Methotrexate and Pegloticase Combination Therapy Proves to be Effective Gout Treatment

Pegloticase (pegylated uricase) is medication approved by the US Food and Drug Administration (FDA) designed to lower sUA in patients with uncontrolled gout. However, 26% of patients have infusion-related reactions (IRs), which may be indicative of the development of antidrug antibodies (ADAs). Due to this, physicians often administer immunomodulators in addition to pegloticase in order to prevent ADAs as well as increase the effectiveness of the therapy.

Patients receiving combination therapy consisting of methotrexate (MTX) and pegloticase had an increased therapeutic response rate at 6 months when compared with pegloticase alone, according to a study published in The Journal of Rheumatology.1 The condition occurs when serum uric acid (sUA) is above the solubility limit (6.8 mg/dL) and is associated with hyperuricemia, hypertension, cardiovascular (CV) disease, diabetes, kidney disease, lower quality of life, significant disability, and death.

Pegloticase (pegylated uricase) is medication approved by the US Food and Drug Administration (FDA) designed to lower sUA in patients with uncontrolled gout. However, 26% of patients have infusion-related reactions (IRs), which may be indicative of the development of antidrug antibodies (ADAs). Due to this, physicians often administer immunomodulators in addition to pegloticase in order to prevent ADAs as well as increase the effectiveness of the therapy.

“Pegloticase has well-established efficacy, but duration of response is limited in some patients due to the development of ADAs that primarily bind to the molecule’s polyethylene glycol components. The presence of ADAs has been shown to coincide with increasing sUA levels in patients on therapy,” investigators state. “Elevated sUA, therefore, serves as a biomarker for loss of therapeutic efficacy and an increased risk of IRs. Since immunomodulating therapies are not part of standard gout care, unlike other biologics, pegloticase has been used historically as monotherapy.”

In this multicenter, open-label efficacy and safety study (NCT03635957), 15 patients (all men) between the ages of 18 and 65 (average age 49.3 ± 8.7 years) with uncontrolled gout were given a combination therapy consisting of methotrexate (MTX) and pegloticase for a maximum of 52 weeks. Uncontrolled gout was defined as serum uric acid (sUA) ≥ 6 mg/dL in addition to 1 of the following criteria: inability to maintain sUA < 6 mg/dL on urate-lowering therapies (ULT), intolerance to their current ULT, or functionally limiting tophaceous deposits. Demographics, medical history and medication information was collected from participants. All patients had a physical exam, during which gout flares were assessed. While 15 patients were enrolled in the study, 1 was lost due to lack of follow-up.

Patients received MTX (15 mg/week) as well as folic acid (1 mg/day) for 4 weeks leading up to the inclusion and throughout pegloticase treatment (8 mg intravenous every 2 weeks). Investigators aimed to examine the proportion of responders with sUA < 6 mg/dL for ≥ 80% of the time during weeks 20, 22, and 24 (month 6). Follow up appointments were scheduled for every 2 weeks.

In addition to combination therapy, patients started a gout flare prophylaxis regimen, which included colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose prednisone. They also had a standard infusion reaction prophylaxis protocol prior to receiving pegloticase in order to prevent poor reaction.

During the study, 12 patients (85.7%) had gout flares during the treatment period, with all but 2 exhibiting mild to moderate symptoms and less than one-third needing to take glucocorticoids. The majority of the flares (75%) occurred during the first 12 weeks. None of the patients experienced major CV adverse events (AEs), but 10 of the 15 patients experienced 1 or more AEs during the MTX run-in period, which included symptoms such as gout flare, nausea and abdominal discomfort. During the combination therapy, all patients had 1 or more AEs, which were most commonly gout flare, diarrhea, and upper respiratory tract infections.

The mean sUA on the first day was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At 6 months, 11/14 (78.6%) patients had responder definition and the remaining 3 patients were discontinued. All patients in the study tolerated MTX and there were no new safety concerns for MTX therapy.

Future studies, including MTX or placebo along with pegloticase are needed to further support these findings. While the study was limited due to the small sample population and no comparator group, the results clearly indicate that a higher percentage of patients treated with the combination therapy had achieved sUA levels < 6 mg/dL when compared with pegloticase alone.

“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,” investigators concluded. “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. These results inform the planned randomized, controlled study of MTX vs placebo with pegloticase to validate the findings observed here.”

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) [published online ahead of print, 2020 Sep 15]. J Rheumatol. 2020;jrheum.200460. doi:10.3899/jrheum.200460