CHICAGO — More patients with psoriatic arthritis responded to secukinumab than to ustekinumab after failing a TNF inhibitor, according to results from the randomized, double-blind, head-to-head AgAIN trial, which were presented at the American College of Rheumatology (ACR) 2025 Annual Meeting.

Odds of improvement on the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 28 weeks were more than three times higher in those receiving secukinumab than ustekinumab (odds ratio, 3.65; 95% CI, 1.60-8.31; P = .002). Outcomes were numerically higher for secukinumab across other primary and secondary endpoints, but there were too few participants to achieve statistical significance.

‘Results Provide a Clear, Pragmatic Message’

“Psoriatic arthritis patients who inadequately respond to TNF-alpha inhibitors represent a clinically challenging population with limited therapeutic options,” Frank Behrens, MD, of Goethe University and the Fraunhofer Institute for Translational Medicine and Pharmacology and Cluster of Excellence Immune-Mediated Diseases in Frankfurt, Germany, and his colleagues wrote, noting the high need for additional treatment options in patients with psoriatic arthritis.

“For clinicians, these results provide a clear, pragmatic message: IL [interleukin]-17 blockade remains the more potent option for joint disease compared to IL-12/23 blockade, particularly in patients who remain functionally limited after TNF inhibition,” Jose U. Scher, MD, a professor of medicine at the NYU Grossman School of Medicine, New York City, who was not involved in the study, told Medscape Medical News. 

Scher, also director of both the NYU Colton Center for Autoimmunity and the NYU Langone Health Psoriatic Arthritis Center, found the results largely unsurprising based on what’s understood about the drugs’ mechanisms.

“Secukinumab (an IL-17A inhibitor) has consistently shown stronger synovial/joint domain efficacy than ustekinumab (an IL-12/23 inhibitor) in psoriatic arthritis,” Scher said. “What makes the AgAIN trial noteworthy is both its context and design. It represents only the third head-to-head study ever conducted in psoriatic arthritis and the first comparing these two mechanisms.” The two previous ones, he said, compared the IL-17A blockade and the TNF inhibitor adalimumab.

The emergence of ustekinumab biosimilars makes cost justification essential in Germany, where this trial was conducted, Scher said, and he noted that the researchers’ use of regulator-mandated HAQ-DI improvement captures functional benefit instead of the more standard endpoints of 20% or 50% improvement in ACR response criteria or minimal disease activity outcomes.

“The finding that secukinumab achieved a significantly greater HAQ-DI response underscores a tangible improvement in disability and quality of life, with fewer discontinuations, confirming its durability of effect,” Scher said. “The use of a patient-reported functional endpoint — unusual for a head-to-head biologic trial — makes the result particularly relevant to payers and real-world decision-making, although perhaps not as relevant in the US.”

Trial Results

The researchers compared outcomes in 119 adults with psoriatic arthritis who had failed at least one TNF inhibitor and were randomly assigned to receive either 300 mg secukinumab or a 45- or 90-mg dose of ustekinumab at one of 28 study centers. Participants were mostly women (67.2%) and had an average age of 53 years, with 15% of the population older than 65 years.

All the participants had a diagnosis of active plaque psoriasis with at least one psoriatic plaque of 2 cm or greater in diameter or nail changes consistent with psoriasis. Nearly all participants had a negative rheumatoid factor (98.3%), most had evidence of current psoriasis (86.6%), and a third had evidence of juxta-articular new bone formation (34.5%). 

The 56 participants assigned to secukinumab had a tender joint count of 14.2 and a swollen joint count of 7.6, while the 63 participants assigned to ustekinumab had a tender joint count of 14.5 and a swollen joint count of 7.3. Since the dosing schedule differs between the two drugs, with many more doses required for secukinumab, participants assigned to ustekinumab received placebo injections as needed to maintain blinding.

The primary endpoint was response based on the HAQ-DI, defined as an improvement of at least 0.35 from baseline. At 28 weeks, 57.1% of participants receiving secukinumab and 27% of participants receiving ustekinumab responded to treatment. Response rates to secukinumab increased throughout the trial and remained higher than those in the ustekinumab group at all time points.

