Table 1.
Inhibition of neutrophils: therapeutic approaches in autoimmune diseases.
| Strategies | Approaches | Target | Drugs and Diseases |
|---|---|---|---|
| Reducing neutrophil numbers |
Targeting production | - GM-CSF receptor | Mavrilimumab in GCA and RA [127,128,129] |
| - GM-CSF |
Otilimab in RA [130]; Namilumab in RA [131], PsO [132] and SpA (NCT03622658); Gimsilumab in AS (NCT04205851; NCT04351243) |
||
| - IL-23/IL-17 axis (a regulator of G-CSF production) |
IL-17 inhibitors in PsO, PsA, ax-SpA; IL-12/23 inhibitors in PsO, PsA [133], CD, and SLE; IL-23 inhibitors in CD, UC, PsO, and PsA |
||
| Inducing depletion | - Circulating neutrophils | -Extracorporeal granulocytapheresis in RA [134], CD, and RCU [135] | |
| Interfering with neutrophil recruitment and chemotaxis |
Selectin and integrin blockers | - α4β1-integrin |
-Natalizumab in CD [136] |
| - Selectins | -TBC1269 (and others) in PsO [137] | ||
| Blocking complement | - C5a and C5a receptor | -Eculizumab and Avacopan in AAV [138,139]; NNC0215-0384 in RA (NCT01611688) | |
| Blocking leucotriens | - LTB4 | -CP-195543 in RA (NCT00424294) | |
| Blocking neutrophils activation |
Signal transduction blockade (cytokine signaling in neutrophils) | - JAK | -Jak-inhibitors in PsA, RA, UC, AS [140] |
| - SYK | -Fostamatinib in RA [141] and SLE [142] | ||
| - PDE4 | -Apremilast in PsO, PsA [143], SLE (NCT00708916) and AS [144] | ||
| Blocking cytokines whose receptors are also on neutrophils | - TNF-α |
-TNF-α inhibitors in RA, PsA, PsO, SpA, AS, CD, UC, uveitis [145] | |
| - IL-6 | -IL-6 inhibitors in RA, AS, SSc, vasculitis, SLE, AOSD [146] | ||
| Blocking neutrophil-derived mediators |
Neutrophil granule enzymes | - MMP9 | -andecaliximab in UC and CD [147,148] |
| NETs (blocking activity of enzymes critical for NETs formation) | - NADPH, MPO, PAD4, DNase Inhibitor | Not yet elucidated in humans affected by autoimmune diseases. | |
| Others | Blocking neutrophil function | - Neutrophil inflammasome |
-β-hydroxybutyrate in gout flares [149] -IL-1β inhibitors in RA, SpA, PsA, AS, AOSD, uveitis, GCA, vasculitis [150] |
| - Neutrophils alarmins (S100A8/S100A9) | -Paquinimod in SLE (NCT00997100) |
Abbreviations: Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Interleukin (IL), (LTB4), (JAK), (SYK), Tumor Necrosis Factor (TNF), phosphodiesterase-4 (PDE4), Metalloproteinase (MMPS), Nicotinamide adenine dinucleotide phosphate (NADPH), ANCA-Associated Vasculitis (AAV), Myeloperoxidase (MPO), Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), Psoriasis (PsO), Spondyloarthritis (SpA), Ankylosing Spondylitis (AS), Ulcerative Colitis (UC), Crohn Disease (CD), Giant Cell Arteritis (GCA), Adult Onset Still’s Disease (AOSD), Systemic Lupus Erythematosus (SLE).