Rasburicase and methotrexate co-therapy in a case of difficult-to-treat gout
MF Pino-Zambrano, P Cardoso-Penafiel, CM Gomez-Gonzalez, E. Calvo-Aranda
Affiliation(s):
Hospital Universitario Infanta Leonor
Background: Gout is caused by the deposition of urate crystals. To dissolve deposits, serum uric acid (UA) levels should be targeted to be below 6 mg/dL (<5 in tophaceous gout) with urate-lowering treatments (ULT) such as allopurinol, febuxostat or benzbromarone. However, some patients are refractory or intolerant to standard treatment, requiring alternative drugs, such as uricases. Rasburicase is a recombinant uricase indicated in patients with hematologic malignancies with risk of tumour lysis syndrome (hyperuricemia and acute renal failure) at the beginning of chemotherapy. It has also been successfully used off-label in difficult-to-treat (D2T) gout, but may cause severe allergic reactions including anaphylaxis. Pegloticase is a uricase indicated for severe gout, but it is not currently available in Europe and may also cause infusion reactions. To reduce immunogenicity, co-therapy with methotrexate has been approved in patients with gout undergoing pegloticase treatment, based on several clinical trials. To date, this strategy has not been reported in patients treated with rasburicase.
Case presentation: 69-year-old male with chronic polyarticular tophaceous gout (figure 1), hypertension, diabetes, ischemic heart disease, and chronic kidney disease (CKD). He had previously received colchicine, NSAIDs, and corticosteroids, with poor tolerance to four ULT (rash with allopurinol, dizziness with benzbromarone and lesinurad, general malaise with febuxostat). Co-treatment with subcutaneous methotrexate (10 mg/week; CKD) and monthly intravenous rasburicase (0.2 mg/kg) was started, with subsequent intensification to biweekly administration after the first months to fasten dissolution of tophi. Blood tests were performed before and after each infusion to monitor UA and hepatic/renal function. Initially, the patient tolerated the treatment well, without significant gout attacks or relevant AEs. However, after 16 months and 22 rasburicase infusions, only a slight decrease in tophus volume was observed, despite subjective progressive improvement in joint mobility and tophus consistency. Furthermore, a progressive increase in UA levels was detected after the last infusions (figures 2-3), leading to treatment discontinuation.
Discussion: D2T tophaceous gout is not uncommon and poses a therapeutic challenge. In these patients uricases can be an effective alternative, but potentially dangerous AEs have been described. Several studies have been conducted with immunomodulators, such as methotrexate, associated with pegloticase in gout, improving response rates and reducing allergic reactions. Nevertheless, there are no reports regarding co-therapy of methotrexate and rasburicase, the only available uricase in Europe. We present a case of D2T tophaceous gout treated with rasburicase and methotrexate. Co-therapy was well tolerated, but only achieved a mild clinical response despite shortening the interval between rasburicase infusions, with progressive increase in post-infusion UA levels. which led to the suspension of the treatment. Among the possible reasons that may justify the lack of response and potential immunogenicity development could be the dose of methotrexate and the shortening of the interval between rasburicase infusions.
Conclusions: This is the first report of rasburicase/methotrexate co-treatment in gout. Despite being well tolerated by our patient with D2T tophaceous gout and cardio-renal comorbidities, it did not achieve the expected benefit, with potential development of immunogenicity. More studies are needed to assess the effectiveness and safety of this co-therapy.
