ustekinumab

**Mechanism of action** - Fully human IgG1κ monoclonal antibody against the **p40 subunit**, which is shared by **IL-12** (p35 + p40) and **IL-23** (p19 + p40). - Blocking p40 prevents binding to the IL-12Rβ1 receptor chain on T cells, NK cells, and APCs. - IL-12 drives **Th1** differentiation (IFN-γ production). IL-23 maintains and expands **Th17** cells (IL-17, IL-22). Both pathways drive chronic inflammation in psoriasis and IBD.

**Indications** - Moderate-to-severe **plaque psoriasis** - **Psoriatic arthritis** - **Crohn disease** (including cases refractory to anti-TNF agents) - **Ulcerative colitis** - Pediatric psoriasis and Crohn disease (age-specific approvals)

**Administration** - Given subcutaneously. For IBD, the induction dose is a single weight-based IV infusion, followed by SC maintenance (typically every 8–12 weeks). - Maintenance dosing is infrequent, which is a practical advantage over many other biologics.

**Adverse effects and safety** - **Infections**: upper respiratory infections, and serious infections including **TB reactivation**. Screen for latent TB (PPD or IGRA) before starting. Avoid live vaccines. - **Reversible posterior leukoencephalopathy syndrome (RPLS/PRES)**: rare. Presents with headache, seizures, confusion, and visual disturbance. - Hypersensitivity reactions and injection-site reactions. - Possible increased risk of malignancy (theoretical; data are mostly reassuring). - Infections with intracellular organisms such as Salmonella, Mycobacteria, and Candida are a theoretical concern. This follows from the role of the IL-12/IFN-γ axis in host defense, as seen in **IL-12 receptor/IFN-γ pathway deficiency (Mendelian susceptibility to mycobacterial disease)**. - Unlike anti-TNF agents, it is not associated with demyelinating disease or lupus-like syndrome. It also has no clear association with heart failure exacerbation.

**Board-relevant comparisons** - **Anti-TNF** (infliximab, adalimumab, etanercept, certolizumab, golimumab): also used for psoriasis, IBD, and RA. Their risks include TB reactivation and demyelination. - **Anti-IL-17** (secukinumab, ixekizumab, brodalumab): used for psoriasis, psoriatic arthritis, and ankylosing spondylitis. They carry a risk of mucocutaneous candidiasis, and in IBD they can worsen disease. - **Anti-IL-23 p19** (guselkumab, risankizumab, tildrakizumab, mirikizumab): more selective than ustekinumab, since they spare IL-12. - **Vedolizumab**: anti-α4β7 integrin, gut-selective, for IBD. - **Anti-IL-5/IL-4/IL-13 agents** (mepolizumab, dupilumab): used for asthma and atopic disease, not psoriasis or IBD.

**High-yield pearls** - The name ends in **-mab**. The infix **-u-** denotes a fully human antibody, and **-li-** or **-ki-** denotes an immunomodulator or interleukin target. Ustekinumab is human and targets an interleukin. - "p40" is the key association: ustekinumab = **anti-IL-12/23 (p40)**. - Always screen for latent TB before starting any biologic, including ustekinumab. - Like other biologics, it can be immunogenic, with anti-drug antibodies that reduce efficacy. This is less common than with infliximab.