Pegloticase (pegylated uricase enzyme) is the only medical therapy indicated for patients with refractory gout and those who can’t tolerate urate-lowering therapy. Unfortunately, the development of antidrug antibodies can require premature discontinuation of pegloticase.

Preliminary clinical trials and case series support using an immunomodulator such as methotrexate in conjunction with pegloticase to increase urate-lowering response durability. Now, investigators at 42 U.S. sites have conducted the first large, randomized, double-blind, placebo-controlled trial of this approach.

In Arthritis & Rheumatology, they report week 24 results of a 52-week trial. That data confirms the superiority of pegloticase plus methotrexate co-therapy to pegloticase monotherapy. It also provides evidence that methotrexate decreases pegloticase immunogenicity by attenuating antidrug antibody development.

Michael E. Weinblatt, MD, co-director of Clinical Rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital and a senior investigator of methotrexate in rheumatic diseases, served as senior author of the report.

Methods

The MIRROR trial (Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase) began with two weeks of methotrexate along with folic acid 1 mg/day. Patients who tolerated methotrexate were randomly assigned 2:1 to receive pegloticase plus methotrexate or pegloticase plus placebo. Patients were required to have a glomerular filtration rate of >40 to enroll in the study.

Randomized participants first entered a four-week run-in period, taking folic acid and either methotrexate or placebo. 145 patients (96 receiving methotrexate, 49 receiving placebo) then entered the 52-week treatment period. Pegloticase 8 mg was given biweekly from day 1 to week 50 (26 infusions), folic acid was continued, and the methotrexate dosage was 15 mg/week.

If a patient had serum urate levels >6 mg/dL at two consecutive visits beginning at week 2, treatment was discontinued, but the patient remained in the study under observation. 73% of patients on methotrexate and 39% of those on placebo completed treatment through week 24, the time point for this analysis.

Efficacy

The primary efficacy endpoint was the proportion of patients with treatment response, defined as serum urate <6 mg/dL for ≥80% of visits during weeks 20–24. That endpoint was met: 71% of patients in the pegloticase plus methotrexate group met response criteria during month 6 compared with 39% in the pegloticase plus placebo group (P<0.0001).

The combination regimen also outperformed monotherapy concerning:

• Mean change from baseline in serum urate through week 24: −7.66 vs. −5.23 mg/dL (P<0.0001)

• Median time to two consecutive serum urate measurements >6 mg/dL: Not estimable (to few patients discontinued) vs. 69 days (P<0.0001)

• Complete tophus resolution at week 24: 35% versus 14% of patients (P=0.0434)

Safety

Reports of adverse events (AE) and serious AEs were comparable between treatment groups, and there was no new safety signal. Gout flare was the most common AE in both groups.

The incidence of infusion reactions was considerably lower with combination therapy (4.2%) than monotherapy (4.2% vs. 30.6%; P<0.001).

Immunogenicity

The immunogenicity of pegloticase was lower in the presence of methotrexate:

• The proportion of patients with postbaseline anti–polyethylene glycol (PEG) antibody positivity: 23% in the pegloticase plus methotrexate group vs. 50% in the pegloticase plus placebo group

• Median time to positive anti-PEG antibody response: Not estimable vs. 155 days (P=0.0008)

In both treatment groups, fewer patients with anti-PEG antibody positivity were treatment responders during month 6 than patients without the antibodies (55% vs. 81%, respectively, in the methotrexate group; 25% vs. 58%, respectively, in the placebo group).