This month, Yvonne H. Datta, MD, discusses the treatment of gout in a patient with G6PD deficiency.
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I have a 36-year-old male Samoan patient with glucose-6-phosphate-dehydrogenase (G6PD) deficiency (World Health Organization class III), chronic tophaceous gouty arthropathy, and chronic renal insufficiency secondary to prolonged nonsteroidal anti-inflammatory drug use. His baseline creatinine is 2.67 mg/dL and his glomerular filtration rate is 27. He has a white blood count of 13.8, hemoglobin level of 11.6 g/dL, hematocrit level of 35.1 percent, and a platelet count of 438×109/L. He is experiencing extreme pain and difficulty walking due to gouty arthropathy and has been disabled for eight years.
His rheumatologist would like to institute pegloticase, a pegylated uric acid–specific enzyme, which is a known cause of hemolysis in patients with G6PD deficiency. The patient wants to try this agent to reduce his extensive, painful tophi. I am looking for other opinions about the possibility of administering pegloticase in a hospital setting with transfusion support if brisk hemolysis should occur.
Pegloticase (Krystexxa), also known as pegylated rasburicase, has been approved for use in severe refractory gout. It is infused every two weeks and has a half-life of 10 to 12 days. Rasburicase metabolizes uric acid into allantoin, lowering serum uric acid levels with decreased crystal formation. A byproduct of rasburicase is hydrogen peroxide, which can cause oxidative stress. G6PD is an enzyme in the pentose phosphate pathway that converts glucose to pentose and also generates NADPH, which protects against oxidative stress. G6PD deficiency is an X-linked abnormality of varying severity that results in hemolysis when red cells are exposed to significant oxidative stress. Patients such as this one, with type III deficiency, have 10% to 60% of normal G6PD activity. There have been several case reports of significant hemolysis and methemoglobinemia when rasburicase or pegloticase have been used in patients with unrecognized G6PD deficiency, even when this deficiency has been mild. In some cases, the hemolysis was worsened when the patient was given methylene blue for the methemoglobinemia, resulting in some deaths. These reports have led to a boxed warning for rasburicase and pegloticase, in which screening for G6PD deficiency is recommended and use in patients with known G6PD deficiency is discouraged.¹
In this patient, I advise against using pegloticase. The use of rasburicase in the acute setting of newly diagnosed high grade leukemia or lymphoma without waiting for G6PD testing may be warranted. In that event, G6PD testing is still advised in case additional doses are needed later. However, in this case, the patient is known to have G6PD deficiency. The use of pegloticase in this patient may cause serious harm. The concern is not just that he may need transfusions. Severe acute hemolysis can cause hyperkalemia, acute kidney injury, and shock. This patient has chronic kidney disease, placing him at greater risk for kidney injury. One reported case of pegloticase-induced hemolysis required transfusion, plasmapheresis, and vitamin C for recovery.² Another reported case required prolonged hemodialysis, possibly related to the long half-life of the pegloticase causing ongoing hemolysis.³ In the setting of G6PD deficiency, the potential harms of pegloticase outweigh the potential benefits.
- Belfield KD, Tichy EM. Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency. Am J Health Syst Pharm. 2018;75:97-104.
- Geraldino-Pardilla L, Sung D, Xu JZ, et al. Methaemoglobinaemia and haemolysis following pegloticase infusion for refractory gout in a patient with a falsely negative glucose-6-phosphate dehydrogenase deficiency result. Rheumatology (Oxford). 2014;53:2310-1.
- Minshar MA, Osman-Malik Y, Bhat ZY. Pegloticase-associated hemolysis. Am J Ther. 2018; PMID: 30211701.
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NEXT MONTH'S CLINICAL DILEMMA
I have a 21-year-old female patient with Fanconi anemia (FA; compound heterozygous for FANCA) and bone marrow failure, 46, triple X syndrome. She presented in October 2018 with moderate-severe cytopenias and was started on granulocyte colony-stimulating factor (until November 2018) and eltrombopag. She does not have physical stigmata of the diagnosis.
She responded to treatment reasonably well, but her response appears to be dwindling. We recently found two matched unrelated donors (she has no matched siblings) and intend to take her for allogeneic hematopoietic cell transplantation (alloHCT) as soon as possible. Could you advise me on the optimal timing for alloHCT, a stem cell source (bone marrow vs. peripheral blood) and conditioning (Flu/Cy/ATG or Flu/Cy/ATG+TBI or other) for alloHCT? I am not sure how triple X syndrome interacts with FA in terms of management and overall prognosis.
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