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

Table 1 Current studies (published articles and finished/on-going clinical trials) investigating the effect of targeting lymphatic circulation and related pathophysiology processes, providing strong evidence to support our hypothesis

Agent class	Agent	Mechanism/pathway	Drug stage	Efficacy	Ref.
Targets of lymphangiogenic factors	VEGFC/Ad-hVEGF-C	VEGFC-VEGFR3 signaling pathway; increase lymph drainage and bacteria antigen clearance	Animal model	Reduced severity of chronic colitis in terms of histological examination, body weight, endoscopic evaluation, and CDAI than control group	[60]
	COMP-Ang1	Reduce inflammation-induced lymphangiogenesis and M1 and M2 macrophage infiltration by inhibiting VEGF-C/D expression	Animal model	Less weight loss, fewer clinical signs of colitis, and longer colons than control group	[109]
TLR4 inhibitor	C34	TLR4-PAMP/DAMP discriminatory mechanism	Animal model	Less weight loss, reduced disease activity score and reduced colon shortening in treatment group	[71]
Anti-trafficking therapies: S1P receptor modulators	Ozanimod	S1P1/5 receptor modulator; induce internalization and degradation of S1P1/5 receptor subtypes	Phase 2 clinical studies in patients with CD	Endoscopic, histological, and clinical improvements within 12 wk of initiating ozanimod therapy in patients with moderate to severe CD	[76]
			Phase 3 clinical studies	Recruiting	NCT03440372, NCT03440385, NCT03464097, NCT03467958
	Etrasimod	S1P1/4/5 receptor modulator	Phase 2/3 clinical studies in patients with CD	Recruiting	NCT04173273
Antiplatelet antibody	GPIb inhibitor	Promote lymphangiogenesis and increase lymphatic vessel densities	Animal model	Suppressed colitis with reduced thickness of the submucosal layer, reduced inflammatory cell infiltration, and reduced histological score	[55]
Anti-bacterial and its related metabolites or secretions1	EB8018	Inhibit bacterial lectin (FimH) to stop the activation of TLR4 and ensuing TNF-α production	Open-label, multicenter, pharmacokinetic Study	Finished without results disclosure	NCT03709628
	RHB-104	Anti-MAP (Mycobacterium Avium Ssp. Paratuberculosis	Phase 3 study to assess the efficacy and safety of fixed-dose combination RHB-104	Number of patients in remission at week 16 was higher in RHB-104 compared with placebo	NCT03009396
			A randomized, double blind, placebo-controlled, multicenter, parallel group study	Reduction of the total CDAI score to less than 150 at week 26 was significantly higher in RHB-104 than placebo	NCT01951326
Chemical compound	Artemisinin	Ameliorate inflammation-driven lymphangiogenesis via the VEGFC/VEGFR3 signaling pathway	Animal model	Reduced symptoms of colitis with improved tissue histology, relieved inflammatory edema, and decreased infiltration of inflammatory cells	[110]

¹These studies specifically support the inside-out model of the pathogenesis of Crohn’s disease.

CD: Crohn’s disease; CDAI: Crohn’s disease activity index; COMP-Ang1: Cartilage Oligomeric Matrix Protein – Angiopoietin-1; DAMP: damage-associated molecular pattern; PAMP: Pathogen-associated molecular pattern; S1P: Sphingosine-1-phosphate; TLR: Toll-like receptor; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

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.