Here’s how readers responded to a You Make the Call question about treating gout in a patient with G6PD deficiency.
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I have considerable experience with G6PD deficiency hemolysis, having been part of the group led by Alf Alving, MD, who discovered and characterized this genetic disease. Since all known G6PD mutations cause a loss of G6PD activity as the red cells age, the youngest group of cells in the circulation are resistant to hemolysis. A good strategy for this patient would be to start with a reduced dose of the hemolytic drug, say 25% of the known hemolytic dose, for two weeks. During this time, mild hemolysis would occur but reticulocytosis would allow maintaining only a mild anemia. Recovery to normal hemoglobin levels would ensue, as this is a compensated hemolytic anemia state. Then repeat the process with a higher dose, say 50% of the hemolytic dose, for another two weeks. After the anemia is compensated, increase to the full dose. It should be possible to give the drug indefinitely, recognizing that the patient is in a chronic compensated hemolytic state.
George J. Brewer, MD
University of Michigan
Ann Arbor, MI
An initial erythrocytapheresis to reduce G6PD-deficient red blood cells and administration of pegloticase may work. One can give the latter every four weeks either with or without erythrocytapheresis, depending on the degree of subsequent hemolysis and response to the drug.
Susumu Inoue, MD
Hurley Children’s Hospital
Try pulse corticosteroid therapy at 50 mg once weekly. Taper with improvement and treat side effects, such as diabetes, if needed. Or try dexamethasone 20 mg once weekly. Treat side effects, such as hyperglycemia, as needed.
Herbert Goldman, MD
San Juan, Puerto Rico
I have found only two published case reports of acute hemolytic anemia (AHA) following administration of pegloticase to G6PD deficient patients with gout (Geraldino-Pardilla et al., Rheumatology 53: 2310, 2014; Owens et al., J Clin Rheumatol 22: 97, 2016). One potential reason for the rarity of this serious adverse event is that the drug label states, “Do not administer KRYSTEXXA to G6PD deficient patients.” A test for G6PD deficiency ought to be, and presumably is being, routinely carried out before giving pegloticase to any patient.
Reports of AHA after rasburicase, the parent drug of pegloticase, are numerous (including at least one fatality in a child). Unlike with other drugs, for which the precise mechanism whereby they cause oxidative damage is not clear, in the case of the uricase drugs (rasburicase and pegloticase), the mechanism is straightforward: uricase produces, for every molecule of uric acid that is degraded, one molecule of hydrogen peroxide. That is one of the most powerful oxidizing agents known.
The patient is said to have a G6PD deficient class III variant. It would be interesting to know which variant and what is the actual G6PD enzyme activity level in his red cells. At any rate, the two cases mentioned above both had severe AHA, with their Hb having dropped from normal levels to 8.5 and 5.6 respectively; and both had G6PD A-, that is a class III variant. For the current classification, see Hematol Oncol Clin North Am. 30: 373-93, 2016.
In light of the above, and with respect to the question being asked, I take the liberty of changing the wording slightly. It is not a matter of whether brisk hemolysis should occur – it will. The question is “how brisk will it be?” I have no doubt, as the label states, that pegloticase is contraindicated in this patient.
I realize that there may be a strong clinical indication in a person with severe gout. If, in the opinion of the rheumatologist, there is no viable alternative to uricase, perhaps one might consider the following: (1) The long-acting pharmacokinetics that have driven the development of pegloticase becomes a liability with respect to a serious adverse event. I think it may be better to use the short-acting rasburicase, that can be stopped. (2) Since AHA in G6PD deficiency is markedly dose-dependent, after obtaining baseline hemoglobin, reticulocyte, and bilirubin levels, start the patient on a reduced dose of rasburicase, such as 20-25% of the standard dose. There will be some hemolysis, which can be monitored by the above three parameters. (3) After 3-4 days, another dose can be given. By that time there will be younger red cells in circulation with higher G6PD activity. Accordingly, hemolysis can be expected to be less. (4) Depending on the clinical and hematological response, you may be able to escalate the rasburicase doses.
Lucio Luzzatto, MD