When gout is resistant to oral treatment, it can have a significant impact on a patient’s activities and quality of life. With this in mind, these authors review an intravenous treatment option for refractory gout and share their experience with this therapy in an analysis of nine patient cases.
Gout is the most common inflammatory arthropathy and occurs in the setting of sustained hyperuricemia and deposits of monosodium uric acid (MSU) crystals in joints. Monosodium uric acid crystals act directly and indirectly to stimulate an acute inflammatory response (the clinical gout flare). Over time, they cause tissue damage and destruction (clinical gouty arthritis) through sustained localized subclinical inflammation. This process can then result in polyarticular arthritis, joint destruction, deformity and tophi. As the number and severity of gout flares increase, patients experience a subsequent reduction in their quality of life.1
Gout generally presents as a monoarticular arthritis but can also be oligoarticular and asymmetrical in distribution. Among patients with gout, a longer persistence of elevated urate leads to a greater severity of gouty arthritis. To prevent chronic disease and joint destruction, early and aggressive lowering of serum urate levels to at least below six mg/dL is vital. Treating clinicians may utilize oral therapeutics with a goal of achieving a serum urate level below 5mg/dl in patients with active clinical gout. This new ‘treat to target’ approach helps facilitate positive outcomes for patients.2
What You Need To Know About Intravenous Uricolytic Treatment For Refractory Gout
Intravenous uricolytic class medications treat refractory gout and possess exceptional efficacy in treating to target (serum uric acid less than 6 mg/dL).3 One such medication is pegloticase, (Krystexxa®, Horizon Pharma), an intravenous polyethylene glycol (PEGylated) uricase enzyme (urate oxidase). Pegloticase is approved by the Food and Drug Administration (FDA) for the treatment of chronic gout refractory to conventional therapy in adult patients. Refractory gout can be defined as three gout attacks within 18 months, with serum urate levels greater than 6 mg/dL and usually with presence of visible or non-visible tophi.3
Pegloticase achieves its therapeutic effect by enzymatically converting uric acid to the more soluble metabolite allantoin. Allantoin is inert, water soluble and 99 percent of the metabolite is readily eliminated, primarily through renal excretion. This conversion of circulating uric acid to allantoin creates a uric acid concentration gradient that draws extravascular joint and bone urate into the systemic circulation where it can be converted to allantoin and excreted. Allantoin excretion is easier but it doesn’t relate back to direct precipitation of uric acid.3
Pegloticase has a half-life of approximately 8.9 days and is FDA-approved for administration at a dose of 8 mg intravenously every two weeks. While receiving pegloticase, patients discontinue oral xanthine oxidase inhibitors but maintain medications they use for flare prophylaxis. Prior to each dose of pegloticase, a patient will receive a glucocorticoid and an antihistamine as part of his or her pre-infusion regimen. This regimen is per FDA guidelines in order to decrease the incidence of infusion reactions.3
The PEGylation with pegloticase increases its elimination half-life from about eight hours to 8.9 days, decreasing the immunogenicity of the foreign uricase protein. Due to the added polyethylene glycol components, pegloticase was approved by the FDA for administration every two weeks. Extending time between infusions to longer than two weeks was found to increase the number of infusion reactions due to a build-up of anti-drug antibodies.
Ensuring Appropriate Monitoring Of Serum Uric Acid Levels During Infusion Therapy
While a patient is receiving pegloticase therapy, it is important to routinely monitor his or her serum uric acid levels approximately 48 hours prior to each infusion. One can utilize serum uric acid level as a predictive biomarker to indicate the presence of anti-drug antibodies in patients treated with pegloticase. A rise in serum uric acid above 6 mg/dL is strongly correlated with the development of anti-drug antibodies.3
This is an important monitoring tool when utilizing pegloticase as a rise in serum uric acid greater than 6 mg/dL occurred prior to the first infusion reaction in greater than 90 percent of those who experienced infusion reactions in the every-two-weeks pegloticase treatment arm of the phase 3 clinical trials.3 One should ensure hemodynamic monitoring of the patient throughout the three-hour infusion cycle. The most common adverse effect to pegloticase is rising titers of anti-drug antibodies. If serum uric acid begins to rise, a lack of urate-lowering ability of pegloticase is considered surrogate evidence for the presence of anti-drug antibodies.3
Pegloticase is contraindicated for the use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because of the risks of hemolytic anemia and methemoglobinemia. One should evaluate for G6PD deficiency via bloodwork prior to the initiation of pegloticase therapy.3
Assessing One Center’s Case Series Experience With Pegloticase Treatment
We recently reviewed the use of pegloticase treatment in a case series of patients with refractory gout at our facility over one year. We screened 13 patients with refractory gout for pegloticase infusion therapy. Twelve patients were medically cleared by our facility as candidates to receive the treatment and one patient was rejected due to a low glucose-6-phosphate dehydrogenase level. Out of the 12 patients approved for pegloticase infusion, three patients withdrew prior to the first infusion. Two patients had insurance difficulties and one was not interested in pegloticase therapy for scheduling reasons. Ultimately, nine patients began pegloticase infusions. A remaining patient discontinued treatment due to exacerbation of asthma
A majority (88.9 percent) of the infused patients had at least one of the common comorbidities associated with gout (see “An Overview Of Pertinent Demographics And Comorbidities In The Case Series”). Notably, four patients had significant cardiovascular disease which included atrial fibrillation, a history of pacemaker placement, congestive heart failure or coronary artery disease. All eight patients infused with pegloticase had chronic refractory gout and had failed to respond to over three months of oral xanthine oxidase inhibitor therapy (see “Assessing The Gout History Of Patients And Relevant Medications”).
