ixekizumab

**Mechanism:** Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds IL-17A (both IL-17A/A homodimer and IL-17A/F heterodimer) and prevents it from binding the IL-17 receptor. IL-17A is produced mainly by Th17 cells (also γδ T cells, ILC3s, and neutrophils/mast cells). It acts on keratinocytes, synoviocytes, and entheseal cells to induce proinflammatory cytokines (IL-6, TNF-α), chemokines (e.g., CXCL1, CXCL8/IL-8, which recruit neutrophils), and antimicrobial peptides. In psoriasis, the IL-23 → Th17 → IL-17 axis drives keratinocyte hyperproliferation, producing plaques with Munro microabscesses (neutrophils in the stratum corneum), acanthosis, parakeratosis, and loss of the granular layer.

**Indications:** - Moderate-to-severe plaque psoriasis (adults and children, candidates for systemic therapy or phototherapy) - Psoriatic arthritis - Ankylosing spondylitis - Non-radiographic axial spondyloarthritis (with objective signs of inflammation)

**Administration:** Subcutaneous injection. For psoriasis, the usual regimen is a loading dose, then every 2 weeks through week 12, then every 4 weeks.

**Adverse effects and boards-relevant points:** - **Infections:** Upper respiratory infections and mucocutaneous candidiasis (oral, esophageal, vaginal). IL-17 is critical for mucosal defense against Candida, a connection that parallels chronic mucocutaneous candidiasis from IL-17 or IL-17R pathway defects and Job syndrome (hyper-IgE, STAT3 mutation, impaired Th17 differentiation). - **Inflammatory bowel disease:** New-onset or exacerbation of Crohn disease and ulcerative colitis has been reported. IL-17 inhibitors are generally avoided in patients with active IBD, and secukinumab trials in Crohn disease showed worsening. - **Injection-site reactions** and hypersensitivity (including rare angioedema and anaphylaxis). - **Neutropenia** (uncommon). - **Tuberculosis:** Screen for TB before starting. The TB risk is lower than with TNF inhibitors, but screening is still recommended. Avoid live vaccines. - **Immunogenicity:** Anti-drug antibodies can develop and may reduce efficacy.

**Drug class comparisons (high-yield):** - IL-17A inhibitors: secukinumab (Cosentyx), ixekizumab (Taltz) - IL-17 receptor A antagonist: brodalumab (Siliq), which carries a boxed warning for suicidal ideation and behavior - IL-17A/F inhibitor: bimekizumab (Bimzelx) - IL-12/23 inhibitor: ustekinumab (p40 subunit) - IL-23 inhibitors (p19): guselkumab, tildrakizumab, risankizumab - TNF inhibitors: etanercept, infliximab, adalimumab, certolizumab, golimumab. These are contraindicated in demyelinating disease and in severe heart failure, and they can reactivate TB.

**Naming:** The suffix "-kin-" denotes an interleukin target and "-zu-" denotes a humanized antibody, so "-kizumab" means a humanized monoclonal antibody against an interleukin. The "-mab" suffix indicates a monoclonal antibody.

**Clinical vignette pearl:** A patient with plaque psoriasis (silvery scaling plaques on extensor surfaces, Auspitz sign, nail pitting) who has failed topical therapy and phototherapy and starts a biologic, then develops oral thrush or new-onset bloody diarrhea. This should suggest an IL-17 inhibitor such as ixekizumab.