Pegloticase plus methotrexate bested pegloticase alone in uncontrolled gout response
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An increased proportion of patients with uncontrolled gout maintained treatment response at 6 months with concomitant methotrexate and pegloticase, compared with pegloticase alone, according to data published in The Journal of Rheumatology.
“This work was notable as it was the first multi-center, study to objectively look at the effects of methotrexate pretreatment and co-administration with pegloticase in patients with gout,” John K. Botson, MD, RPh, of Orthopedic Physicians Alaska, in Anchorage, told Healio Rheumatology. “It essentially reproduced and helped to validate the work Jeff Peterson and I presented in our original case series, which introduced the concept of methotrexate co-administration as a way to increases the durability of pegloticase.”
He added: “By substantiating multiple single center, published case series from community based-practices, which showed improvement with methotrexate co-administration, this study also helped to inform the randomized, controlled trial with methotrexate verses placebo with pegloticase, which is now ongoing.”
To analyze the efficacy and safety of combination therapy with methotrexate and pegloticase (Krystexxa, Horizon Therapeutics) among patients with uncontrolled gout, Botson and colleagues conducted an exploratory, open-label study at six sites across the United States. In all, the researchers screened 17 adult patients aged 18 to 65 years, and enrolled 14 of them. Participants received oral methotrexate in doses of 15 mg per week, as well as 1 mg per day of folic acid, 4 weeks before and throughout pegloticase treatment.
The primary study outcome was the proportion of responders, defined as a serum urate acid level of less than 6 mg/dL for at least 80% of the time during month 6 of the trial. The researchers conducted all analyses on a modified intent-to-treat population, defined as patients who received at least one pegloticase infusion.
According to the researchers, the day-1 mean serum urate acid level was 9.2 ± 2.5 mg/dL, and 12 of the 14 enrolled participants had visible tophi. At 6 months, 11 participants — or 78.6% (95% CI, 49.2-95.3%) — met the responder definition. Moreover, three patients discontinued treatment after meeting protocol-defined treatment discontinuation rules, defined as pre-infusion serum urate acid values greater than 6 mg/dL at two consecutive scheduled visits. All participants tolerated methotrexate. There were no new safety findings.
“The key takeaway for clinicians from this study is that pegloticase dramatically reduces the serum uric acid in patients with chronic gout that essentially have no other options,” Botson said. “Methotrexate co-administration significantly increased the response rate to pegloticase, compared with pegloticase monotherapy, with no new safety concerns.”
“The clinical significance of these findings is that while additional studies are needed, patients undergoing treatment for chronic gout with pegloticase, who have no other options, should be considered for co-administration with methotrexate to improve the response rates,” he added. “This study also adds to the growing body of evidence that immunomodulation — with methotrexate or other agents — provides better outcomes in patients treated with pegloticase.”
Perspective
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Paul J. DeMarco, MD, FACP, FACR, RhMSUS
In their study, Botson and colleagues examined using pegloticase with methotrexate, without a comparator group but a record of historical controls of patients treated with pegloticase alone. Researchers found that 78.6% of patients in the study met response criteria compared with the historical response with pegloticase alone of 42%. The lower historical rate is attributed to the development of anti-drug antibodies which accelerate drug clearance. Other case reports and case series with pegloticase and DMARDs, such as azathioprine, methotrexate and leflunomide, have suggested this approach is promising. They correctly call for a randomized study.
Trial design is a critical part of this discussion and comparison between clinical trials and publications is important to the extent that the trials are conducted in a similar manner. The MIRROR trial allowed prophylaxis with either colchicine and/or NSAIDs and/or low-dose prednisone ≤10 mg/day; Premedication in MIRROR included intravenous glucocorticoid (200 mg hydrocortisone or 125 mg methylprednisolone over 10-30 min) immediately prior to pegloticase infusion. In their 2011 study in JAMA, Sundy and colleagues used only NSAIDs and colchicine for prophylaxis, and hydrocortisone 200 mg before infusion. Since prednisone and methylprednisolone have immunosuppressive qualities, there may be an additive effect on the tolerability of pegloticase.
Overseeing a clinical trials program for my group, I have noticed that trials for rheumatoid arthritis and systemic lupus erythematosus pay particularly close attention to directing the use of corticosteroids as to preserve the purity of the data. It remains unclear why a gouty arthritis trial is not conducted in the same manner.
I applaud Botson and colleagues for their accomplishment and publication, as pegloticase is an important breakthrough for the management of gouty arthritis. However, we have to acknowledge that we are comparing the entire treatment approach of Botson et al to the results of treatment by Sundy et al. If rheumatologists want to clearly know the effect of methotrexate, a randomized trial with attention to corticosteroid application must be conducted.
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