Is Skyrizi an Immunosuppressant or Selective Biologic?

Skyrizi (risankizumab) is a selective biologic, not a traditional immunosuppressant, though the line between those categories is blurrier than most patients realize. It works by blocking a single immune signaling molecule rather than dampening the immune system broadly, and this distinction has real consequences for infection risk, vaccine response, and long-term safety. The question matters because the label “immunosuppressant” carries baggage that may not accurately describe what Skyrizi does inside your body.

How Skyrizi Targets the Immune System

Skyrizi is a monoclonal antibody that binds to the p19 subunit of interleukin-23 (IL-23), a signaling protein involved in driving inflammation. By latching onto this subunit, risankizumab prevents IL-23 from docking with its receptor on immune cells, which shuts down the downstream inflammatory cascade.¹ Think of it as removing one specific key from a janitor’s keyring rather than confiscating the whole ring. The rest of the immune system’s doors stay open and functional.

IL-23 plays a particular role in maintaining a type of immune cell behavior associated with chronic inflammation. Research has shown that IL-23 keeps certain immune cells locked into an inflammatory state, sustaining the production of inflammatory signals without necessarily making more of those cells or helping them survive longer.² In diseases like psoriasis, Crohn’s disease, and ulcerative colitis, this maintenance loop is a core driver of tissue damage. Skyrizi interrupts that loop at a precise point.

An older biologic called ustekinumab (Stelara) also targets IL-23, but it does so by binding a different part of the molecule, the p40 subunit, which is shared between IL-23 and another signaling protein called IL-12. That means ustekinumab blocks two pathways at once. Skyrizi and the other newer IL-23 inhibitors (guselkumab and tildrakizumab) bind only p19, leaving IL-12 signaling intact.³ IL-12 has its own role in immune defense, particularly against certain infections, so sparing it is considered an advantage in terms of preserving immune function.

Why “Immunosuppressant” Is Misleading Here

Traditional immunosuppressants like corticosteroids, methotrexate, and azathioprine work by broadly turning down the immune system’s activity. They suppress multiple pathways simultaneously, which is effective at controlling inflammation but comes with a wide range of side effects because the immune cells you need for fighting infections and surveilling for cancer are also dampened. A narrative review comparing biologics with these older drugs in inflammatory bowel disease described the traditional agents as having “broad immunosuppressive effects and significant adverse events,” while biologics were characterized as offering “targeted immune modulation” that reduces systemic side effects.⁴

That said, the review also noted that biologics still carry risks including infections and immunogenicity, and it referred to them as providing “targeted immune suppression.”⁴ This is the honest nuance: Skyrizi does suppress part of the immune system. It just does so with a much narrower scope than the drugs most people picture when they hear “immunosuppressant.” You are not on the same footing as someone taking high-dose prednisone or a transplant rejection drug. But you are altering immune function in a specific, measurable way.

What the Infection Data Show

If Skyrizi were suppressing your immune system in a meaningful, broad way, you would expect to see elevated rates of serious infections and opportunistic pathogens. The clinical trial data tells a different story. A long-term safety analysis of risankizumab in psoriasis and psoriatic arthritis patients found that the rate of serious infections (excluding COVID-related ones) was about 1.2 events per 100 patient-years in people with psoriasis and 1.4 in those with psoriatic arthritis. Opportunistic infections, excluding tuberculosis and herpes zoster, were extremely rare at less than 0.1 events per 100 patient-years in both groups.⁵

An earlier pooled analysis across 17 clinical trials in people with moderate-to-severe plaque psoriasis filled in more detail. The rate of serious infection during long-term follow-up was about 1.2 events per 100 patient-years, comparable to what was seen in the placebo group during the controlled portions of the trials. There were no cases of active tuberculosis. Herpes zoster occurred at a rate of about 0.5 events per 100 patient-years, which was actually below published benchmarks for people with moderate-to-severe psoriasis on systemic therapy. Candida infections were uncommon, and none were deep or systemic.⁶

Real-world data from a post-marketing surveillance database did flag COVID-19, pneumonia, and urinary tract infections as the most commonly reported events in the infection category.⁷ These numbers are hard to interpret in isolation because adverse-event reporting databases capture everything that happens while someone is on a drug, whether or not the drug caused it. Still, the overall picture from both controlled trials and real-world reporting is that serious infections on Skyrizi are uncommon.

