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.