Methotrexate May Enhance Pegloticase Response in Gout Save

For patients with gout exacerbations while on pegloticase (Krystexxa), adding methotrexate may help reduce uric acid levels, researchers suggested at the European League Against Rheumatism (EULAR) virtual meeting.

In a small open-label study of 14 patients experiencing acute gout attacks, use of the pegloticase/methotrexate combination reduced uric acid levels to near undetectable levels in 11 patients, reported John Botson, MD, medical director of Orthopedic Physicians Alaska in Anchorage. He noted that this was far below the 5 mg/dL level recognized as the threshold for development of inflammation that causes gout attacks.

Although pegloticase has been approved since 2010, "it hasn't gotten a lot of traction" because the effectiveness is attenuated by development of anti-drug antibodies and infusion reactions, Botson told MedPage Today. He said the study, which will be followed by a larger controlled clinical trial, follows case reports suggesting that methotrexate might help overcome the problems.

Pegloticase (pegylated uricase) is the only FDA-approved medication for uncontrolled gout. When used as monotherapy in phase III trials, 42% of patients responded -- i.e., were able to reduce uric acid to less than 6.0 mg/dL during treatment months 3 and 6. About 26% of patients had infusion-related reactions.

"As is often done for other rheumatic diseases treated with biologics, some physicians are using immunomodulation therapy with pegloticase," Botson noted. "Recent case series have supported the use of pegloticase/methotrexate co-therapy, with reported responder rates of 80% to 100%. However, the cases had varying doses, timing, and routes of administration."

The study reported at the EULAR meeting showed an efficacy of 78.6%.

"Pegloticase is an interesting drug, because if it works in patients, its success in lowering uric acid is dramatic," he continued. "But if it doesn't work, it has almost no impact, and you then know almost immediately."

But one rheumatologist not connected with the study had words of caution about the drug.

Sara Tedeschi, MD, of Brigham and Women's Hospital/Harvard Medical School in Boston, told MedPage Today, "Rheumatologists have real concerns about infusion reactions and anaphylaxis with pegloticase. We are especially worried if patients miss dosing because that can result in anti-drug antibody development, and, in turn, anaphylaxis with the next dose.

"Pegloticase is also very expensive, which is one reason it is unlikely it will gain much traction until the ongoing phase III trial can show efficacy. It will also be important to know whether methotrexate prevents the formation of anti-pegloticase antibodies and whether it increases serum levels of pegloticase."

As well, she added, the population appropriate for pegloticase is small: those few patients who don't respond or are contraindicated for other urate-lowering medications. Guidelines from the American College of Rheumatology (released in draft form in late 2019 and finalized this month) relegate pegloticase to last-line treatment for patients with high serum urate.

In the study, the mean serum uric acid level was 8 mg/dL at baseline, and after 2 weeks of treatment, the level was reduced to a mean of 1 mg/dL. When patients who did not respond to therapy were removed from the study after 12 weeks, the mean level of uric acid in the remaining patients reached undetectable levels, Botson said.

He explained that pegloticase reduces the serum uric acid level, making it possible for other therapies to then maintain the reduction, but patient compliance is often problematic, which is the main reason that gout attacks may recur.

"An increased proportion of patients treated with pegloticase and methotrexate maintained a therapeutic response during month 6 compared with previously reported rates for pegloticase alone," Botson said. "Results of the current trial are in agreement with two recent case series, and no new safety concerns were identified."

"A definitive randomized, double-blinded trial evaluating pegloticase with methotrexate versus pegloticase with placebo is needed to confirm our results and is ongoing," he added, referring to the MIRROR RCT study, which is planning to enroll 135 participants.

In the open-label trial Botson reported at the EULAR meeting, patients underwent a 2-week screening program, followed by a 4-week methotrexate run-in phase in which 15 mg of methotrexate was taken weekly, followed by a 52-week period in which pegloticase was given at 8 mg intravenously every 2 weeks along with oral methotrexate 15 mg every week.

"Patients with uncontrolled gout -- visible tophi, chronic arthropathy, and/or frequent gout attacks -- have serum uric acid levels chronically above 6.8 mg/dL, the plasma solubility limit of uric acid," Botson said. "The 2016 EULAR and 2012 [American College of Rheumatology] guidelines recommend that these patients maintain serum uric acid below 5 mg/dL."

"A small proportion of patients do not respond to or cannot tolerate oral urate-lowering therapies, and approximately 10% of patients with gout have chronic tophaceous disease," he continued. "Patient quality of life is severely impacted by treatment-failure gout, with significant physical disabilities playing a large role."

Disclosures

The study was supported by Horizon Therapeutics. Botson disclosed financial relationships with Horizon Therapeutics, Radius Health, Celgene, Eli Lilly, Mallinckrodt, Novartis, and Pfizer.  Tedeschi disclosed no relevant relationships with industry.

Source Reference: Botson J, et al "Pegloticase Response Improvement by Co-treatment with Methotrexate: Results From the Mirror Open-label Clinical Trial in Patients with Uncontrolled Gout" EULAR 2020; Abstract THU0416.