TOGETHER-PsA:Tirzepatide + Ixekizumab Rapidly Improves PsA Disease Control With Obesity/Overweight

Adding tirzepatide (TZP), a GLP-1/GIP receptor agonist, to ixekizumab (IXE) produced superior disease control compared with IXE alone as early as week 4 in patients with active psoriatic arthritis (PsA) and obesity or overweight, according to phase 3b results from the TOGETHER-PsA trial presented at the European Alliance of Associations for Rheumatology (EULAR), held June 3-6 in London, United Kingdom.¹

Investigator Laura C. Coates, MBChB, PhD, NIHR Research Professor and Associate Professor of Rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, and Honorary Consultant Rheumatologist at Oxford University Hospitals, presented the data and sat down with RheumatologyLive during the congress to go over its clinical implications.

TOGETHER-PsA (NCT06588296) was a randomized, multicenter, assessor-blinded, open-label phase 3b trial enrolling adults with active PsA and obesity (BMI >30 kg/m²) or overweight (BMI ≥27 to <30 kg/m²) plus ≥1 additional weight-related comorbidity. Patients were randomized 1:1 to IXE+TZP (n = 138) or IXE alone (n = 133), with both agents dosed per the US FDA label and all patients receiving individualized counseling for diet and exercise. Clinical assessments were conducted at weeks 4, 12, 24, and 36.¹

The study population was clinically complex. Mean (standard deviation [SD]) BMI was 37.2 (SD, 8.0) kg/m² for IXE+TZP and 38.4 (SD, 7.4) for IXE; mean (SD) tender joint count was 25.5 (SD, 15.8) and 27.9 (SD, 17.7), swollen joint count was 11.9 (SD, 9.0) and 12.8 (SD, 10.6), and mean (SD) DAPSA was 47.2 (SD, 22.7) and 55.4 (SD, 24.3), respectively. Prior advanced therapy had been received by 64.5% and 61.7% of patients. Patients were predominantly female (70.3% IXE+TZP; 69.2% IXE).¹

The primary endpoint — achievement of both ACR50 and ≥10% weight reduction at week 36 — was met by 31.7% of IXE+TZP patients versus 0.8% of IXE patients (P <.001).¹ Given that ixekizumab alone does not produce clinically meaningful weight loss, this endpoint was structurally designed to favor the combination arm, as Coates acknowledged. The more clinically informative question for rheumatologists concerned the secondary outcomes in joint disease.

ACR50 response alone was significantly greater with IXE+TZP versus IXE from week 4 onward: 11.1% versus 3.9% at week 4 (P = .029), increasing to 33.5% versus 20.4% at week 36 (P = .02). ACR20 and ACR70 showed similar patterns. Improvements were observed across ACR component scores as early as week 4, including mean change from baseline (standard error [SE]) in swollen joint count (IXE+TZP: −5.1 [SE, 0.57]; IXE: −3.7 [SE, 0.78]), tender joint count (IXE+TZP: −8.5 [SE, 0.98]; IXE: −7.7 [SE, 1.05]), and HAQ-DI (IXE+TZP: −0.3 [SE, 0.03]; IXE: −0.2 [SE, 0.03]).¹

DAPSA mean change from baseline at week 4 was −17.5 (SE, 1.42) for IXE+TZP and −14.1 (SE, 1.66) for IXE, with significantly greater improvement in the IXE+TZP arm from week 12 through week 36 (P <.001). DAPSA low disease activity or remission rates were 17.2% versus 9.9% at week 4 and 39.9% versus 26.1% at week 36. Minimal disease activity (MDA) at week 36 was achieved by 26.3% versus 15.3% (P = .026).¹ Early improvements in PhGADA, PaGADA, pain VAS, and hsCRP were also observed from week 4 in both arms. Adverse events were mostly mild to moderate and consistent with the known profiles of each agent; the most frequently reported were nausea, diarrhea, constipation, and injection site reaction.¹

"We can see a very early separation at week 4 — by that point patients are already losing weight, but only around 2.5% of their body weight, so not a huge amount," Coates said. "The question has been whether the drug is having a more direct effect... we know it's going to reduce inflammation by reducing obesity, because obesity is inflammatory, but here we're seeing improvement in ACR50 before we've got much weight loss." She stressed that further research is necessary to determine how much of the effect is due directly to tirzepatide’s potential anti-inflammatory action or not.

Coates reports disclosures including AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Enlivex, Janssen, Moonlake, Novartis, Oruka, Pfizer, Proximi-T, Sitryx, Takeda, and UCB.

References

1. 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

2. Gossec L, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis. 2024;83(6):706–719.