DENVER — Adding the weight-loss drug tirzepatide to the biologic ixekizumab significantly improved joint and skin outcomes in patients with psoriatic arthritis (PsA) and overweight or obesity, early results from a randomized phase 3b trial found. 

A total of 31.7% of patients reached at least 50% improvement in PsA symptoms according to American College of Rheumatology response criteria (ACR50) and at least a 10% weight reduction by week 36 vs 0.8% of the ixekizumab-alone group (P < .001), Joseph F. Merola, MD, professor and chair of dermatology, University of Texas Southwestern Medical Center, Dallas, reported in a late-breaker session here at the American Academy of Dermatology (AAD) 2026 Annual Meeting. In the combination therapy group, 33.5% reached ACR50 (a key secondary endpoint) vs 20.4% in the ixekizumab-only group (P < .05).

“This represents an important paradigm shift as we think about how other combination therapies have not made a major dent in our ability to move ACR50 and other endpoints. We’re seeing clear improvement here,” Merola said. He also highlighted similar findings in a related trial of patients with psoriasis. 

For the 52-week TOGETHER-PsA trial, researchers enrolled 271 patients — 138 for the those on the combination of tirzepatide (Zepbound/Mounjaro), a GLP-inhibitor, and ixekizumab (Taltz), an interleukin-17A inhibitor, and 133 for ixekizumab alone — with PsA and either overweight and at least one weight-related comorbidity or obesity (69.7% female; mean BMI, 37.6). Doses of ixekizumab were 80 mg monthly after a starting dose of 180 mg, and tirzepatide was increased from 2.5 mg to 15 mg weekly over time.

Merola noted that the study population was especially difficult to treat because of factors such as the high BMI and high level of previous advanced treatment. However, he noted that only 4.4% had moderate-to-severe psoriasis.

The change in both weight and PsA symptoms was the primary endpoint. Among PsA-related secondary endpoints, 71.3% in the combo group reached ACR20 vs 48.5% of the ixekizumab-only group (P < .001); and 26.3% of the combo group reached minimal disease activity vs 15.3% of the ixekizumab-only group (P < .05).

Merola noted that ACR50 began to improve as early as week 4 “before there’s been any meaningful weight change in the groups,” a sign that “maybe there’s impact beyond just weight loss.”

Patient-reported outcomes — per measures of physical function, fatigue, mental health/function, and physical health/function — were better in the combination therapy group than the ixekizumab-only group, as were psoriasis outcomes. 

As for dermatologic outcomes (secondary endpoints) in the study, simultaneously published in Arthritis & Rheumatology, there was a significant difference in the change from baseline in absolute Psoriasis Area and Severity Index ( PASI) scores among those on the combination vs those on ixekizumab alone (P < .01). In addition, among those with body surface area ≥ 3% at baseline, response rates among those on combination therapy were “numerically higher” than those on ixekizumab alone, for PASI75, PASI90, and PASI100. 

Adverse effects were “generally aligned with established drug profiles.” Tirzepatide is linked to various gastrointestinal effects, and patients on combination therapy were much more likely to experience nausea, diarrhea, constipation, and vomiting. About 5% in both groups discontinued treatment because of treatment-emergent adverse effects. 

Results in Patients With Psoriasis 

Merola also previewed 36-week findings from the sister TOGETHER-PsO trial, which enrolled patients with moderate-to-severe plaque psoriasis and obesity or overweight. Among 138 who took the combination therapy, 27.1% reached the primary endpoint — a PASI100 and at least 10% weight reduction — vs 5.8% of the ixekizumab-only group (P < .001.)

Also, 40.6% of the combination therapy group reached PASI100 vs 29.0% of the ixekizumab-only group.

Rheumatologist Eric M. Ruderman, MD, professor of medicine at Northwestern University, Chicago, who was familiar with the findings but did not take part in the study, said the early improvement in PsA symptoms at week 4 was revealing. “There's something unique to the GLP-1 that improved the joint symptoms that was, at least in part, independent of weight loss,” he told Medscape Medical News.

Ruderman added that the findings fit a pattern clinicians have been observing informally. “We've seen anecdotal reports from patients for quite some time now that inflammatory arthritis, whether it’s psoriatic arthritis or rheumatoid arthritis, is better in people on GLP-1s,” he said. 

He didn’t suggest that all PsA patients should take GLP-1s but noted that there’s “an added benefit there” if they’re appropriate candidates for treatment. 

As for cost, both drugs are expensive. And “you’ve got to jump through some hoops to get approved prior authorization” for biologics, Ruderman said, although “it's not awful.”

The study was funded by Eli Lilly, which makes both tirzepatide and ixekizumab. Merola disclosed relationships with Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, AbbVie, Dermavant, Eli Lilly, Moonlake, Novartis, Janssen, Oruka, UCB, Sanofi, Regeneron, Sun Pharma, Galderma, and Pfizer. Other authors report multiple and various disclosures, including relationships with and employment by Eli Lilly. Ruderman disclosed relationships with Eli Lilly, Janssen, AbbVie, Merck, and Novartis.