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P054. Interactions between neutrophil elastase and biologics in IBD

K. Kok1, R. Curciarello1, P. Giuffrida1, N. Joshi2, P. Biancheri1, T. MacDonald1, 1Barts and The London School of Medicine and Dentistry, Centre for Immunology and Infectious Disease, London, United Kingdom, 2Barts Health NHS Trust, Gastroenterology, London, United Kingdom

Background

Human neutrophil elastase (HNE) is highly expressed in IBD but the balance between HNE and its inhibitor elafin remains poorly understood. Biologics exert their action in 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 extract mucosal proteins and serum was also collected. Elastase and elafin quantity and function was assessed using ELISA and enzyme activity assays. Adalimumab, Etanercept and Infliximab were incubated with HNE in the absence or presence of elafin. Immunoblotting and ELISA were used to determine anti-TNF degradation and function.

Results

Mucosal protein homogenates from IBD patients display increased mucosal elastase activity (p = 0.002) and increased elafin concentrations (p = 0.003) in comparison to healthy subjects. Addition of recombinant elafin restores elastase activity to normal levels. Serum elastase concentrations are higher in IBD patients (p = 0.02). Elastase fully degrades all anti-TNF agents which is prevented by recombinant elafin (p = 0.0002).

Conclusion

IBD mucosa displays higher neutrophil elastase activity in comparison to healthy controls despite the presence of higher levels of the elastase inhibitor elafin. The addition of recombinant elafin has a restorative effect on the elastase activity in IBD mucosa. Neutrophil elastase degrades anti-TNF agents and this can be prevented by elafin. This work demonstrates a possible mechanism for primary non-responsiveness to anti-TNF therapy. This work also illustrates the potential role for elafin in the treatment of IBD and as a strategy to overcome primary non-responsiveness to biologics.