Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review

Table 1 Predictors of primary nonresponse in Crohn’s disease and ulcerative colitis

Predictor	Crohn’s disease	Ulcerative colitis
Clinical features
Age	Yes: Older[27,28]; No[21,29]	Yes: Older[30]; No[31,32]
Gender	Yes: Male[21], female[29]; No[33-35]	Yes: Male[36]; No[30,37]
Smoking	Yes: Smoker[28,39,40]; No[41]	Yes: Ex-smoker[42]; No[37,43]
Previous surgery	Yes[27,28,34,48]
Disease duration	Yes: Longer[49-51]; No[48]	Yes: Longer[32,52]; No[30,53]
Phenotype	Yes: Isolated ileitis[29,48]
Pharmacokinetic
Drug concentration	Yes: Low[16,17,57,58]	Yes: Low[57,59]
Antidrug antibodies	Yes[17]	Yes[59]
Weight	Yes: High[16,60]	Yes: High[61]
Serum albumin	Yes: Low[57]	Yes: Low[57,65]
FCGR3A	Yes: FCGR3A-158V/V[67,68]	Yes: FCGR3A-158V/V[68]
Pharmacodynamic
PK/PD model	Yes[69,70]	Yes[69,70]
Biologic markers
CRP	Yes: Low[72], High[73]	Yes: Low[71]
ANCA and ASCA	Yes: pANCA+[76,77]	Yes: ANCA+[75], pANCA+[77], pANCA+/ASCA-[78]
Fecal calprotectin	Yes: High[79]	Yes: High[52]; No[81,82]
Fecal lactoferrin	Yes: High[84]	Yes: High[84]
Genetic markers
TNF genes	Yes: Lymphotoxin alpha NcoI-TNFc-aa13L-aa26 haplotype 1-1-1-1[76], TNF-308A[85]	Yes: TNF-308A[85]
TNFRSF	Yes: TNFRSF1A (rs767455_G)[87], TNFRSF1B (rs1061624_A-rs3397_T)[87]
ATG16L1	Yes: ATG16L1 (rs10210302_CC)[90]
Apoptosis genes	Yes: Fas ligand-843 TT genotype[91]
NOD2	Yes: NOD2 mutation[94,95]
Cytokines
Interleukin	Yes: IL-8 (high)[97], IL-6 (low)[97], IL17A (high)[98], IL1B (high)[98], OSM (high)[100,101]	Yes: OSM (high)[100,101]
TREM1	Yes: Low[102]	Yes: Low[102]
Gut microbes	Yes: Abundance of short-chain fatty acid-producing bacteria (decreased)[105]	Yes: Dysbiosis indexes (high)[103]; Abundance of short-chain fatty acid-producing bacteria(decreased)[105]

FCGR3A: Fcγ receptor type IIIA; PK/PD model: Pharmacokinetic/pharmacodynamic modeling; CRP: C-reactive protein; ANCA: Antineutrophil cytoplasmic antibody; ASCA: Anti-Saccharomyces cerevisiae antibody; pANCA: Perinuclear anti-neutrophil cytoplasmic antibody; TNF: Tumor necrosis factor; TNFRSF: TNF-receptor superfamily; ATG16L1: Autophagy-related 16 like 1; NOD2: Nucleotide-binding oligomerization domain 2; OSM: Oncostatin M; TREM1: Triggering receptor expressed on myeloid cells 1.

Table 2 Predictors of secondary nonresponse in Crohn’s disease and ulcerative colitis

Predictor	Crohn’s disease	Ulcerative colitis
Clinical features
Gender	Yes: Female[107,108], male[109]; No[21]	Yes: Female[107], male[110]; No[31,37]
Smoking	Yes: Smoker[28,39,111]; No[41]
Previous surgery	Yes[27]; No[16,112]
Disease duration	Yes: Longer[49,113,114]
Phenotype	Yes: Upper digestive tract[27], fistula[27,115], stenosis[115]
Pharmacokinetic
Drug concentration	Yes: Low[16,116]	Yes: Low[116]
Antidrug antibodies	Yes[117]	Yes[117]
Weight	Yes: High[16,118,119]	Yes: High[118,119]
Serum albumin	Yes: Low[28,119,120]	Yes: Low[119,120]
Serum γ-globulin	Yes: High[120]	Yes: High[120]
MMP3	Yes: High[123]	Yes: High[123]
FCGR3A	Yes: FCGR3A VV[125]	Yes: FCGR3A VV[125]
HLA	Yes: HLADQA1*05[127]	Yes: HLADQA1*05[127]
Biologic markers
CRP	Yes: Low[128], high[129]	No[82]
ANA	Yes: ANA+ [130]	Yes: ANA[130]
Fecal calprotectin	Yes: High[28]; No[131]
Fecal lactoferrin	Yes: High[132]	Yes: High[132]
Genetic markers
TNFRSF	Yes: TNFRSF1B (rs976881)[86]
Cytokines
Interleukin	Yes: OSM (high)[100,133]	Yes: OSM (high)[100]

MMP3: Matrix metalloproteinase 3; FCGR3A: Fcγ receptor type IIIA; HLA: Human leukocyte antigen; CRP: C-reactive protein; ANA: Antinuclear antibody; TNFRSF: Tumor necrosis factor receptor superfamily; OSM: Oncostatin M.