Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data

Table 2 Current studies (published articles and finished/on-going clinical trials) investigating the effect of targeting lymphatic circulation and related pathophysiology processes, providing moderately strong evidence to support our hypothesis

Agent class	Agent	Mechanism/pathway	Drug stage	Efficacy	Ref.
JAK inhibitors	Filgotinib/GLPG0634	Selective JAK1 inhibitor; inhibiting JAK-STAT pathway	Phase 2 clinical studies in patients with CD	Filgotinib induced clinical remission in significantly more patients with active CD compared with placebo (47% vs 23%)	[111]
			Phase 3 clinical studies	Recruiting or finished without result disclosure	NCT02914600, NCT02914561, NCT02048618
	MT-1303	Selective JAK1 inhibitor; inhibiting JAK-STAT pathway	Phase II, open-label, multicenter studies for moderate to severe active CD	Finished without results disclosure	NCT02389790, NCT02378688
	Upadacitinib1	Selective JAK1 inhibitor; Inhibiting JAK-STAT pathway	Multicenter, randomized, double-blind, placebo-controlled induction study of its efficacy and safety in moderate to severe active patients with CD	Upadacitinib induced CDAI remission at week 12 in significantly more patients with active CD compared with placebo (49.5% vs 29.1%)	NCT03345849, NCT03345836
Anti-trafficking therapies: target of adhesion molecules	AS101	Inhibit lymphocyte trafficking by blocking ligand for α4β7 integrin, MAdCAM-1 and Il-1β. Regulate the intestinal epithelial barrier by the PI3K/AKT pathway	Animal model	Suppressed colitis with reduced colonic inflammatory cytokine levels, reduced histopathology score and fewer clinical symptoms	[112]
	Vedolizumab	Inhibit lymphocyte trafficking by block the ligand for α4β7 integrin, MAdCAM-1	Induction and maintenance study for active CD	The rate of clinical remission is significantly higher in treatment group (300 mg) at week 6	[113]
	Firategrast	α4β7 and α1β7 inhibitor	Randomized, double-blind, placebo-controlled, parallel-group study	Finished without results disclosure	NCT00101946
	Abrilumab	Inhibit lymphocyte trafficking by blocking the ligand for α4β7 integrin, MAdCAM-1	Phase 1, randomized, double-blind, placebo-controlled, ascending multiple dose study	Finished without results disclosure	NCT01290042
	CCX282-B	Anti CCR9 and its related Ca2+ mobilization and inflammatory cell attraction	Pilot, double-blind, placebo-controlled, parallel group study	Finished without results disclosure	NCT00102921
	Risankizumab	Monoclonal antibody against the p19 subunit of IL-23	Phase 2 clinical studies in patients with CD	Effective in clinical remission, response, and endoscopic remission at week 12 compared to placebo	[114,115]
					NCT03105128
IL-23 inhibitors	Ustekinumab	Monoclonal antibody against p40 subunit of IL-12/IL-23	Induction and maintenance study for active CD	Rate of response was significantly higher in treatment group (dosage as 130 mg or 6 mg/kg) in both UNITI 1 and UNITI	[116]
	Brazikumab	Monoclonal antibody against the p19 subunit of IL-23	Phase 1 clinical trial in healthy people	Finished without results disclosure	NCT05033431
Other IL inhibitors	Semapimod	IL-1β/IL-6 inhibitors	Open label single arm study for CD	Finished without results disclosure	NCT00740103

¹There are two clinical trials on upadacitinib from the same leading team but with different designs and recruiting patient numbers. For the word limitations of this article, please refer to the relative number of clinical trials required.

CD: Crohn’s disease; CDAI: Crohn’s disease activity index; IL: Interleukin; JAK: Janus kinase; MAdCAM: Mucosal vascular addressin cell adhesion molecule; PI3K: Phosphoinositide 3-kinase.