The ustekinumab group had a notably higher number of treatment discontinuations (25.4%) than the secukinumab group (3.6%). The primary reason for discontinuations, lack of efficacy, was cited by one secukinumab patient and six ustekinumab patients. 

Participants receiving secukinumab also fared better than those receiving ustekinumab on secondary endpoints. The secukinumab participants experienced a mean change of -9.6 in tender joint count compared with -7.6 in the ustekinumab group and a mean change in swollen joint count of -6.8 for secukinumab and -5.3 for ustekinumab, although statistical significance was not reported for these differences.

The Psoriasis Area and Severity Index (PASI) 90 response was higher in the secukinumab group than the ustekinumab group (48.2% vs 39.7%, respectively), as was the PASI 100 response rate (37.5% vs 27%, respectively). The rate of ACR50 responses was also higher in the secukinumab group at weeks 4, 8, 12, and 28, ending up at 48.2% in the secukinumab group and 23.8% in the ustekinumab group.

Participants receiving secukinumab also reported less fatigue and pain and greater improvement in quality of life. At 28 weeks, 71.4% of secukinumab participants and 50.8% of ustekinumab participants reported improvement on the average Functional Assessment of Chronic Illness Therapy fatigue scale. In the secukinumab group, 69.6% of participants reported an improvement of at least 15 mm on the visual analog scale, compared with 44.4% of participants in the ustekinumab group. Similarly, more participants receiving secukinumab reported improvement in their global disease activity (76.8% vs 55.6%) and in their psoriasis and arthritis disease activity (66.1% vs 46%).

Differences were more modest on the Dermatology Life Quality Index, where 53.6% of secukinumab patients and 50.8% of ustekinumab patients reported improvement. The mean change in the Psoriatic Arthritis Quality of Life score was -2.5 with secukinumab and -2 with ustekinumab. Improvements were also greater for secukinumab than ustekinumab in the mean change on the Leeds Enthesitis Index (-0.9 vs -0.5), the Leeds Dactylitis Index (-9.7 vs -7.2), and the dactylitis count (-1.3 vs -0.6).

“The AgAIN study strengthens the rationale for earlier or preferential use of secukinumab when the treatment goal is improving daily function and long-term disability, and [the results] may offer valuable support for reimbursement justification in healthcare systems sensitive to drug costs,” Scher said.

“Beyond Germany, the findings reinforce a phenotype-driven treatment strategy — favoring IL-17 inhibition for patients with enthesitis, axial symptoms, or high inflammatory burden, and reserving IL-12/23 agents for skin-dominant or IBD [inflammatory bowel disease]-associated cases,” he said. “As one of only a handful of direct comparative studies in PsA [psoriatic arthritis], AgAIN provides real-world evidence that IL-17 blockade not only improves inflammation but also restores function, bridging clinical efficacy with regulatory and economic relevance.”

The researchers did not find any new safety signals, with treatment-emergent adverse events reported by 76.8% of patients taking secukinumab and 81% taking ustekinumab. Discontinuations resulting from adverse events occurred among 3.6% of the secukinumab group and 12.7% of the ustekinumab group. Among the 8.9% of serious adverse events in the secukinumab group, two (esophageal candidiasis and pneumonia) were suspected to be related to the drug. None of the 3.2% of serious adverse events in the ustekinumab group were deemed related to the drug.

The research was funded by Novartis Pharma. Behrens reported consulting and speaking honoraria from AbbVie/Abbott, Acelyrin, Amgen, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Eli Lilly, GlaxoSmithKline, Janssen-Cilag, MoonLake Immunotherapeutics, Novartis, Pfizer, Sandoz, and UCB Pharma. Three of his coauthors are Novartis employees, and one reported consulting and speaking honoraria from AbbVie/Abbott, Alfasigma Global, Eli Lilly, and Novartis. Scher reported having financial relationships with Johnson & Johnson, UCB Pharma, BMS, Oruka Therapeutics, Novartis, and Pfizer.

Tara Haelle is a science/health journalist based in Dallas.