Immunomodulatory Enzyme Therapy and Conventional Therapy to Boost Therapeutic Outcomes in Chronic Refractory Gout

Chronic gout is characterized by hyperuricemia, inflammation, and the deposition of monosodium urate (MSU) crystals in the joints and other tissues.¹ Deposition of MSU crystals progresses to chronic synovitis, bony erosions, cartilage damage, and tophi.² Over time, untreated or suboptimally-treated patients with hyperuricemia progress to severe pain, limited mobility, functional disability, and loss of productivity.¹ Furthermore, gout is associated with diabetes mellitus, hypertension, cardiovascular disease, kidney disease, and an increased risk of death.^2-4

The prevalence of gout increases with age (Figure)¹ and is reported to be higher in men. Approximately 9.2 million people in the United States have gout, representing 3.9% of the adult population.¹ The reported world prevalence of gout is between 1% to 4%.^2,4

Xanthine oxidase inhibitors, primarily allopurinol and febuxostat, are the mainstay of treatment. The goal of chronic gout management includes lowering serum urate levels to below 6 mg/dL.⁵ Overall, the clinical goals of therapy are directed towards reducing tophus burden, functional disability, work disability, pain, and joint inflammation as well as improving health-related quality of life and global patient health status.⁶ By lowering serum urate levels below the MSU saturation point, therapy leads to the dissolution of urate crystals which reduces acute flares and joint damage and improves overall disease outcomes.² 

Several urate-lowering therapies (ULTs) have emerged over the years. However, approximately 2% of patients who have been treated with ULTs fail to reach clinical target goals and progress to refractory gout, defined as a serum urate level above 6 mg/dL with ongoing symptoms of recurrent flares, arthritis, and increased tophi despite maximum recommended or tolerated doses of ULTs.⁷ The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) recommend pegloticase for treating gout that is refractory to conventional therapy.^5,8

Challenges Associated With Pegloticase for the Treatment of Refractory Gout

Uricase metabolizes urate to allantoin, which is water-soluble and easily excreted by the kidneys. However, uricase has a short half-life. Rasburicase, a recombinant uricase from Aspergillus flavus, was developed for the short-term management of hyperuricemia and may be administered intravenously for up to 7 days. The rasburicase molecule is not PEGylated; PEGylation increases the half-life of uricase and is moderately successful in mitigating immunogenicity. Pegloticase, a pegylated mammalian recombinant uricase, has a half-life between 6.4 days and 13.8 days and is administered as a twice-monthly infusion.⁹
Available evidence demonstrates the effectiveness of pegloticase in the treatment of gout. A study of 225 participants treated with pegloticase had their serum urate levels normalized within 24 hours of receiving the first infusion. Additionally, treatment with pegloticase resulted in tophi resolution, reduced pain, and improved physical function and quality of life.^10-12 However, response waned over time, as only 42% of patients on biweekly pegloticase infusion achieved a serum urate level below 6 mg/dL.¹⁰

Pegloticase is indicated in patients who fail to achieve the serum urate level target and have at least 2 gout flares each year. Similarly, patients with nonresolving tophi also are eligible for pegloticase therapy.⁵ 

Similar to other ULTs, there is an increased risk of flares during treatment with pegloticase, with the highest risk occurring in the first 3 months of initiating treatment.¹² There is a significant reduction in flares 4 to 6 months into treatment, necessitating flare prophylaxis with nonsteroidal anti-inflammatory drugs, colchicine, or steroids when treating patients with pegloticase.¹⁰ Another major challenge in using pegloticase is that between 41% to 60% of patients who receive treatment develop antibodies to the drug, resulting in increased clearance and reduced response to the medication.^12,13 Antipegloticase antibodies increase the risk of drug and infusion reactions. Flushing, vomiting, urticaria, and hypotension have been reported.¹² Patients also can stop responding to the urate-lowering effect of pegloticase before a first infusion reaction is evident. Serum urate levels should be checked before the next infusion.

A rising serum urate level is a surrogate for antidrug antibodies (ADAs), associated with the loss of lowering serum urate levels and a risk for infusion reactions, which would eventually lead to failure of treatment.¹³ Discontinuing pegloticase in patients with elevated preinfusion serum uric acid levels above 6 mg/dL while on therapy can minimize or avoid most infusion reactions. Data from 3 clinical trials of pegloticase showed that only 2 of 22 patients would have had infusion reactions if pegloticase had been discontinued after a single preinfusion serum urate level above 6 mg/dL.¹⁴ It is recommended to stop pegloticase if serum urate levels rise above 6 mg/dL, especially when there are 2 consecutive instances of serum urate levels higher than 6 mg/dL.¹⁵ Pegloticase should not be prescribed with other ULTs to avoid masking the loss of its urate-lowering ability.