Patients with symptomatic chronic gout who fail to normalize serum uric acid concentration to less than 6 mg/dL after three months on oral urate-lowering therapy medications are considered candidates for pegloticase treatment. Upon the initiation of pegloticase treatment, patients are required to stop all urate-lowering drugs but continue colchicine during the time they are receiving pegloticase treatment.
Treating clinicians infuse patients with 8 mg pegloticase over a two-hour period at two-week intervals. Sessions consist of a two-hour infusion and one hour of post-infusion monitoring. During the pre-infusion preparatory phase, patients receive intravenous methylprednisolone 125 mg, diphenhydramine 25 or 50 mg/mL (weight-based) and 0.9 percent normal saline 250 mL. We continuously monitor patients during the two-hour pegloticase infusion phase. During the post-infusion monitoring phase, we perform hemodynamic monitoring, a review of systems and a physical exam prior to discharge.
We check serum uric acid and renal function 24 to 48 hours prior to infusion. If urate rises beyond therapeutic levels (greater than 6 mg/dL), one can administer pegloticase one more time. The treating physician should discontinue intravenous pegloticase therapy after two sessions with urate greater than 6 mg/dL and have the patient resume oral urate-lowering therapy.
Additionally, an off-label practice exists where methotrexate and folic acid are employed to improve response to pegloticase. Botson and Peterson presented their positive findings regarding this practice at the 2018 American College of Rheumatology Conference in an abstract.4 A randomized, controlled trial, MIRROR, is currently fully enrolled and will examine the use of methotrexate as an immunomodulator reducing immune response to pegloticase.5 Our practice has used this alternative regimen to methylprednisolone, antihistamine and acetaminophen in some patients with diabetes.
Overall, pegloticase therapy has been seemingly well-tolerated by the nine patients that began in our case series. There were no significant hemodynamic changes during the 90 administered infusions or during the monitoring periods immediately following the infusions. All nine patients experienced a profound and immediate reduction in their uric acid levels following the initial infusion with a serum uric acid of less than 2.2 mg/dL.
Of the nine patients, five patients were classified as persistent responders as their serum uric acid levels remained in therapeutic range below 6 mg/dL for the entirety of treatment. Three persistent responders have received greater than 15 infusions and are currently receiving pegloticase therapy.
Three patients were classified as transient responders as their serum uric acid initially fell to therapeutic levels during treatment but subsequently rose out of the therapeutic range. Two transient responders of the three patients discontinued treatment with one patient developing musculoskeletal pain and the other patient developing anti-drug antibodies. The last transient responder is currently active in treatment and receiving concurrent methotrexate and folic acid. A remaining patient, as previously noted, discontinued treatment due to an unrelated exacerbation of asthma.
In our clinical experience, we have found pegloticase to be a safe and efficacious drug in the treatment of patients with chronic refractory gout and multiple comorbidities. Patients typically achieve therapeutic serum uric acid levels after only a single pegloticase infusion. In our case series, all nine patients experienced improvement in activity of daily living. One may continue Infusions given a positive response and patient-physician collaboration on medical, social or insurance issues. In our experience, we have found that real-world limitations of this treatment regimen include the duration of infusion time as well as the every two-week dosing interval.
We intend to further investigate and report our findings related to pegloticase’s effect on activities of daily living and renal function as well as implementing imaging studies throughout the course of treatment.
Dr. Ciccone is a Fellow of the American College of Emergency Medicine and a Diplomate of the American Academy of Pain Management. He is Board Certified in Emergency Medicine, Family Practice and Osteopathic Medicine. He practices in multiple locations in New Jersey.
Mr. DiMaggio is a second-year student at the Touro College of Osteopathic Medicine in Middletown, NY. He holds a Bachelor of Science in Behavioral Neuroscience from Lehigh University in Bethlehem, PA.
Ms. Cozzarelli is an Accelerated Bachelor of Science in Nursing Student at Seton Hall University in South Orange, NJ and holds a Bachelor of Science Degree from Sacred Heart University in Fairfield, Conn.
Dr. Cozzarelli is a Fellow of the American College of Foot and Ankle Surgeons, the Association of Professional Acupuncturists and the Association of Extremity Nerve Surgeons. He is in private practice in Belleville, NJ. Dr. Cozzarelli discloses that he is a speaker for Horizon.
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- Khanna D, FitzGerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout part I: systematic non-pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446.
- Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720.
- Botson JK, Peterson JR. Pretreatment and coadministration with methotrexate improved durability of pegloticase (Krystexxa) response: a prospective, proof-of-concept, case series. Abstract at 2018 American College of Rheumatology Annual Meeting. October 22, 2018. Available at: https://acr.confex.com/acr/2018/meetingapp.cgi/Paper/73607 . Accessed October 3, 2019.
- Study of Krystexxa (pegloticase) plus methotrexate in patients with uncontrolled gout (MIRROR RCT). Clinicaltrials.gov Website. Available at: https://clinicaltrials.gov/ct2/show/NCT03994731 . Accessed October 3, 2019.
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- Cozzarelli J, Turner D, Cozzarelli N. Non-invasive diagnosis of refractory and chronic gout. Podiatry Management. 2019. https://www.podiatrym.com/cme/CME319.pdf. Accessed September 6, 2019.
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