Continuing Education Activity

Pegloticase is a pegylated, recombinant uricase (urate-oxidase) FDA-approved in 2010 for its use in the management of chronic gout refractory to standard therapy in adult patients. This activity reviews the indications, action, and contraindications for pegloticase as a valuable agent in treating and managing chronic gout refractory to conventional therapy. This activity will highlight the mechanism of action, adverse event profile, and other key factors of pegloticase use in a clinical setting, pertinent to members of the interprofessional team in the care of patients with chronic gout and related conditions.

Objectives:

• Identify the mechanism of action of pegloticase.
• Describe the potential adverse effects of pegloticase.
• Review the contraindications of pegloticase.
• Summarize interprofessional team strategies for improving care coordination and communication to advance pegloticase use in the care of chronic gout refractory to conventional therapy in adult patients and improve outcomes.

Indications

Pegloticase is a pegylated, recombinant uricase (urate-oxidase) FDA-approved in 2010 for its use in the management of chronic gout refractory to standard therapy in adult patients.[1] Conventional therapy for chronic gout includes xanthine oxidase inhibitors such as allopurinol and febuxostat.[2] Patients with unresponsive uric acid levels and or have two or more gout flares, and subcutaneous tophi persisting despite treatment at maximum dosages of conventional therapy are considered refractory and qualify as indications for pegloticase.[2] Patients with increased uric acid levels and not experiencing gout symptoms are not recommended for treatment with pegloticase. 

Pegloticase's safety and efficacy were assessed in two replicate multination, six-month randomized, double-blind, placebo-controlled clinical trials.[3] The study comprised 225 participants with severe gout and intolerance to conventional therapy.[3] The participants were randomized to three study groups: pegloticase every two weeks, pegloticase every four weeks, and placebo group.[3] The study's primary goal was to achieve plasma uric acid levels below 6.0 mg/dL at the three-month and six-month periods.[3] Among the three groups, the treatment groups of 8mg biweekly group and 8 mg monthly of pegloticase exhibited lower serum uric acid levels when compared with the participants of the placebo group.[3] 

FDA Approved Use

• Chronic gout (refractory to conventional therapy)

Mechanism of Action

Pegloticase is a pegylated, recombinant uricase (urate-oxidase), created by a genetically altered variant of Escherichia coli that exerts its mechanism of action by catalyzing uric acid to the water-soluble purine metabolite allantoin.[1] Once the uric acid is oxidized to allantoin, it is readily excreted by the kidneys for elimination, making it a helpful agent in treating chronic gout.[4] It does not block uric acid formation.

Administration

Chronic Gout (refractory to conventional therapy)

• 8 mg IV every 2 weeks

The recommended dosage of pegloticase for chronic refractory gout is 8 mg/mL (1 mL) administered intravenously (IV) every two weeks.  The pegloticase diluted solution is to be infused gradually over no lower than 120 minutes intravenously. Infusion should be delivered through gravity feed, syringe-type pump, or infusion pump.

Patients receiving pegloticase should be treated with pre-infusion medications, antihistamines, and corticosteroids to decrease the risk and prevent anaphylaxis and infusion reactions from occurring. Patients starting pegloticase are recommended to discontinue treatment with any oral urate reducing agents. Concomitant use of pegloticase with other oral urate-lowering agents is not recommended. Infusion should be slowed or halted in the event an infusion reaction transpires and restarted at a more gradually slower rate. Monitoring patients for an hour after finishing an infusion is recommended as infusion reactions may also occur during this period.

Adverse Effects

• Gout flare (77%)
• Infusion reaction (26%) 
• Nausea (12%)
• Contusion or ecchymosis (11%)
• Nasopharyngitis (7%)
• Constipation (6%)
• Chest Pain (6%)
• Anaphylaxis (5%)
• Vomiting (5%)
• CHF exacerbation (2%)

The adverse effects were reported from randomized, double-blind placebo-controlled clinical trials in subjects receiving pegloticase at 8 mg dosage every two weeks.[5]

US-Boxed Warning

• Anaphylaxis[6]
• Infusion reactions[6]
• G6PD deficiency (hemolysis and methemoglobinemia)[7]

