Study Demonstrates Increased Benefits of Pegloticase and Methotrexate Cotherapy for Uncontrolled Gout


At month 12, response rate was significantly higher in patients receiving pegloticase and methotrexate when compared with concomitant placebo.

Results of the 12-month MIRROR randomized controlled trial (RCT) supported pegloticase injection plus methotrexate for the treatment of uncontrolled gout, according to a study published in ACR Open Rheumatology.1 The resolution of tophi continued to increase through week 52, which indicated a continued benefit beyond the initial 6-month trial.

Study Demonstrates Increased Benefits of Pegloticase and Methotrexate Cotherapy in Uncontrolled Gout

Kenneth Saag, MD

Credit: The University of Alabama at Birmingham

As pegloticase is generally the last treatment option for this patient population, achieving sustained lowered urate levels is critical. Previous research has demonstrated the benefits of concomitant immunomodulation therapy, which increased biochemical response rates and decreased infusion reaction (IR) rates.2

“Publication of these 12-month data reinforces key findings shown at month 6, including the durability of urate-lowering response, reduced infusion reactions and reduced immunogenicity of pegloticase when co-administered with methotrexate,” stated Kenneth Saag, MD, director of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

The phase 4 randomized, double-blind, parallel-group, placebo-controlled, multicenter study evaluated the efficacy, safety, immunogenicity, and pharmacokinetics of concomitant pegloticase and methotrexate treatment in patients with uncontrolled gout. Uncontrolled gout was defined as a serum urate (SU) level of ≥7 mg/dl, failure or intolerance to oral urate-lowering therapy, and the presence of ≥1 gout symptoms.

Patients were randomized 2:1 to receive pegloticase (8 mg infusion every 2 weeks) with blinded methotrexate (oral 15 mg/week) or placebo for 52 weeks. Efficacy endpoints included the proportion of patients with resolution of ≥1 tophi in the intent-to-treat (ITT) population, mean SU reduction (ITT), time to pegloticase discontinuation, and the proportion of responders (ITT) at months 6, 9, and 12. Response was defined as SU level <6 mg/dl for ≥80% of the examined month. Safety was determined using laboratory values and adverse events.

In total, 152 patients were included in the trial, of which 100 were placed in the methotrexate cohort and 52 were randomized to placebo cotherapy. Most patients were male (88.8%) and White (69.1%) with a median age of 54.7 years and a median disease duration of 10.8 years.

At month 12, response rate was significantly higher in patients treated with concomitant methotrexate when compared with placebo (60% [n = 60/100] vs 30.8% [n = 16/52], respectively). The cotherapy cohort also reported fewer SU discontinuations (22.9% [n = 22/96] vs 63.3% [n = 31/49], respectively). Further, complete resolution of ≥1 tophi occurred in 53.8% of the methotrexate group compared with 31.0% of those receiving placebo at the end of the study (95% confidence interval [CI]: 1.2%-44.4%, P = 0.048), which showed greater improvements when compared with week 24 (34.6% vs 13.8%, respectively).

Immunogenicity and pharmacokinetic data were consistent with initial 6-month observations, which reported increased exposure and lower immunogenicity of pegloticase when given with concomitant methotrexate, as well as a comparable safety profile. Although most patients in both treatment arms experienced ≥1 adverse events (84.4% in the methotrexate group vs 95.9% in the placebo group), most adverse events were rated as mild to moderate in severity. The most common adverse events were gout flare, musculoskeletal-related issues, infection, and gastrointestinal disorders. No IRs occurred after 24 weeks.

Investigators noted the study did not assess optimum pegloticase therapy duration, the use of oral urate-lowering therapy following pegloticase discontinuation, or immunomodulation treatment with agents other than methotrexate. Further, it did not evaluate methotrexate toxicities specific to patients with uncontrolled gout.

“Given the damage that uncontrolled gout can cause to bones and joints, as well as its significant impact on a person’s daily life, it is crucial to provide data that demonstrate how a co-treatment approach can quickly lower a patient’s serum urate level and sustain it over time,” concluded Brian LaMoreaux, MD, MS, senior medical director, Horizon. “As clinicians, when we commit ourselves to improving the quality of care provided to people who live with uncontrolled gout, we’re also working to improve their quality of life.”


  1. Botson JK, Saag K, Peterson J, et al. A Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving Pegloticase: 12-Month Findings [published online ahead of print, 2023 Jun 29]. ACR Open Rheumatol. 2023;10.1002/acr2.11578. doi:10.1002/acr2.11578
  2. Botson JK, Tesser JR, Bennett R, et al. Pegloticase in combination with methotrexate in patients with uncontrolled gout: a multicenter, open-label study (MIRROR). J Rheumatol 2021; 48: 767– 74.
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