Obesity and GLP-1 RAs: Why TOGETHER-PsA Matters, With Philip Mease, MD

The TOGETHER-PsA trial, which evaluated the combination of tirzepatide and ixekizumab versus ixekizumab alone in patients with active psoriatic arthritis (PsA) and obesity or overweight, did not emerge in a scientific vacuum. For Philip Mease, MD, Director of Rheumatology Research at Providence Swedish Medical Center and Clinical Professor of Medicine at the University of Washington School of Medicine, Seattle, it represents the clinical translation of a mechanistic argument he has been making through GRAPPA — the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis — for some time.

"There is a genetic proclivity to having obesity, and being obese is in and of itself a pro-inflammatory problem," Mease said. Adipocytes from obese fatty tissue produce adipokines — bioactive proteins including leptin, visfatin, and resistin — that contribute to systemic inflammation independently of the immune dysregulation that drives joint and skin disease in PsA.¹ The result is a compounding of inflammatory burden: patients with PsA and obesity carry both disease-specific inflammation and a background of adipose-tissue–mediated pro-inflammatory signaling that is not addressed by conventional or biologic DMARDs.

This is why treatment response is consistently lower in obese PsA patients across the approved biologic classes, and why obesity has emerged as one of the most clinically consequential modifiable comorbidities in the disease.² Mease noted that patients in his practice who have started GLP-1 receptor agonists for weight management are increasingly reporting not just improvement in weight-related outcomes but subjective improvement in their inflammatory disease — a pattern that has drawn rheumatologists' attention to the potential immunomodulatory effects of this drug class beyond weight loss.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, was the agent selected for TOGETHER-PsA (NCT06588296), a phase 3b randomized, multicenter, assessor-blinded, open-label trial pairing tirzepatide with ixekizumab against ixekizumab alone in adults with active PsA and BMI ≥30 kg/m² or overweight with a weight-related comorbidity. Results presented at the European Alliance of Associations for Rheumatology (EULAR), held June 3-6 in London, United Kingdom, showed that the combination achieved significantly greater ACR50 response rates as early as week 4 — before substantial weight loss had occurred — raising questions about potential direct anti-inflammatory effects of tirzepatide that extend beyond adiposity reduction.

Mease is currently leading a GRAPPA working group developing global educational materials on obesity as a driver of disease severity in PsA and psoriasis, reflecting the field's growing recognition that managing the disease requires managing the whole patient.

"Not only do patients feel better about losing weight, but their inflammation feels [lesser]," Mease said.

Mease’s disclosures include AbbVie, Acelyrin, Amgen, BMS, Century, Cullinan, Eli Lilly and Company, Inmagene, Johnson & Johnson, MoonLake Immunotherapeutics, Novartis, Pfizer, Inc., Sana, Spyre, Takeda, and UCB.

References

1. Queiro R, Lorenzo A, Tejón P, Coto P, Ballina J. Adipokines, cardiovascular risk, and therapeutic management in obesity and psoriatic arthritis. Front Immunol. 2020;11:590749. doi:10.3389/fimmu.2020.590749

2. Coates LC, Mease P, Merola JF, et al. Ixekizumab and concomitant tirzepatide achieved early disease control in adults with psoriatic arthritis and obesity/overweight: phase 3b TOGETHER-PsA trial [abstract OP069]. Ann Rheum Dis. 2026;85(suppl 1). doi:10.1136/annrheumdis-2026-eular.B.3012