Current stage in inflammatory bowel disease: What is next?

Table 1 Azatioprine treatment basis of individual thiopurine methyltransferase status

TMPT genotype	TPMT fenotype (pmol/mgHb)	Treatment dosis(mg/kg)
Homozygous	< 10	Avoid or consider 0.1-0.2
Heterozygous	10-24	1-1.5
Wild type (normal)	25-35	2-2.5
Wild type (high)	> 35	0.5 + 100 mg allopurinol

TMPT: Thiopurine methyltransferase.

Table 2 Genetic association studies of adverse events secondary to azathioprine in inflammatory bowel disease patients

Study (year)	No. of patients	Conclusion
Marinaki et al[34] (2004)	130	Significant association with flu-illness, rash, and pancreatitis
		No association with mielotoxicity
Allorge et al[35] (2005)	72	No association with flu-illness, rash, pancreatitis, or mielotoxicity
Gearry et al[36] (2004)	147	No association with flu-illness, rash, and pancreatitis
De Ridder et al[37] (2006)	72	No association with side effects
Hindorf et al[38] (2006)	60	No association with side effects
von Ahsen et al[39] (2005)	71	Early withdrawal of therapy but no association with specific adverse events
Ansari et al[40] (2008)	202	Association with flu-like symptoms but not withdrawal of therapy
van Dieren et al[41] (2005)	109	Not associated with an increased risk for the development of leucopenia and other side effects
Zelinkova et al[42] (2006)	262	Increased risk of leucopenia
Uchiyama et al[43] (2009)	16	Increase risk of mielotoxicity (leucopenia)
Shipkova et al[44] (2011)	160	Increase risk of mielotoxicity
Kim et al[45] (2010)	248	No association with leucopenia
Zabala-Fernández et al[46] (2011)	232	Significant association with artralgia

Table 3 Genetic association studies of infliximab response in inflammatory bowel disease patients

Study (year)	Patients recruited	Response criteria	Genes investigated	Conclusion
Taylor et al[55] (2001)	75	CDAI	Polymorphims TNF/LTA region	Homozygosity for the LTA1-1-1-1 haplotype may identify subgroups with poorer response
Louis et al[56] (2002)	226	CDAI	TNFA	No association with treatment outcome
Mascheretti et al[57] (2002)	90	CDAI	TNF and TNFR polymorphism	196Arg homozygotes had poorer clinical response than 196Met
	444			heterozygotes and homozygotes (P = 0.036)
				No predictive treatment outcome
Mascheretti et al[58] (2002)	534	CDAI	CARD15/NOD2	A strong relation to susceptibility to CD but not association with treatment outcome
Vermeire et al[59] (2002)	245	CDAI	CARD15/NOD2	Not predictive of treatment outcome
Pierik et al[60] (2004)	166	CDAI	TNF/TNFR	Biological response to infliximab was lower in patients carrying TNFR1-36G
Matsukura et al[61] (2008)			TNFRSF1A	28% of G allele heterozygotes and homozygotes responded
	80	HBI	TNFRSF1B	compared to 73% of A allele homozygotes (P = 0.04)
				5% of patients with AT haplotype responded compared to 20%-40% of patients with other haplotypes (P = 0.01)
Louis et al[62] (2004)	200	CDAI	FcγRIIIa	Positive (V/V genotype) association with good treatment outcome
Urcelay et al[63] (2005)	40	CDAI	IBD5(5q31)	Polymorphims TT is associated with negative response
Hlavaty et al[64] (2005)	287	CDAI	FASL/CASP9	Positive association
Hlavaty et al[65] (2007)	287	CDAI	FASL	Negative association (stadistical model)
Willot et al[66] (2006)	189	CRP	CRP	Polymorphims evaluated are not associated with treatment outcome
Dideberg et al[67] (2006)	214	CDAI	TNF/LTA region	No association
Dideberg et al[68] (2006)	186	CDAI and CRP	ADAM17	Minor allele homozygotes for each SNP associated with clinicalresponse (P < 0.002)
Jürgens et al[69] (2010)	90	CAI	IL-23RIL-2/IL-21	Homozygous carriers of IBDrisk-increasing IL-23R variants more likely to respond to infliximab than homozygous carriers of IBD risk-decreasing IL-23R variants (P = 0.001)
Dubinsky et al[70] (2010)	94	HBI and Partial Mayo score	rs2241880 2q37/ATG16L1rs21889625q31rs6908425 6p22/CDKAL1rs762421 21q22/ICOSLGrs2395185 6p21/HLA-DAQ1rs2836878 21q22/BRWD1	Six known susceptibility lociassociated with primary nonresponse(P < 0.05). Only the 21q22.2/BRWDIloci remained significant in thepredictive model

