Skyrizi (risankizumab) does affect your immune system, but it works very differently from traditional immunosuppressants like methotrexate or cyclosporine. Rather than broadly dampening immune function, Skyrizi blocks a single immune signaling protein called interleukin-23 (IL-23). This makes it a selective immunosuppressant, technically qualifying it as one while carrying a meaningfully different risk profile than older drugs in that category.
How Skyrizi Targets the Immune System
Skyrizi is a monoclonal antibody that binds to the p19 subunit of IL-23 with high affinity. IL-23 is a signaling protein your immune system uses to activate and maintain certain inflammatory cells, particularly a type called TH17 cells. In conditions like psoriasis, these TH17 cells overproduce inflammatory molecules (IL-17 and IL-22) that trigger skin cells to proliferate out of control, creating the thick, scaly plaques characteristic of the disease.
By neutralizing IL-23 specifically, Skyrizi cuts off the signal that drives this inflammatory chain reaction. It does not bind to IL-12, a related but distinct immune protein that shares a structural component with IL-23. This selectivity is important: IL-12 helps coordinate other branches of immune defense, so leaving it alone means Skyrizi disrupts less of your overall immune function.
In the gut, IL-23 drives inflammation through additional cell types beyond TH17 cells, which is why Skyrizi is also used for inflammatory bowel disease. The drug interrupts chronic intestinal inflammation and the tissue damage that comes with it, again by targeting this one upstream signal rather than suppressing immunity broadly.
Selective Biologic vs. Broad Immunosuppressant
Traditional immunosuppressants like methotrexate and cyclosporine work by suppressing large portions of the immune system. Methotrexate interferes with rapidly dividing cells throughout the body, affecting immune cells but also gut lining, liver cells, and bone marrow. Cyclosporine broadly inhibits T-cell activation across many pathways. These drugs carry well-known risks of widespread side effects, from liver damage to bone marrow suppression.
Skyrizi’s approach is far narrower. It blocks one cytokine out of the dozens your immune system relies on, leaving most immune defenses intact. In a head-to-head clinical trial comparing Skyrizi to methotrexate for moderate-to-severe plaque psoriasis, the methotrexate group experienced more overall adverse events (83.3% vs. 77.6%). Methotrexate caused notably higher liver enzyme elevations, with increases averaging 5 to 8 units per liter compared to changes of 1 unit or less with Skyrizi. Serious infections occurred in the methotrexate group (2.1%) but not in the Skyrizi group during that trial.
So while Skyrizi technically qualifies as immunosuppressive because it modifies immune function, calling it “an immunosuppressant” in the same breath as methotrexate or cyclosporine gives a misleading impression of how much immune suppression it actually causes.
What Skyrizi Is Approved to Treat
The FDA has approved Skyrizi for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, and for active psoriatic arthritis in adults. It is also used for Crohn’s disease. For both psoriasis and psoriatic arthritis, the standard dosing schedule is a 150 mg injection at the start of treatment, another at week 4, then once every 12 weeks after that.
Infection Risk in Clinical Trials
Because Skyrizi does modify part of your immune response, infection risk is a legitimate concern. The clinical trial data, however, is reassuring. Across multiple Phase 3 trials, infection rates were generally low and comparable to placebo groups during the first 16 weeks of treatment. The most commonly reported infections were upper respiratory tract infections and viral upper respiratory infections, the kind of colds and minor illnesses that affect everyone.
In one trial (IMMvent), patients on Skyrizi did report a higher rate of viral upper respiratory infections (26.4%) compared to those on another biologic, adalimumab (12.5%), during one phase of the study. Serious infections, though, were rare across all trials. Fungal infections occasionally occurred but were not classified as serious adverse events. Overall, Skyrizi has not shown the kind of significant, broad infection vulnerability associated with traditional immunosuppressants.
Screening and Precautions Before Starting
Even though Skyrizi’s immune effects are targeted, your doctor will screen for tuberculosis before prescribing it. This typically involves a TB skin test, a blood test called an interferon-release assay, or a chest X-ray within six months of starting treatment. If you’ve never taken a biologic before, this screening is standard. If you have risk factors for TB, yearly re-testing is recommended while on therapy. Active TB must be ruled out, and latent TB needs treatment before you can begin Skyrizi.
Live vaccines are not recommended while you’re on Skyrizi, or immediately before or after treatment. This includes vaccines like the live shingles vaccine (Zostavax), the MMR vaccine, and the live nasal flu spray. Inactivated vaccines are not specifically restricted, though no formal data exists on how well patients on Skyrizi respond to any vaccine. The FDA label advises completing all age-appropriate vaccinations before starting treatment when possible.
Liver Effects
Mild to moderate liver enzyme elevations occur in up to 10% of patients on Skyrizi, but these are typically temporary and don’t cause symptoms. In large clinical trials for psoriasis, liver-related events occurred in about 7% of patients on Skyrizi compared to 2% on placebo. In studies of Crohn’s disease patients, liver enzyme elevations were more frequent, occurring at a rate of about 10 per 100 patient-years, likely reflecting higher doses used for that condition.
Importantly, no cases of clinically apparent liver injury or severe liver events were attributed to Skyrizi in the major pre-approval trials. This stands in contrast to methotrexate, which requires regular liver monitoring due to its potential for cumulative liver toxicity over time.
What This Means Practically
If you’re trying to decide whether Skyrizi is “safe” relative to other options, the distinction between selective and broad immunosuppression matters. Your immune system has many layers. Skyrizi turns down one specific dial that happens to be stuck too high in autoimmune conditions, while leaving the rest of your immune defense largely functional. Traditional immunosuppressants turn down many dials at once, which is why they tend to come with more side effects and greater infection risk.
That said, Skyrizi is not immunologically neutral. The TB screening requirement, the live vaccine restriction, and the possibility of increased upper respiratory infections all reflect the fact that it does alter immune function in a clinically meaningful way. It’s most accurate to think of it as a targeted immune modifier that carries a fraction of the risk profile people typically associate with the word “immunosuppressant.”