Understanding the efficacy of individual Janus kinase inhibitors in the treatment of ulcerative colitis for future positioning in inflammatory bowel disease treatment

Figures & data

Table 1. Summary of intracellular signaling pathways and functions mediated by JAK-STATs.

Cytokines	Phosphorylated JAK	Phosphorylated STAT	Function
IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21	JAK 1 and JAK 3	STAT1, STAT 3, STAT 5, and STAT 6	T cell proliferation and survival T cell memory and regulatory cell function B cell function
IL-12 and IL-23	JAK 2, TYK 2	STAT 3 and 4	T cell differentiation Lymphocyte effector function
IFN α IFN β, and IFN γ	JAK 1, JAK 2, TYK 2	STAT 1, STAT 2, and STAT 3	Antiviral, Antimycobacterial, Inflammation
IL-10, 19, 20,22, and IL-26	JAK1, JAK3, and TYK2	STAT3	Anti-inflammatory, Epithelial barrier function B cell activation
EPO, TPO, G-CSF, GM-CSF, GH, Leptin, IL-3, and IL-5	JAK2	STAT3 and STAT 5	Hematopoiesis, growth, anabolic metabolism
Il-6, IL-11, IL-13, OSM, and LIF	JAK1, JAK2, and TYK2	STAT1, STAT3, and STAT 6	T cell proliferation and survival T cell memory and regulatory cell function B cell function Wound healing

EPO: erythropoietin; G-CSF: granulocyte colony-stimulating factor; GH: growth hormone; GM-CSF: granulocyte–macrophage colony-stimulating factor; IFN: interferon; LIF: leukaemia inhibitory factor; OSM: oncostatin M; TPO: thrombopoietin.

Table 2. Different IC 50 in enzyme assay, metabolic pathways, and IM concomitant availability among the three JAK inhibitors.

General name	Trade name	Enzyme	assay	IC 50	(nM)	Route, Number of doses	Main metabolic pathway	Concomitant with IMs
		JAK1	JAK2	JAK3	Tyk2
Tofacitinib	XELJANZ	15.1	77.4	55.0	489	Orally, twice	Hepatic metabolism	No
Filgotinib	JYSELECA	363	2400	>10,000	2600	Orally, once-daily	Renal excretion	Yes
Upadacitinib	RINVOQ	8	600	139	NA	Orally, Once-daily	Hepatic metabolism	No

Enzyme assay data cited from Reference [57].

Table 3. Incidence of HZ, MACE, and DVT (%) in tofacitinib.

	Induction	cohort	Maintenance	cohort
	Placebo	TOF	Placebo	TOF 5mg	TOF 10mg
HZ (%)	0	0.2	0.5	1	2
MACE (%)	0	0.2	0	0.5	0.5
DVT (%)	0.4	0	0.5	0	0
PE (%)	0.4	0	0.5	0	0
	Overall cohort	Overall plus P3b/4	cohort
	TOF all	PD TOF 5mg	PD TOF 10mg	TOF all
HZ (%)	1.5	3.6	2.1	2.3
MACE (%)	0.4	2.0	0.5	0.8
DVT (%)	0.0	0.0	0.1	0.1
PE (%)	0.3	0.0	0.6	0.5

Data for the Induction, Maintenance and Overall (Dec 2016) cohort and Overall plus P3b/4 (2020). TOF: tofacitinib; HZ: herpes zoster; MACE: major cardiovascular events; DVT: deep venous thrombosis; PE: pulmonary embolism.

Table 4. Incidence of HZ, MACE, and DVT (%) in filgotinib.

	Induction	FIL	FIL	Maintenance		FIL		FIL
	Placebo	100 mg	200 mg	Placebo^a	Placebo^b	100 mg	Placebo^c	200 mg
HZ(%)	0	0.2	0.6	0	1.1	0	0	0.5
MACE (%)	0.4	0	0	0	0	0.6	0	0
DVT (%)	0	0	0	2.2	0	0	0	0
PE (%)	0	0	0.2	0	0	0	0	0

FIL: filgotinib; HZ: herpes zoster; MACE: major cardiovascular events; DVT: deep venous thrombosis; PE: pulmonary embolism.

Data for SELECTION trial.

^aPatients who responded placebo in the induction studies and continued to receive placebo in the maintenance study.

^bPatients who responded FIL 100 mg in the induction studies and were randomly assigned to placebo in the maintenance study.

^cPatients who responded FIL 200 mg in the induction studies and were randomly assigned to placebo in the maintenance study.

Table 5. Incidence of HZ, MACE, and DVT (%) in upadacitinib.

	UC1		UC2		UC3
	Placebo	UPA 45 mg	Placebo	UPA 45 mg	Placebo	UPA 15 mg	UPA 30 mg
HZ (%)	0	<1	0	1	0	4	4
MACE (%)	0	0	0	0	1	0	0
DVT and PE (%)	0	0	1	0	0	0	1

UPA: upadacitinib; HZ: herpes zoster; MACE: major cardiovascular events; DVT: deep venous thrombosis; PE: pulmonary embolism.

Data for U-ACHIEVE induction (UC1), U-ACCOMPLISH (UC2), and U-ACHIEVE maintenance (UC3).

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