How Skyrizi Stacks Up Against Other Biologics on Safety

Not all biologics carry the same infection risk. A systematic review and network meta-analysis that combined evidence from randomized trials and observational studies compared the serious infection risk of various systemic treatments for psoriasis. Risankizumab ranked first for safety with a probability score of 0.87 out of 1. Adalimumab, a widely used TNF inhibitor, had roughly two and a half times the risk of serious infection compared to risankizumab. Infliximab, another TNF inhibitor, also showed higher risk than risankizumab.⁸

This fits with the broader understanding of the biologic landscape. TNF inhibitors suppress a more centrally important inflammatory molecule, and TNF itself plays a direct role in fighting certain bacterial and fungal infections. Blocking it broadly increases susceptibility to things like tuberculosis reactivation, which is why TB screening is standard before starting any TNF inhibitor. IL-23 inhibitors are more peripheral in that sense: the pathway they target matters for chronic inflammation but is less critical for acute immune defense.

Fungal infections provide another useful comparison. IL-17, the downstream signal that IL-23 helps sustain, plays an important role in mucosal defense against Candida. Drugs that directly block IL-17 (like secukinumab, ixekizumab, and brodalumab) have measurably higher rates of Candida infections compared to drugs that target IL-12/23 or IL-23. A meta-analysis of randomized trials found that the Candida infection rate with IL-17 blockers was about twice that of IL-12/23 blockers, with the difference being statistically significant.⁹ By targeting the upstream signal (IL-23) rather than IL-17 itself, Skyrizi dials down that inflammatory pathway without completely eliminating the mucosal defense against yeast.

A prospective real-world study (the VALUE study) that tracked patients with moderate-to-severe psoriasis found that those on risankizumab had numerically lower rates of adverse events, serious adverse events, and infections compared to patients on other biologics.¹⁰ Observational studies like this cannot prove causation in the same way a randomized trial can, but they offer reassurance that the favorable safety signal from clinical trials holds up in everyday clinical use.

Vaccines on Skyrizi

One of the clearest practical tests of whether a drug meaningfully suppresses immunity is how well people respond to vaccines while taking it. Some immunosuppressive drugs, particularly B-cell-depleting therapies like rituximab, can dramatically blunt vaccine responses. For drugs that target specific cytokine pathways, the picture tends to be more encouraging.

Research into COVID-19 vaccine responses in patients on biologic therapies for psoriasis suggested that these drugs did not reduce the immune response to vaccination, with the authors specifically distinguishing biologics as “immunomodulating and not immunosuppressive agents” in contrast to traditional systemic drugs.¹¹ That framing is worth noting: the researchers themselves preferred the term “immunomodulating” to describe drugs like risankizumab.

Still, vaccination while on any biologic deserves some thought. A comprehensive review of vaccination strategies for patients on monoclonal antibodies noted that these agents have “highly heterogeneous immunosuppressive effects, mechanisms of action, and pharmacokinetics,” meaning blanket advice does not work well.¹² The general guidance is that inactivated vaccines are safe on IL-23 inhibitors, while live vaccines require more caution. Your prescriber should have a specific conversation with you about timing, particularly if a live vaccine is recommended.

