Medication | Mechanism of action | Current RA treatment effects on Immune System Cells | Predicted effects on ResoleomicsPhase 1: initiation, Phase 2: resolution, Phase 3: termination |
---|---|---|---|
COX-1 inhibition, COX-2 acetylationPGE2 ↓ATLs (15-epi-LX) ↑Activation of the ALX/FPR2 receptor ↑PLA2 ↓: free AA, PGE & LT ↓ | PMN infiltration ↓, PGEs ↓, chemokines ↓Leucocyte accumulation ↓Neutrophil recruitment ↓Vascular permeability ↓Nonphlogistic phagocytosis of apoptoticneutrophils ↑ | Negative: PG < LT levels: Phase 1 ↑Positive: PG not completely ↓: switch from phase 1 to phase 2 ↑Positive: ATLs ↑: phase 2 ↑ and 3 ↑ | |
COX-2 inhibition > COX-1 inhibitionPGE2 ↓, LTB4 ↑PGF2α, PGD2 ↓ | COX-2 expression macrophages ↓:Chemotaxis of neutrophils, eosinophils and monocytes into synovium ↓ | Negative: PG < LTB4 levels: Phase 1 ↑Switch from phase 1 to 2 ↓Switch from phase 2 to 3 ↓ | |
Transcription of IKB ↑: NFkB ↓Transcription by GCR &CREB-binding protein (CBP) ↓PLA2 ↓: free AA, PGE & LT ↓Annexin-1 ↑Activation of the ALX/FPR2 receptor ↑ | PMN infiltration ↓, PGEs ↓, chemokines ↓Leucocyte accumulation ↓Neutrophil recruitment ↓NFkB - transcription ↓Expression of inflammatory genes ↓Macrophage migration and phagocytosis ↑ | Negative: PGE, LT ↓: switch from phase 1 to 2 ↓Cortisol resistance: switch from phase 1 to phase 2 ↓ or no switchLipoxins ↓: switch from phase 2 to 3 ↓ | |
Folate analogs:1. Folate-dependent enzymes ↓:1a. Thymidylate synthetase1b. AICAR transformylase1c. Dihydrofolate reductase2. Cytosol peroxide (ROS) ↑ | Ad 1a. Synthesis of DNA & RNA ↓T-cell- proliferation & protein- & cytokine-expression by T-cells ↓, LT & IL-1 ↓Ad 1b. Adenosine ↑: NK-cell, monocytes & macrophages functioning↓, Cytokine synthesis of TNF-α, IL-1, IL-6 & IL-8 ↓ |  | |
1c. THF ↓: purine & pyrimidine ↓Ad 2. T-cell apoptosis ↑ | Negative: cytokines, T-cell activity ↓, LT ↓: switch from phase 1 to 2 ↓ or no switch |  |  |
DMARDs:Sulphasalazine (SSZ)[86] | SSZ: strong and potent inhibitor of NFkB-activation5-amino acytelate (5-ASA): PG ↓sulpha-pyridine | Less NFkB activation ↓: IL-2 of activated T-cells ↓, TNF alfa & IL-1 macro-phages ↓, Antibody in plasma cells ↓, Neutrophils, monocytes, macrohages, granulocyte activation ↓, IKB ↓: NFkB translocation ↓ & transcription of cytokines, adhesion molecules, chemokines ↓: COX-2 & PG↓ | Negative: Immune cell activity ↓: switch from phase 1 to 2 ↓ |
TNF-alfa signalling of mono's, PMN's, T-cells, endothelial cells, synovial fibroblasts & adipocytes ↓COX-2 induction ↓ | Monocyte activation, cytokine & PG release ↓PMN priming, apoptosis and oxidative burst; T-cell apoptosis, clonal regulation & T-cell receptor ↓Endothelial-cell adhesion molecule expression, cytokine release ↓synovial fibroblast proliferation, collagen synthesis, MMP & cytokine release ↓Adipocyte FFA release ↑ | Negative: Immune cell activity ↓: switch from phase 1 to 2 ↓ | |
IL-1 signalling of monocytes, B-cells, endothelial cell, synovial fibroblasts, chrondrocytes ↓COX-2 induction ↓ | Synovial fibroblast cytokine, chemokine, MMP, iNOS & PG release ↓Mono's cytokine, ROI & PG release ↓Osteoclast activity ↑GAG synthesis ↓, iNOS ↑, MMP & aggrecanaseEndothelial-cell adhesion molecule expression↓ | Negative: Immune cell activity ↓: switch from phase 1 to 2 ↓ |