Aailable from: URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419078/.

Table 4 Risk factors associated to primary failure

Crohn's disease	Ulcerative colitis
Duration of the disease > 2 yr	Old age
Smoking	Anti-neutrophil cytoplasmic (ANC) antibodies
Extensive small bowel involvement	Negative antibodies against Saccharomyces cerevisiae
Low C-reactive protein levels	Previous exposure to anti-TNF-α drugs
Genetic mutations or polymorphisms of the apoptosis and caspase 6 genes and locus IBD 5

IBD: Inflammatory bowel disease.

Table 5 Risk factors associated to secondary failure or loss of response

Individual differences in bioavailability and pharmacokinetics

Symptoms not due to inflammatory bowel disease

Lack of adherence to therapy

Drug loss in stools

Intermittent treatments

Non-inflammatory symptoms

Structuring disease pattern

Smoking

Development of antibodies

Table 6 Treatment algorithm according to antidrug antibodies and drug levels

Anti-TNF-αdrug levels	Antibodies	Action
Low	Negative	Increase dose
Low	Positive	Switch drug
High	Not determined	Switch to a drug with a different mechanism of action

Table 7 Treatment with herbal remedies

Author	n	Producto	Comparador	Indicación	Remisión/response herbal vs PB or drug (%)
Langmead	44	Aloe vera	Placebo	Induction remission CU	30 vs 7
Ben-Arye	23	Triticum aestivum	Placebo	Induction remission CU	91 vs 42
Khan	14	Bovine colostrum enema	Placebo	Induction remission CU
Sandborn	224	HMPL-004	Placebo	Induction remission CU	38/60 vs 25/40
Fukunaga	30	Xilei-san suppository	Placebo	Induction remission CU	46 vs 0
Zhang	35	XIlei-san enema	Enema dexametasona	Induction remission CU
Tang	120	HMPL-004	Mesalazina	Induction remission CU	21 vs 16
Gupta	30	Boswellia serrata	Sulfasalazina	Induction remission CU	70 vs 40
Cheng	153	Jian Pi Ling tablet	Sulfasalazina	Induction remission CU	53 vs 28/19
			Placebo
Wang	106	Kui Jie Quing enemas	Sulfasalazina	Induction remission CU	72 vs 9
			Prednisolona
Cheng	118	Yukui tang ablets	Prednisolonoa	Induction remission CU	33 vs 17
			Neomicina
			Vitamina B
Fernández Bañares	105	Plantago ovata sedes	Mesalazine	Maintenance remission CU	60 vs 65
Hanai	89	Curcumin	Placebo	Maintenance remission CU	95 vs 79
Greenfield	43	Oenothera biennis	Evening primrose oil and olive oil	Maintenance remission CU
Omer	40	Artemisia absinthium	Placebo	Treatment and prevention recurrence EC	65 vs 0
Krebs	20	Artemisia absinthium	Placebo	Treatment and prevention recurrence EC	80 vs 20
Gerhardt	102	Boswellia serrata extract	Mesalazine	Treatment and prevention recurrence EC	36 vs 31
Ren	20	Tripterygium wilfordii	Placebo	Treatment and prevention recurrence EC
Holtmeier	108	Boswellia serrata extract	Placebo	Treatment and prevention recurrence EC	60 vs 55
Tao	45	Tripterygium wilfordii	Mesalazine	Treatment and prevention recurrence EC	68 vs 61
Liao	39	Tripterygium wilfordii	Sulphasalazine	Treatment and prevention recurrence EC	94 vs 75

Adapted from Ng et al[203].