sarilumab

**Mechanism:** Sarilumab is a human IgG1 monoclonal antibody that binds the alpha subunit of the IL-6 receptor (mIL-6Rα and sIL-6Rα), which inhibits IL-6 signaling through the JAK/STAT pathway. IL-6 is produced by macrophages, T cells, and fibroblasts. It drives the acute-phase response (hepatic CRP, fibrinogen, hepcidin, and serum amyloid A), B-cell differentiation and autoantibody production, Th17 differentiation, fever, and osteoclast activation. Blocking it lowers CRP and ESR and improves joint inflammation. Because CRP is suppressed, it can mask infection, so a normal CRP is unreliable for detecting infection in treated patients.

**Indications:** - Moderate-to-severe rheumatoid arthritis (RA) with inadequate response to one or more DMARDs. It can be used as monotherapy or with methotrexate. - Polymyalgia rheumatica (PMR) with inadequate response to corticosteroids, or when steroids cannot be tapered. - It is not approved for COVID-19 in the US. Its sister drug tocilizumab has that role.

**Dosing/administration:** Subcutaneous injection every 2 weeks (the dose is reduced for neutropenia, thrombocytopenia, or elevated liver enzymes).

**Adverse effects (high-yield):** - Serious infections, including TB, invasive fungal infections, and opportunistic infections. Screen for latent TB (and hepatitis B) before starting. - Neutropenia and thrombocytopenia. Monitor CBC. - Hepatotoxicity (elevated ALT/AST). Monitor LFTs. - Dyslipidemia (increased LDL, HDL, and triglycerides). Monitor lipids. - GI perforation, especially with diverticulitis, NSAID or corticosteroid use. - Injection-site reactions. - Hypersensitivity reactions. - Avoid live vaccines.

**Comparison with related drugs:** - Tocilizumab is also an anti-IL-6R antibody (IV or SC). It is used for RA, giant cell arteritis, systemic JIA, and cytokine release syndrome (such as with CAR-T therapy). - Siltuximab binds the IL-6 ligand itself. It is used for multicentric Castleman disease. - Anakinra blocks the IL-1 receptor. - TNF-α inhibitors include infliximab, adalimumab, etanercept, and certolizumab. - JAK inhibitors, such as tofacitinib, act downstream of the cytokine receptors.

**Naming tip:** The suffix "-mab" means monoclonal antibody. The "-u-" infix indicates a fully human antibody. The "-li-" infix is for immunomodulating targets. So "sar-i-lu-mab" is a human immunomodulatory antibody.

**Clinical pearl:** In a patient with RA on an IL-6 inhibitor who has fever but a normal CRP, still evaluate for infection, because the drug blunts the acute-phase response. The same warning applies to monitoring disease activity, since CRP-based scores such as DAS28-CRP may underestimate it.