Currently, pegloticase is the only approved therapy for refractory gout. Therefore, patients who develop ADAs will experience drug reactions that lead to failure of treatment. The coadministration of pegloticase with immunosuppressive agents has been shown to minimize the development of ADAs.¹⁶ Consequently, immunomodulation has been explored as a strategy to reduce the immunogenicity of pegloticase and improve clinical outcomes, thereby offering patients with an effective treatment against refractory gout.^16,17

Immunomodulation and Enzyme Therapy for Improved Efficacy

Concomitant administration of an immunosuppressive agent with pegloticase can improve the response rate in patients with uncontrolled gout. This combination should be considered as an option for minimizing drug intolerance and lowering the risk of adverse events.^18,19 A systematic review of 10 publications evaluating pegloticase use combined with an immunomodulatory agent found that patients experienced an overall response rate of 82.9%, comparatively higher than the patients who received pegloticase monotherapy (42%).¹⁹  

The immunosuppressive agent of choice requires careful consideration of the patient’s medical profile, including comorbidities, contraindications, or factors that may increase the risk of adverse events. While evidence-based recommendations are not available on combined immunosuppressive agents and pegloticase therapy, several studies have explored different immunomodulation protocols (Table 1).^20-26

In the exploratory open-label MIRROR trial (ClinicalTrials.gov Identifier: NCT03635957), 11 of 14 patients who received oral methotrexate, folic acid, and pegloticase maintained serum urate levels below 6 mg/dL more than 80% of the time.²⁰ The study demonstrated that treatment with a methotrexate/pegloticase combination resulted in a greater response than pegloticase alone. Similarly, in a retrospective study of 10 patients with uncontrolled tophaceous gout, a methotrexate/pegloticase combination with preinfusion prophylaxis resulted in a superior response compared with pegloticase alone.²¹

Other studies have found similar results. A case series of 7 patients treated with a methotrexate/pegloticase combination achieved lower serum urate levels and completed treatment without having adverse effects such as infusion reactions.²² In an observation case series, all 10 patients showed superior response to a combination therapy of methotrexate/pegloticase with no infusion reaction or methotrexate dose adjustment.²³ In another study, 1 patient who had 73 MSU-affected joints, identified with a dual-energy computed tomography scan, had their affected joints reduced to 4 at the end a 52-week treatment period with pegloticase/methotrexate combination therapy, and MSU volume decreased by 99%.²⁷

A supplemental biologics license application was submitted in January 2022 to the US Food and Drug Administration (FDA) to expand the approved indication for pegloticase plus methotrexate for patients with uncontrolled gout.²⁸ The supplemental biologics license application is primarily supported by the MIRROR randomized controlled trial results, showing that 71% (n=71/100) of patients randomly assigned to receive pegloticase plus methotrexate achieved a complete serum urate levels response, defined as serum urate levels below 6 mg/dL at least 80% of the time during month 6.²⁸

The side effects of concomitant methotrexate plus pegloticase treatment are fatigue, gastrointestinal toxicity, and liver toxicity.²⁹ In the MIRROR study, 1 patient experienced leucopenia and elevated liver enzymes. These adverse effects were managed by lowering the dose of methotrexate and the patient was able to successfully continue treatment throughout the 6-month study duration.²⁰ 

While methotrexate is an effective immunotherapy, contraindication in some patients requires alternative immunotherapy. Cyclosporine and mycophenolate mofetil have been explored in this context. Treatment with cyclosporine prior to pegloticase infusion in a patient with liver disease successfully lowered serum urate levels from 8.9 mg/dL to below 1.5 mg/dL after the first infusion. The reduction was maintained for the remainder of the treatment course with no infusion reaction.²² Similarly, 32 patients treated with mycophenolate mofetil and pegloticase achieved a serum urate level below 6 mg/dL in 86% of the patients compared to 40% of patients treated with pegloticase alone (P =.01).³⁰ Azathioprine and leflunomide also have shown promising results.^25,26

It should be noted that the adverse effects of immunomodulation can be potentially serious and require monitoring (Table 2).^31-35 Nevertheless, available data show promising results for efficacy and safety, suggesting that combined enzyme immunomodulation therapy is a worthwhile practice. However, there is a need for more robust evidence from clinical trials and standardized treatment guidelines. Until consensus recommendations are available, consideration should be given to comorbidities and contraindications when choosing an immunomodulatory agent.