Methotrexate Enhances Pegloticase Response in Uncontrolled Gout

In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.

In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).

“This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” study investigator John K. Botson, MD, RPh, CCD, said in reporting the trial’s findings.

This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.

“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.

Rationale for Using Methotrexate

“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Botson, a rheumatologist in private practice from Anchorage, Alaska.

“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”

One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.

Dr John Botson

However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.

“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Botson.

In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).

Study Design and Results

A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.

The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Botson explained.

The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.

Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.

The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Botson reported.

The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.

There was a “dramatic resolution of tophaceous deposits,” Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).

One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.

In Patients With Renal Insufficiency

Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.

“That’s been a debate that we’ve had in this study and others,” said Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.

“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.

Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx, Horizon, Eli Lilly, and Novartis.

This article originally appeared on, part of the Medscape Professional Network.

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