Methotrexate plus pegloticase superior to pegloticase alone in gout
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Adding methotrexate to pegloticase increased treatment response, compared with pegloticase alone, in patients with uncontrolled gout, according to data published in Arthritis & Rheumatology.
“Immunomodulator use with pegloticase has been recommended by consensus from gout experts across multiple subspecialities,” John K. Botson, MD, of Orthopedics Physicians Alaska, in Anchorage, and colleagues wrote. “Despite these consistent and positive findings, there are no large double-blind randomized placebo-controlled trials examining the effect of immunomodulation co-therapy on pegloticase response rates.”
To investigate the efficacy of combination therapy with methotrexate and pegloticase, compared with pegloticase plus placebo, in patients with gout, Botson and colleagues conducted a randomized, controlled, double-blind trial. Patients were eligible for inclusion if they were aged 18 years or older with uncontrolled gout, either refractory to standard therapy or with ongoing gout symptoms. Patients were excluded if they were pregnant, had an acute bacterial infection, were using a systemic immunosuppressive agent, were positive for HIV or hepatitis B or C, or had advanced kidney disease.
Before full initiation into the trial, patients entered a 2-week methotrexate tolerance test. Those who passed were randomized into the intent-to-treat population. These patients underwent a 4-week run-in period, where they received methotrexate and folic acid, followed by the first trial infusion of pegloticase 8 mg, combined with either methotrexate 15 mg per week or placebo.
The primary efficacy outcome was the proportion of patients in the intent-to-treat population who responded to the therapy at 6 months. Secondary endpoints included the proportion of therapy responders at 12 months, the proportion of patients at baseline who presented with one or more tophi who had total resolution, and change from baseline at week 52 in Health Assessment Questionnaire scores.
The trial included a total of 152 patients, of whom 100 received combination therapy with methotrexate while 52 received placebo alongside their pegloticase. According to the researchers, patients in the methotrexate group demonstrated a higher treatment response rate at 6 months , compared with the placebo group — 71% vs. 38.5% (difference = 32.3%; 95% CI, 16.3-48.3%).
Additionally, during the first 6 months of the trial, 81.3% of patients receiving methotrexate experienced an adverse event compared with 95.9% of patients receiving placebo. Although the rate of adverse events was comparable between groups, there were fewer instances of infusion reactions in patients receiving methotrexate, compared with those receiving placebo, according to the researchers.
“These results confirm superiority of pegloticase plus [methotrexate (MTX)] co-therapy to pegloticase monotherapy in terms of both treatment efficacy and safety in uncontrolled gout management,” Botson and colleagues wrote. “Further, this trial provides evidence that MTX enhances drug survival and decreases pegloticase immunogenicity through attenuation of antidrug antibody development. Based on these findings, this trial strongly supports MTX co-administration with pegloticase in uncontrolled gout patients.”
References:
Boston JK, et al. Curr Rheumatol Rep. 2022;doi:10.1007/s11926-022-01055-9.
Perspective
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Pegloticase has offered real relief to many patients suffering from chronic, painful gout. It is gratifying to see tophi decreasing in size and number, and patients recounting improved quality of life. However, pegloticase also has the reputation of a medication that comes with the potential for some real and serious side effects.
I know, as I’m in the infusion world and I see the nurses working hard to administer the drug correctly and safely. This involves confirming SUAs within the past 48 hours — no small feat for a busy infusion nurse who has to chase the patient down to find out where labs were drawn and then try to obtain the results — premedicating and waiting the appropriate time before starting the infusion, and monitoring the patient during the infusion, all while caring for other infusion patients.
The MIRROR study has given nurses the confidence to infuse these patients knowing that co-treatment with methotrexate attenuates the formation of anti-drug antibodies. The fact that this has been shown to decrease pegloticase immunogenicity leading to an increased response rate and fewer infusion reactions is reassuring to the nurse caring for the patient at chairside during infusion. However, I echo the sentiments of the authors of this paper that more immunomodulators need to be studied in combination with pegloticase for those patients who are unable to tolerate methotrexate.
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