Contraindications

Pegloticase is contraindicated in individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency.[8] Individuals at increased risk of G6PD, such as the Mediterranean for African American descent, should be screened prior to administering pegloticase to minimize the risk of hemolysis and methemoglobinemia.[5]

Monitoring

While receiving therapy, patients should be monitored for anaphylaxis and infusion reactions.[6] Treatment with pegloticase should be administered in a healthcare setting and by healthcare professionals equipped for such responses to therapy. Serum uric acid levels should be monitored prior to treatment with pegloticase and routinely onwards. Uric acid levels rising above 6 mg/dL and or two sequential levels above 6 mg/dL are noted; suspending treatment should be considered. Patients at increased risk of G6PD deficiency (African, Mediterranean) should be screened before treatment with pegloticase.[8]

Subjects with pre-existing congestive heart failure and receiving pegloticase should be monitored periodically for CHF exacerbations. Immunogenicity to therapy may occur while being treated with pegloticase.[9] Antipegloticase and anti-PEG antibodies were observed during clinical trials in subjects receiving pegloticase every two weeks.[10] The antibodies were related to increased transfusion reactions and the inability to sustain normal uric acid levels.[10]

Toxicity

Currently, no antidote has been identified in the event of an overdose. Patients suspected of or experiencing an overdose should be managed supportively. The highest maximum dosage administered during clinical trials was 12 mg intravenously. The safety and efficacy of pegloticase in individuals under the age of 18 have not been reported.

Pegloticase use in pregnancy has not been adequately evaluated in reproductive studies in humans or animals and is not distinguished if fetal harm may occur. Pegloticase is labeled as Pregnancy Category C. It is also not fully understood if pegloticase is excreted in the human milk of nursing mothers; therefore not recommended in women who are breastfeeding.

Enhancing Healthcare Team Outcomes

Pegloticase is a pegylated, recombinant uricase (urate-oxidase) FDA-approved for chronic gout refractory to conventional therapy in adult patients. The management of patients with chronic gout requires emphatic and interprofessional care from a team of healthcare professionals. Thorough clinical investigations and communication can lead to more effective management strategies, which can further increase the impacts of pharmacologic management, decreasing flares and increase the quality of life. The interprofessional team of healthcare professionals includes a primary care physician (PCP), a rheumatologist, nurses, a physical therapist (PT), and a pharmacist.

Patients being treated should be thoroughly educated on chronic gout and treatment with pegloticase and its possible adverse effects. Alongside therapy, lifestyle modifications should also be counseled. The primary care provider and rheumatologist should maintain regular follow-ups to ensure the management of symptoms and maintain a normalized targeted range for uric acid levels. The interprofessional team should also continually be updated with the latest guidelines on chronic gout management.

Treatment with pegloticase should be administered in a healthcare setting by a healthcare professional. Patients receiving treatment should be informed about anaphylaxis and transfusion reactions and be administered antihistamines and corticosteroids as pre-infusion medications. Healthcare providers should screen subjects at increased risk for G6PD deficiency as a contraindication to therapy as hemolysis and methemoglobinemia may ensue.

Patients receiving treatment should be counseled by their healthcare provider of no concomitant oral urate-lowering medications while on therapy with pegloticase. Patients with underlying CHF should be consulted with a cardiologist prior to initiation of treatment as CHF exacerbation may occur while being treated. If pegloticase is considered in these patients, regular follow-ups are essential. The PCP and rheumatologist should routinely monitor uric acids levels as levels rising above 6 mg/dL and or two sequential levels above 6 mg/dL are observed; suspending treatment should be considered.

Childbearing women considering treatment with pegloticase should be counseled about the possible risks to the fetus as currently, no reproductive studies in humans or animals have been reported. The rheumatologist and obstetrician should be consulted to consider the benefits and risks of therapy during pregnancy. Women who are breastfeeding should also be advised treatment with pegloticase is not recommended as it is not sufficiently understood if pegloticase is excreted in the human milk. Communication between healthcare providers and their patients is vital to establishing rapport and a physician-patient relationship. Thorough interaction and guidance on disease course and management can improve patient education on medication compliance and decrease disease progression.