Interaction between neutrophil elastase and biologics in IBD

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

Copenhagen

Congreso; ECCO 2014; 2014

European Crohn's and Colitis Organisation

Background: Human neutrophil elastase (HNE) is highlyexpressed in IBD but the balance between HNE and its inhibitorelafin remains poorly understood. Biologics exert their actionin the protease-rich inflamed mucosa but a third of patientsdo not respond to this treatment. The aim of this studywas to determine if HNE degrades biologics, rendering themineffective.Methods: Biopsies from patients with UC or CD and healthycontrols were used to extract mucosal proteins and serum wasalso collected. Elastase and elafin quantity and function wasassessed using ELISA and enzyme activity assays. Adalimumab,Etanercept and Infliximab were incubated with HNE in theabsence or presence of elafin. Immunoblotting and ELISA wereused to determine anti-TNF degradation and function.Results: Mucosal protein homogenates from IBD patientsdisplay increased mucosal elastase activity (p = 0.002) andincreased elafin concentrations (p = 0.003) in comparison tohealthy subjects. Addition of recombinant elafin restores elastaseactivity to normal levels. Serum elastase concentrationsare higher in IBD patients (p = 0.02). Elastase fully degradesall anti-TNF agents which is prevented by recombinant elafin(p = 0.0002).Conclusions: IBD mucosa displays higher neutrophil elastaseactivity in comparison to healthy controls despite the presenceof higher levels of the elastase inhibitor elafin. The additionof recombinant elafin has a restorative effect on the elastaseactivity in IBD mucosa. Neutrophil elastase degrades anti-TNF agents and this can be prevented by elafin. Thiswork demonstrates a possible mechanism for primary nonresponsivenessto anti-TNF therapy. This work also illustratesthe potential role for elafin in the treatment of IBD and as astrategy to overcome primary non-responsiveness to biologics.