Joints, Weight, and Mental Health: Ixekizumab + Tirzepatide for PsA, With Joseph Merola, MD

Combination treatment with ixekizumab (Taltz) and tirzepatide (Zepbound) produced superior joint outcomes compared with ixekizumab alone in a population of patients with difficult-to-treat psoriatic arthritis (PsA) and excess body weight.

Joseph F. Merola, MD, MMSc, FAAD, professor and chair of the Department of Dermatology and professor of internal medicine in the Division of Rheumatic Diseases and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern Medical Center in Dallas, presented these findings, from the TOGETHER-PsA trial, as a late-breaking oral at the 2026 American Academy of Dermatology (AAD) Annual Meeting held in Denver, Colorado, from March 27-31. The results were simultaneously published in Arthritis & Rheumatology.

TOGETHER-PsA (NCT06588296) was a 52-week, randomized, open-label, assessor-blinded phase 3b trial enrolling 271 adults with active PsA and obesity (BMI ≥30 kg/m²) or overweight (BMI 27–29.9 kg/m²) with at least 1 weight-related comorbidity. The trial population reflected the clinical reality that an estimated 65–82% of patients with PsA in the United States meet overweight or obese criteria. Participants had a mean age of 55.0 years (SD, 11.9), mean baseline weight of 106.1 kg (SD, 24.8), and mean BMI of 37.6 kg/m² (SD, 7.6). Both arms received diet and exercise counseling; patients were randomized 1:1 to ixekizumab plus tirzepatide or ixekizumab alone.

In an interview onsite with HCPLive, Merola emphasized several features of the enrollment that distinguished TOGETHER-PsA from earlier PsA trials. Approximately 70% of participants were women — a group he noted is historically harder to treat in PsA — and more than 60% had prior exposure to at least 1 advanced therapy, with at least 20% having received 2 or more prior treatments. A substantial proportion carried BMI levels in the class III obesity range. Despite this treatment-experienced, high-burden population, the combination arm still demonstrated meaningful separation from monotherapy across multiple endpoints.

The composite primary endpoint — simultaneous achievement of ACR50 and ≥10% weight reduction at week 36 — was met by 31.7% of patients on combination therapy versus 0.8% on ixekizumab alone (P <.001). On ACR50 alone, combination therapy achieved 33.5% versus 20.4% (P = .02). Merola highlighted the early onset of separation between arms — detectable by week 4, before clinically meaningful weight loss had accrued — as mechanistically provocative, suggesting tirzepatide may act through direct modulation of the adipokine and cytokine milieu that drives psoriatic inflammation rather than exclusively through weight reduction. Consistent improvements were observed across joint inflammation, pain, physical function, and health-related quality of life.

Among the secondary findings Merola called out specifically, the improvement in the SF-36 mental component score (MCS) stood out as clinically meaningful. Mental health measures frequently remain static across PsA clinical trial programs — either because they are not collected, or because the data are not highlighted on the assumption they will not change. In TOGETHER-PsA, the MCS did improve, a finding Merola attributed to the multidomain nature of the intervention: simultaneous improvement in skin, joints, and body weight appears to carry a psychological benefit that single-domain therapy may not replicate. He raised the additional possibility, acknowledged as speculative, that reduced systemic inflammation may itself carry direct central nervous system effects. On safety, the combination regimen was well tolerated. GI adverse events led to discontinuation in 2.9% of patients in the combination arm versus 1.0% on ixekizumab monotherapy — a rate Merola cited as reassuring, noting that the great majority of patients remained on treatment and derived benefit across multiple domains.

“This is not something where patients are running for the hills because of GI side effects, just the opposite. The vast majority of patients stayed in this study and saw multiple benefits. I think that's important to highlight,” Merola emphasized.

Merola also addressed the question of who should prescribe GLP-1/GIP receptor agonists in this setting. He framed the minimum expectation as ensuring dermatologists and rheumatologists initiate the conversation with patients about concurrent use, leaving the prescribing decision to individual clinician comfort — whether that means owning the prescription directly or co-managing with endocrinology or primary care. Week 52 data from TOGETHER-PsA and the companion TOGETHER-PsO skin trial are forthcoming.

Merola’s disclosures include Amgen, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Moonlake, Novartis, Janssen, Oruka, UCB, Sanofi, Regeneron, Sun Pharma, Galderma, Biogen and Pfizer.

References

1. Merola JF, et al. Ixekizumab with tirzepatide achieved greater disease control than ixekizumab alone in adults with psoriatic arthritis and overweight or obesity: results from a randomized clinical trial. Arthritis Rheumatol. 2026. doi:10.1002/art.70134

2. Eli Lilly and Company. Phase 3b data presented at AAD Annual Meeting show Lilly's Taltz (ixekizumab) plus Zepbound (tirzepatide) delivered superior efficacy for adults with psoriatic arthritis and obesity. Press release. March 28, 2026. https://investor.lilly.com/news-releases/news-release-details/phase-3b-data-presented-aad-annual-meeting-show-lillys-taltz. Accessed March 28, 2026.