Newer oral small-molecule therapies, including apremilast and deucravacitinib, offer effective treatment for plaque psoriasis with generally favorable long-term safety profiles compared with traditional systemic agents. For example, long-term clinical trial data have shown no new safety signals for apremilast, while deucravacitinib has demonstrated a consistent safety profile, with lower rates of the serious adverse events that are typically associated with oral JAK inhibitors, making both drugs valuable options for patients requiring systemic therapy after topical treatment failure.

Our newer small-molecule therapies, which include apremilast and deucravacitinib, differ from the traditional systemic small-molecule treatments we have used in the past, such as methotrexate, cyclosporine, and acitretin, which were broader immunosuppressants. When we look at apremilast and deucravacitinib, they work well and have different mechanisms of action and generally better safety profiles than what we have come to expect from older systemic therapies.

Apremilast is an oral PDE4 inhibitor that works inside the cell to help modulate inflammation by blocking the PDE4 enzyme, thereby creating a more anti-inflammatory environment. In phase 3 clinical trials and long-term extension studies, the adverse events that occurred more commonly with apremilast included gastrointestinal side effects such as diarrhea and nausea, along with slight increases in upper respiratory tract infections and headache. Overall, this is a drug that has been well tolerated in clinical trials, and long-term studies have not identified any new safety signals.

Deucravacitinib represents a different type of small molecule. It is an oral TYK2 inhibitor that targets the key inflammatory IL-23, IL-12, and type I interferon signaling pathways, blocking some of the downstream effects that drive plaque psoriasis and may contribute to psoriatic arthritis. Although TYK2 inhibitors belong to the same family as JAK inhibitors, deucravacitinib selectively binds to the regulatory domain of TYK2, differing from JAK1, JAK2, and JAK3 inhibitors. This selectivity may help explain why it does not produce many of the unwanted downstream metabolic and hematologic effects. As a result, deucravacitinib is expected to have a more favorable safety profile than oral JAK inhibitors.

In clinical trials comparing deucravacitinib with apremilast and placebo, the adverse event profiles differed between the treatments. With deucravacitinib, adverse events reported more commonly with active treatment included upper respiratory tract infections and mild increases in creatine phosphokinase, herpes infection, mouth ulceration, and folliculitis or acne. For apremilast, the most common adverse events included diarrhea, nausea, upper respiratory tract infections, and headache. Importantly, long-term safety data for both agents have not shown the adverse events that are typically associated with oral JAK inhibitors. There has been no increase in malignancies, serious infections, blood clots, or major adverse cardiovascular events. Overall, apremilast and deucravacitinib appear to be relatively safe and effective treatment options, and they are valuable additions to the therapeutic toolbox.

When initiating apremilast treatment, no baseline laboratory monitoring is required. Patients should be counseled about the possibility of gastrointestinal side effects, and the prescribing information includes a warning regarding depression and suicidal ideation with apremilast use. Depression is already common among patients with moderate to severe plaque psoriasis, so screening for mood symptoms should be part of routine care, regardless of the treatment being used. Patients with moderate to severe psoriasis are also at an increased risk for several comorbidities, including metabolic and cardiovascular diseases. Every patient should have a primary care physician and should receive routine physical examinations and appropriate baseline laboratory testing, regardless of which psoriasis medication is prescribed.

In practice, these small molecules fit well as a potential first systemic treatment option after topical therapy has failed. When a patient is ready to move beyond topical treatment, an oral medication can be a very appropriate next step before considering other systemic therapies.