T Helper 2 IL-4/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17‒Type Diseases, Including Seronegative Arthritis and Enthesitis/Enthesopathy, but Not to Humoral Autoimmune Diseases

Abstract

Dupilumab, an IL-4/IL-13 receptor blocker, has been linked to emergent seronegative inflammatory arthritis and psoriasis that form part of the spondyloarthropathy spectrum. We systematically investigated patterns of immune disorders, including predominantly T helper 17‒(spondyloarthropathy pattern) and T helper 2‒mediated disorders and humoral autoimmune pattern diseases, using VigiBase, the World Health Organization's global pharmacovigilance of adverse drug reactions. Several bioinformatics databases and repositories were mined to couple dupilumab-related immunopharmacovigilance with molecular cascades relevant to reported findings. A total of 37,848 dupilumab adverse drug reaction cases were reported, with skin, eye, and musculoskeletal systems most affected. Seronegative arthritis (OR= 9.61), psoriasis (OR= 1.48), enthesitis/enthesopathy (OR= 12.65), and iridocyclitis (OR= 3.77) were highly associated. However, ankylosing spondylitis and inflammatory bowel disease were not conclusively associated. Overall, classic polygenic humoral‒mediated autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus were not associated with dupilumab use. Pathway analysis identified several biological pathways potentially involved in dupilumab‒associated adverse drug reactions, including the fibroblast GF receptor (in particular, FGFR2) pathway. MicroRNAs analysis revealed the potential involvement of hsa-miR-21-5p and hsa-miR-335-5p. In conclusion, IL-4/IL-13 blockers are not unexpectedly protective against humoral autoimmune diseases but dynamically skew immune responses toward some IL-23/IL-17 cytokine pathway‒related diseases. IL-4/13 axis also plays a role in homeostatic tissue repair and we noted evidence for a link with ocular and arterial pathology.