Long-Term Efficacy in Psoriasis

Part of why the immunosuppressant question matters is that patients want to know if a drug that acts so selectively can actually control a serious disease over the long haul. The answer for psoriasis is an emphatic yes. The LIMMitless extension trial followed patients on continuous risankizumab treatment for up to six years. At the final analysis (week 304), about 86% of patients achieved a 90% or greater improvement in their psoriasis severity score, and over half achieved complete clearance. Quality-of-life scores showed that roughly three-quarters of patients reported no impact of psoriasis on their daily lives.¹³

These results held up remarkably well across different patient groups. Subgroup analyses of the same trial showed that responses were numerically similar regardless of age, sex, body weight, or whether the patient had psoriatic arthritis at baseline. Patients with difficult-to-treat forms of psoriasis affecting the nails, scalp, or palms and soles also saw substantial improvements, with average improvement from baseline exceeding 81% for nails, 94% for scalp, and 97% for palmoplantar disease by week 256.¹⁴ The consistency across such a broad range of patients is unusual and speaks to the robustness of the IL-23 pathway as a therapeutic target in psoriasis.

Anti-drug antibodies, where the body mounts an immune response against the biologic itself, are another long-term concern with any monoclonal antibody. This can reduce a drug’s effectiveness over time or cause injection-site reactions. Studies of risankizumab have found that anti-drug antibody rates were comparable across formulations and that their presence did not appear to undermine the drug’s long-term performance.¹⁵

Beyond Psoriasis

Risankizumab has expanded beyond skin disease into inflammatory bowel disease, where the immunosuppressant-versus-biologic question takes on a different flavor. Gut inflammation in Crohn’s disease and ulcerative colitis involves overlapping but distinct immune pathways compared to psoriasis, and patients with these conditions are often more immunologically vulnerable because of the disease itself and their treatment history.

In ulcerative colitis, two randomized clinical trials demonstrated that risankizumab significantly outperformed placebo during induction. About 37% of patients on risankizumab achieved endoscopic improvement compared to 12% on placebo. During the maintenance phase, both the 180 mg and 360 mg doses produced roughly 50% endoscopic improvement rates versus about 32% for placebo.¹⁶ The magnitude of the benefit was consistent across multiple endpoints measuring different depths of healing.

Early real-world data from the STAR trial in Crohn’s disease, representing the first Asian cohort reported, showed more modest numbers at 12 weeks: about 29% of patients achieved endoscopic remission and roughly 18% reached combined transmural healing.¹⁷ These patients were often heavily pretreated and had refractory disease, which typically yields lower response rates across all drugs. The fact that a drug targeting a single cytokine pathway can induce endoscopic healing in this population reinforces that selectivity does not equal weakness.

When the Label Actually Does Matter

There are situations where the distinction between immunosuppressant and selective biologic has concrete consequences beyond your infection risk. Insurance coverage and prior authorization pathways sometimes treat biologics and immunosuppressants as separate categories, and the required step therapy (trying cheaper drugs first) can differ. Some travel vaccine requirements and occupational health screenings ask specifically whether you are on immunosuppressive therapy, and how you answer can affect clearance decisions.

Regulatory agencies have handled the terminology inconsistently. Prescribing information for risankizumab does include warnings about infection risk and notes that it may increase susceptibility, language that sounds immunosuppressive. But the same label does not carry the boxed warnings for serious infections that accompany TNF inhibitors, which reflects the difference in clinical risk. If your employer, insurer, or travel medicine provider asks whether you are immunosuppressed, the honest answer is that you are on a drug that selectively alters one immune pathway. You are not broadly immunocompromised in the way that term usually implies, but you are not on a completely immunologically inert drug either.

For most people on Skyrizi, the practical reality is that you can expect a functioning immune system that responds to infections and vaccines while the drug quietly disables one of the feedback loops responsible for your chronic inflammatory disease. The evidence accumulated over six years of clinical trials and growing real-world data supports that framing. Calling it an immunosuppressant in the traditional sense overstates the systemic impact; calling it entirely non-immunosuppressive understates the fact that it does, deliberately and by design, turn off a piece of the immune machinery.