Pegloticase + MTX for Gout Not Effective After Pegloticase Monotherapy

New research has confirmed low response rates and higher infusion reaction (IR) rates of pegloticase plus methotrexate (MTX) in patients with gout following failed monotherapy, highlighting the importance of initiating immunomodulation prior to first pegloticase exposure.1

“Pegloticase is often the last treatment option for patients with uncontrolled or refractory gout. However, antidrug antibody development (ADA) can lead to loss of serum urate (SU)–lowering response and put patients at risk for IRs. Evidence from both real-world and clinical trial data support the use of immunomodulation as cotherapy to pegloticase to increase urate-lowering response rate and minimize IR risk2,” lead investigator Orrin M. Troum, MD, Division of Rheumatology, University of Southern California Keck School of Medicine and Providence Saint John’s Health Center, and colleagues wrote.1

The small open-label ADVANCE trial enrolled patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate–lowering therapy failure or intolerance, and ≥1 gout sign or symptom) whose disease previously stopped responding to pegloticase monotherapy. Patients with moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m2 were excluded from the trial. Participants first completed a 6-week subcutaneous MTX run-in (25 mg per week) then entered a 24-week pegloticase (at 8 mg biweekly) plus MTX treatment period. The trial’s primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20–24). Investigators assessed adverse events (AEs) and completed laboratory monitoring for safety.1

Troum and colleagues followed 11 participants with gout who began pegloticase plus MTX treatment. These participants were mostly male (91%), had a mean age of 58.6 years (standard deviation [SD], 11.3), mean SU levels of 8.5 mg/dL (SD, 3.2), and 91% had tophaceous gout. Participants had received previous pegloticase courses ranging from 2 to 27 infusion, with the last infusion administered at a mean of 3.7 years (SD, 2.4) prior to the trial.1

The investigators found that 1 patient (9%) maintained their response during month 6. On the other hand, the other 10 patients prematurely discontinued treatment due to loss of SU lowering (n = 8) and IRs (n = 2). Eight patients (73%) experienced at least 1 AE, most commonly gout flare. All AEs were mild or moderate.1

“In conclusion, ADA attenuation with MTX has emerged as an important advancement for improving both the efficacy and safety of pegloticase. These results of the ADVANCE open-label trial demonstrate the challenge of overcoming established ADAs against pegloticase in patients with previous loss of urate-lowering response. Given that pegloticase is often the last treatment option for patients with uncontrolled gout, maximizing treatment benefit is of the utmost importance in this patient population. The current study supports the importance of MTX coadministration during initial pegloticase treatment course in achieving this in patients without contraindication to MTX,” Troum and colleagues concluded.1

REFERENCES

1. Troum OM, Botson JK, Obermeyer K, et al. Pegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial. ACR Open Rheumatol. Published online January 23, 2025. doi.org/10.1002/acr2.11789

2. Botson JK, Saag K, Peterson J, et al. A randomized, placebo-controlled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: primary efficacy and safety findings. Arthritis Rheumatol 2023; 75(2): 293–304