Targetable pathogenic mechanisms in nasal polyposis

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) represents a challenging disease entity with significant rates of recurrence following appropriate medical and surgical therapy. Recent approval of targeted biologics in CRSwNP compels deeper understanding of underlying disease pathophysiology. Both of the approved biologics for CRSwNP modulate the type 2 inflammatory pathway, and the majority of drugs in the clinical trials pathway are similarly targeted. However, there remain multiple other pathogenic mechanisms relevant to CRSwNP for which targeted therapeutics already exist in other inflammatory diseases that have not been studied directly. In this article we summarize pathogenic mechanisms of interest in CRSwNP and discuss the results of ongoing clinical studies of targeted therapeutics in CRSwNP and other related human inflammatory diseases.

Keywords: biologic therapies; chronic rhinosinusitis with nasal polyps; type 2 inflammation.

Figure 1

Type 2 Inflammation in CRSwNP with targeted drug therapies superimposed. All discussed cytokines and cell types have been reported to be elevated in CRSwNP tissue. TSLP, IL-33, and IL-1 are epithelial-derived cytokines that are secreted in response to various stimuli. They activate both adaptive and innate responses by myeloid dendritic cells (mDC), Type 2 innate lymphoid cells (ILC2s) and mast cells. These adaptive and innate responses generate the Type 2 cytokines IL-4, IL-5 and IL-13 which have further downstream effects such as eosinophilia, mucus secretion and B cell activation including secretion of IgE. Overlaid on the pathogenic mechanisms are precision biologics targeting the various aspects of the inflammatory cascade. Compounds in blue have been approved for use or are being studied in CRSwNP. Compounds in red have been approved for use or are being studied in inflammatory diseases other than CRSwNP.

Figure 2

Other targetable pathogenic mechanisms in CRSwNP. In addition to Type 2 inflammatory mediators, other lines of evidence find that other phenomenon may play important role in the inflammation observed in CRSwNP. These include evidence that: 1) activated ILC2s and neutrophils release epithelium-disrupting compounds; 2) B-cells, plasmablasts and plasma cells are expanded which produce antibodies, including autoantibodies, to epithelial basement membrane epitopes; 3) there is significant complement activation in the vicinity of the epithelial basement membrane and 4) there is a profound accumulation of subepithelial fibrin in a nasal polyp which may result in part from reduction in epithelial derived fibrinolytic factors or an over-production of clotting factors. These mechanisms have pharmacologic agents in red that have been approved for, or are being studied in other diseases. Items in blue represent broad conceptual areas for which numerous targeted therapeutics have previously been developed.