Interactions Between Neutrophil Elastase and Biologics in IBD

KOK K.; CURCIARELLO R; GIUFFRIDA P; JOSHI N; BIANCHERI P; MACDONALD TT

Washington DC

Congreso; Digestive Disease Week 2014; 2014

Background - Human neutrophil elastase (HNE) is highly expressed in IBD but the balancebetween HNE and its inhibitor elafin remains poorly understood. Biologics exert their actionin the protease-rich inflamed mucosa but a third of patients do not respond to this treatment.The aim of this study was to determine if HNE degrades biologics, rendering them ineffective.Methods - Biopsies from patients with UC or CD and healthy controls were used to extractmucosal proteins and serum was also collected. Elastase and elafin quantity and functionwas assessed using ELISA and enzyme activity assays. Adalimumab, Etanercept and Infliximabwere incubated with HNE in the absence or presence of elafin. Immunoblotting and ELISAwere used to determine anti-TNF degradation and function. Results - Mucosal proteinhomogenates from IBD patients display increased mucosal elastase activity (p=0.002) andincreased elafin concentrations (p=0.003) in comparison to healthy subjects. Addition ofrecombinant elafin restores elastase activity to normal levels. Serum elastase concentrationsare higher in IBD patients (p=0.02). Elastase fully degrades all anti-TNF agents which isprevented by recombinant elafin (p=0.0002). Conclusion - IBD mucosa displays higherneutrophil elastase activity in comparison to healthy controls despite the presence of higherlevels of the elastase inhibitor elafin. The addition of recombinant elafin has a restorativeeffect on the elastase activity in IBD mucosa. Neutrophil elastase degrades anti-TNF agentsand this can be prevented by elafin. This work demonstrates a possible mechanism forprimary non-responsiveness to anti-TNF therapy. This work also illustrates the potential rolefor elafin in the treatment of IBD and as a strategy to overcome primary non-responsiveness tobiologics.