Combination Methotrexate and Pegloticase Therapy Proven More Effective Than Monotherapy in Patients With Gout

Patients maintained therapeutic response at 6 months when treated with a combination of methotrexate (MTX) and pegloticase (pegylated uricase), according to a study published in the Journal of Clinical Rheumatology.¹ As treatment options for gout are limited, these results are promising, especially when compared with the 42% response rate for patients receiving pegloticase alone.

“In autoimmune conditions, if disease-modifying anti-rheumatic drugs (DMARDs) are ineffective, a biologic can be initiated with the DMARD continuing in combination,” stated investigators. “The absence of antidrug antibodies (ADAs) to biologics correlates with longer therapy duration, better efficacy response, and fewer Adverse events (AEs), including infusion-related reactions (IRs).”

In this multicenter, open-label efficacy and safety study (NCT03635957), investigators analyzed the efficacy of pegloticase, a medication that is highly effective in lowering serum uric acid (sUA) levels by converting uric acid to allantoin. The study was conducted at 6 sites in the United States. Eligible patients were between 18 and 65 years of age and had a history of uncontrolled gout, defined as an sUA ≥ 6 mg/dL, with an inability to maintain < 6 mg/dL on other therapies, intolerance to urate-lowering therapies (ULT), or functionally limiting tophaceous deposits.

Participants received 15 mg/week oral MTX as well as 1 mg/day folic acid for 4 weeks leading up to and throughout the 52 weeks of treatment. They then initiated pegloticase treatment (8 mg intravenous) every 2 weeks in conjunction with follow-up appointments. Patients also adhered to a prophylaxis regimen of colchicine and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose prednisone ≤ 10 mg/day. The primary outcome focused on how many patients had sUA levels of < 6 mg/dL for ≥ 80% of the time during Month 6. Secondary endpoints focused on pegloticase responders during Month 3, as well as Month 3 and 6 combined, and patients who had an sUA of < 5 mg/dL during Months 3 and 6 and overall for at least 80% of the time.

Patients with serious acute or chronic/recurrent bacterial infection, immunocompromised status, severe chronic renal impairment, or liver disease were excluded from the study. Demographics, medical history, blood and urine samples, and medication usage were collected, and a physical exam and recent gout flares were assessed. Adverse reactions (AEs) were also accounted for.

A total of 14 men were enrolled between September 26, 2018 and April 2, 2019, with an average age of 49.3 years, a mean sUA of 9.2 ± 2.5 mg/dL, and 12/14 patients had visible tophi. At the 6-month mark, 11 out of 14 participants (78.6%, 95% CI 49.2–95.3%) met the primary outcome, with 3 discontinuing treatment. All 14 patients tolerated MTX and no new safety concerns were noted.

When utilizing the stricter sUA response criteria of < 5 mg/dL for at least 80% of the time during Month 3, Month 6, and overall, 78.6% of patients reach the primary endpoint for all 3 time periods. The sUA change from baseline was –9.0 ± 2.8 mg/dL at both Week 14 and 24. During the run-in period, 10 out of 15 participants (66.7%) experienced 1 or more AEs, including gout flare, nausea, and abdominal discomfort. During the combination MTX and pegloticase therapy period, all patients experienced AEs, most commonly exhibited as gout flare (85.7%), diarrhea (21.4%), and upper respiratory tract infection (21.4%). From Weeks 12 to 24, 5 of the 11 patients who remained on combination therapy experienced a mean of 3.0 ± 2.6 flares. In total, 75% of flares occurred in the first 12 weeks for the 11 patients who completed 24 weeks of therapy.

The small sample size, open-label design, and lack of comparator group limited the study. Investigators believe, however, that a higher number of patients treated with combination therapy achieved sUA levels that were over 6 mg/dL than previous studies focused on pegloticase alone. Further studies are needed to confirm that response rates resulted from MTX and not differences in other factors, such as prophylactic agents. Another study (NCT03994731) is currently addressing these concerns.

“Pegloticase is indicated for chronic gout in patients refractory to conventional therapy. The ability of pegloticase to dramatically lower sUA and ultimately overall urate burden, in those patients who have no other options, creates a unique, singular opportunity for treatment that is only limited by the treatment response rate,” concluded investigators. “Paramount is any mechanism that can improve the pegloticase response rate and provide an opportunity to further fulfill the unmet need. In the current study, the markedly increased pegloticase response rate observed with immunomodulation agrees and substantiates those found in previously reported case series from community-based practices.”

Reference:

Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021;48(5):767-774. doi:10.3899/jrheum.200460