Rethinking the Role of Orals: Where TYK2 Inhibitors Fit in Psoriasis Management

At the Fall Clinical 2025 session, “Setting Sights Higher With New and Emerging TYK2 Inhibitors for Psoriasis,” April W. Armstrong, MD, MPH; Bruce Strober, MD; and Ronald Vender, MD, explored the evolving role of TYK2 inhibitors within an increasingly effective but injectable-dominated treatment landscape. The discussion centered on patient preferences, mechanism-driven selectivity, and a growing oral therapy pipeline that may shift long-standing practice paradigms.

Dr Armstrong opened the session with a case of a 47-year-old man with moderate-to-severe plaque psoriasis, including scalp involvement. Although initially managed with etanercept, he later requested a more convenient, oral therapy due to frequent travel and lifestyle factors. Dr Armstrong initiated treatment with deucravacitinib 6 mg daily, resulting in substantial improvement across multiple sites by 4 months.

“This was very encouraging for him,” Dr Armstrong said. “He’s still on this medication and doing well.”

The panel emphasized that while biologics remain highly effective, unmet needs persist. “Patients often just prefer oral medications,” said Dr Vender. “Some are needle phobic. Others are already taking pills for other conditions—it’s just easier to add one more.”

Referencing dermatologist surveys, Dr Vender noted that oral IL-23 and IL-17 agents were top choices for future development, even though TYK2 inhibitors like deucravacitinib remain under-recognized. “TYK2 is part of the JAK family,” he explained, “but it’s the cousin that can do no harm.”

Dr Strober emphasized that mechanism of action is key to understanding TYK2’s clinical potential. TYK2 mediates signaling for IL-12, IL-23, and type I interferons—all relevant to psoriasis pathogenesis—without engaging the broader hematopoietic and metabolic pathways tied to JAK1/2/3.

“Why can we elevate systemics like TYK2 inhibitors?” Dr Strober asked. “Because modern orals deliver better efficacy without compromising safety.”

Deucravacitinib’s allosteric inhibition of TYK2’s regulatory domain preserves specificity, avoiding cross-activation of Janus kinase pathways and reducing off-target effects. “It’s like the cousin in the family who doesn’t cause trouble,” Dr Vender said.

Dr Strober referenced the International Psoriasis Council’s revised classification, which simplifies treatment candidacy into topical-appropriate vs systemic-appropriate. Systemics are indicated not just for patients with ≥10% body surface area (BSA) involvement, but also those with:

• High-impact sites (scalp, face, palms, soles, nails, genitals)
• Topical failure
• Quality-of-life limitations

“Importantly, oral therapies are systemic therapies,” Dr Strober noted. “So, when you’re thinking about what’s next after topicals, an oral agent like deucravacitinib is a very appropriate next step.”

Dr Strober presented data from the CorEvitas registry, showing that patients who achieved BSA clearance of ≤1% were less likely to develop psoriatic arthritis (PsA). The data suggest that stricter treatment targets may help mitigate systemic inflammation and reduce risk of associated comorbidities.

“This was the first demonstration that hitting a treatment target like 1% BSA or less actually reduces the risk of PsA,” Dr Strober said. “It’s a call to treat beyond just symptom control.”

Panelists discussed how the field has evolved from legacy oral agents (methotrexate, cyclosporine, acitretin) to more targeted and tolerable options. The introduction of apremilast a decade ago paved the way for more sophisticated small molecules.

Deucravacitinib demonstrated high efficacy in trials, with Psoriasis Area and Severity Index 75 rates around 58% at 16 weeks and maintenance of response through 1 year and beyond. New agents in the TYK2 pipeline include:

• ESK-001, another selective TYK2 inhibitor
• Icotrokinra, an oral IL-23 receptor blocker anticipated to receive approval in the next year

“Now we have oral agents that not only work but work well and work safely,” Dr Strober emphasized.

In patient-preference studies, most individuals with moderate-to-severe psoriasis preferred oral therapy over injectables if efficacy and safety were comparable. “Even if patients are happy with their shot, 9 out of 10 said they’d switch to an oral if it worked just as well,” Dr Vender noted.

Patients also report anxiety around injection timing, even with infrequent dosing. For many, a daily pill feels more natural than quarterly injections, particularly in moderate cases.

“Oral therapies reduce anxiety and improve compliance for many patients,” Dr Vender said. “Especially when they’re already taking other medications.”

TYK2 inhibitors are carving out a distinct role in psoriasis care by offering an oral, mechanism-targeted, safe systemic option that aligns with both clinical efficacy goals and patient preferences. With new agents on the horizon and increasing comfort with allosteric inhibition, dermatologists have an opportunity to set their sights higher, and meet their patients there.

Reference
Armstrong A, Strober B, Vender R. Setting sights higher with new and emerging TYK2 inhibitors for psoriasis. Presented at: 2025 Fall Clinical Dermatology Conference. October 23–26, 2025; Virtual.