients with ADRs	TPMT*2, TPMT*3A	Not mentioned	Dose of thiopurine not mentioned
			50 treated IBD patients without ADRs	TPMT*3B, TPMT*3C
Regueiro et al[11], 2002	USA	Cross-sectional	71 treated CD patients	TPMT*3A, TPMT*3B	AZA 2.35 mg/kg per day	38 patients had determination of TPMT by phenotype
				TPMT*3C	or 1.28 mg/kg per day
Evans et al[12], 2001	USA	Cross-sectional	23 treated patients with ADRs	TPMT*2, TPMT*3A	AZA 32 mg/m2 per week	Non-IBD patients
				TPMT*3B, TPMT*3C	or 175 mg/m2 per week
					or 280 mg/m2 per week
Naughton et al[13], 1999	UK	Cross-sectional	15 treated IBD patients	TPMT*2, TPMT*3A	Not mentioned	Dose of thiopurine not mentioned
				TPMT*3B, TPMT*3C

Dose of thiopurine: mean or median dose of thiopurine. TPMT: Thiopurine S-methyltransferase; IBD: Inflammatory bowel disease; AZA: Azathioprine; ADRs: Adverse drug reactions; 6-MP: 6-mercaptopurine; CD: Crohn’s disease.

Table 2 Characteristics of included studies

Author	Location	Study design	Participants	TPMT genotypes was determined	Dose of thiopurine	ADRs and definitions
Ansari et al[14], 2008	UK	Prospective cohort	215 treated IBD patients	TPMT*3A, TPMT*3B	AZA 2 mg/kg per day	All ADRs
				TPMT*3C		BMT: WBC < 3.5 × 109 or Ne < 1.5 × 109
						H: ALT > 2 × ULN
						P: AP and amylase > 4 × ULN and supportive radiological findings
Hawwa et al[15], 2008	UK	Cross-sectional	36 treated IBD patients	TPMT*3A, TPMT*3B	AZA 1.49 mg/kg per day	BMT: WBC < 3.0 × 109 or Ne < 1.5 × 109 or PLT < 150 × 109
				TPMT*3C
Winter et al[5], 2007	UK	Cross-sectional	130 treated IBD patients	TPMT*2, TPMT*3A	AZA 1.6 mg/kg per day	All ADRs
				TPMT*3C		BMT: WBC < 3 × 109
						H: No definition
						P: No definition
Stocco et al[16], 2007	Italy	Cross-sectional	70 treated IBD patients	TPMT*2, TPMT*3A	AZA: 2 mg/kg per day	All ADRs
				TPMT*3B, TPMT*3C		BMT: WBC < 3 × 109 or PLT < 100 × 109
						H: ALT, AST or ALP > 2 × ULN
						P: AP and amylase > 2 × ULN
Palmieri et al[17], 2007	Italy	Cross-sectional	422 treated IBD patients	TPMT*3A, TPMT*3B	AZA 2-2.5 mg/kg per day	All ADRs
				TPMT*3C	or 6-MP 1-1.25 mg/kg per day	BMT: WBC < 3 × 109 or PLT < 100 × 109
						H: ALT > 2 × ULN
						P: Amylase, lipase > 2 × ULN and AP
Zelinkova et al[18], 2006	Netherlands	Cross-sectional	262 treated IBD patients	TPMT*2, TPMT*3A	AZA 2-2.5 mg/kg per day1	BMT: WBC < 3 × 109 or PLT < 100 × 109
				TPMT*3B, TPMT*3C		H: ALT > 2 × ULN
Hindorf et al[3], 2006	Sweden	Prospective cohort	60 treated IBD patients	TPMT*2, *3A, *3B	AZA 2.5 mg/kg per day	All ADRs
				TPMT*3C, *3D, *4	or 6-MP 1.25 mg/kg per day	BMT: WBC < 3 × 109 or PLT < 100 × 109
				TPMT*5, *6, *7, *8		or Ne < 1.5 × 109
				TPMT*10, *14, *15		P: No definition
Derijks et al[19], 2004	Netherlands	Prospective cohort	30 treated IBD patients	TPMT*2, TPMT*3A	6-MP 0.71 mg/kg per day	BMT: WBC < 4 × 109 or PLT < 100 × 109
				TPMT*3B, TPMT*3C
Schwab et al[20], 2002	Germany	Cross-sectional	93 treated IBD patients	TPMT*2, TPMT*3A	AZA 1.5 mg/kg per day	All ADRs
				TPMT*3B, *3C, *3D	or 1.9 mg/kg per day	BMT: WBC < 3 × 109 or PLT < 100 × 109
						H: ALT or AST > 2 × ULN
						P: Amylase, lipase > 2 × ULN and AP

¹The initial dose. White blood cells (WBC), neutrophils (Ne), and platelets (PLT) are expressed per liter; H: Hepatotoxicity; P: Pancreatitis; AP: Abdominal pain; BMT: Bone marrow toxicity; ALT: Alanine transaminase; ULN: Upper limit of normal; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase.