Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies

Table 1 Selected list of biomarkers in inflammatory bowel disease

Biomarker class	Biomarker	Clinical utility
Prognostic biomarkers	Anti-ompC, ASCA, ANCA, anti-CBir1, flagellin	Prediction of more severe CD phenotype- particularly stricturing and need for surgery
	CD 8+ T cell clonal signature	Prediction of more severe disease course and relapse in CD and UC
Surveillance of disease activity	Fecal calprotectin	Predictor of endoscopic disease activity as well as histologic inflammation, and relapse in asymptomatic patients with IBD
	MMP-9	Associated with disease activity in UC
	IL-22	Associated with disease activity in CD
Pharmacogenomics and prediction of safety	TPMT	Risk of thiopurine adverse reaction
	NUDT15	Risk of thiopurine adverse reaction, more common in East Asian/Asian populations
	Thiopurine metabolites (6TG, 6MMP)	Levels associated with adverse drug reaction: myelosuppression, hepatotoxicity. 6TG range also associated with therapy response
Prediction of response to therapy	Oncostatin M	Higher levels predictor of non-response to anti-TNF
	TREM-1	Low levels predictor of non-response to anti-TNF
	HLA-DQA1*05	Expression associated with risk of antibody formation to anti-TNF
	IL-22	Higher level associated with response to anti-IL23p19 (brazikumab)

ANCA: Anti-neutrophil cytoplasmic antibody; ASCA: Anti-Saccharomyces cerevisiae antibody; CD: Crohn’s disease; IBD: Inflammatory bowel disease; IL: Interleukin; MMP: Matrix metalloproteinase; NUDT15: Nudix hydrolase 15; ompC: Outer membrane protein C; TG: Thioguanine; TNF: Tumor necrosis factor; TPMT: Thiopurine methyltransferase; TREM: Triggering receptor expressed on myeloid cells; UC: Ulcerative colitis.

Table 2 Publications of dual biologics

Ref.	Type	Number of participants/IBD type	Biologic combinations	Therapy duration or follow up (mo)	Outcomes
Buer et al[97], 2018	Case series, prospectively followed	Adult: 10 (4 CD, 6 UC)	Anti-TNF, adding on vedolizumab. Combination was intended as a bridging therapy	12-20	Clinical: HBI, PMS, 100 % CRem, 50% endoscopic remission. No serious AE (3 minor infections)
Olbjørn et al[98], 2020	Case series	Pediatric: 13 (9 CD, 4 UC)	Anti-TNF + vedolizumab (8), anti-TNF + ustekinumab (5), (for anti-TNF side effects)	N/A	3/8 (37.5%) Clinical and biochemical remission
Kwapisz et al[99], 2021	Case series	Adult: 15 (14 CD, 1 UC)	8 vedolizumab + anti-TNF, 2 ustekinumab + anti-TNF, 5 vedolizumab + ustekinumab	24	73% CRes, 44% ERes, 27% SE, 20% surgery
Yang et al[100], 2020	Retrospective cohort	Adult: 22 (CD)	24 combinations: 13 vedolizumab + anti-TNF, 8 vedolizumab + ustekinumab, 3 ustekinumab + anti-TNF	1	Endoscopic, PRO2 response/remission, CRP, 50% CRes, 36% SF CRem, 43% ERes, 4% SE (1 SLE-1 cancer), 33% surgery
Glassner et al[101], 2020	Retrospective cohort	50	53 combinations: 25 vedolizumab + ustekinumab, multiple other combinations	5.5-13	50% CRem, 34% ERem, 16% SE, 12% surgery
Privitera et al[102], 2020	Case series, indication active IBD and active EIM	Adult: 16 (11 CD, 4 UC)	Variety of combinations. Most frequent: 3 vedolizumab + adalimumab, 3 vedolizumab + ustekinumab	0.5	At 6 mo: Response IBD/EIM: 42.8%, 11%; Remission IBD/EIM: 14.2%, 55.5%, AE: 3/16 (18.8%)
Dolinger et al[103], 2021	Case series	Pediatric: 16: (CD 7, UC 8, IBD-U 1)	Vedolizumab + ustekinumab, vedolizumab + tofacitinib, ustekinumab + tofacitinib	6	SF remission at 6 mo 12/16 (75%)
Goessens et al[104], 2021	Retrospective cohort, heterogenous, active IBD and/or EIM	Adult: 98 (CD 58, UC 40)	Anti-TNF + vedolizumab, anti-TNF + anti-IL, anti-IL + vedolizumab, tofacitinib + anti-TNF, tofacitinib + vedolizumab, anti-IL + anti-IL, others	5-16	PGA: Complete or partial improvement was observed in 21/80 (26%) and 35/80 (44%); Mean clinical disease activity for IBD: Significantly higher prior to combination than during combination (2.2 +/- 0.7 vs 1.2 +/- 1.1; P < 0.0001). Simple clinical activity scores (quiescent scores 0, mild scores 1, moderate scores 2 and severe scores 3

AE: Adverse events; CD: Crohn’s disease; CRes: Clinical response; CRem: Clinical remission; EIM: Extraintestinal manifestations; ERem: Endoscopic remission; ERes: Endoscopic response; HBI: Harvey Bradshaw index; IBD: Inflammatory bowel disease; IL: Interleukin; N/A: Not applicable; PGA: Physician global assessment; PMS: Partial Mayo score; PRO2: Patient reported outcome scores; SE: Serious infection; SF: Steroid free; TNF: Tumor necrosis factor; UC: Ulcerative colitis.