Canakinumab suppresses IL-1β, IL-6, and hepcidin levels and inhibits activation of immune response, complement pathways, and myeloid differentiation. Pre- and post-treatment proteomic data from SomaScan and individual cytokine ELISA revealed key pathways that are modulated by canakinumab. (A) Volcano plot of multiplexed proteomic data in post-canakinumab patients at month 3 compared with baseline. Highlighted are significant proteins from the complement pathway (blue), erythropoiesis pathway (orange), and inflammatory pathways (pink) among those with FDR < 0.05. (B-C) Top 15 GO terms enriched in proteins downregulated (B) and upregulated (C) after canakinumab treatment showing FDR and fold enrichment. (D) Canakinumab suppresses key regulators of AI, including IL-1β, IL-6, and hepcidin. (E) Canakinumab increases RBC numbers, as evidenced by upregulated proteins in RBCs, including AChE and hemoglobin (HBA1 and HBB). (F) Changes in IL-6 and hemoglobin levels between baseline and month 3. Patients treated with canakinumab (blue) have 3.46 times higher odds of having both an increase in hemoglobin and a decrease in IL-6 than patients treated with placebo (red). (G) Changes in hepcidin and hemoglobin levels between baseline and month 3. The odds of having both an increase in hemoglobin and a decrease in hepcidin were 1.88 times higher in patients treated with canakinumab (light blue) compared with placebo (red). AChE, acetylcholinesterase; C1RL, complement component 1, r subcomponent-like; C1S, complement component 1, s subcomponent; C3, complement component 3; C4BPA, complement component 4 binding protein alpha; C9, complement component 9; CFB, complement factor B; CRIPSLD2, cysteine-rich secretory protein LCCL domain containing 2; CST7, cystatin F; FC, fold change; FCN1, ficolin 1; FTH1, ferritin; HAMP, hepcidin; HBA1, hemoglobin alpha; HBB, hemoglobin beta; HP, haptoglobin; HPX, hemopexin; MBL2, mannose-binding; lectin 2; PRTN3, proteinase 3.