Lesinurad, Febuxostat Combination Treatment Improves Tophaceous Gout Symptoms

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Patients with tophaceous gout undergoing combination therapy with lesinurad and febuxostat showed a greater degree of symptom resolution than with febuxostat monotherapy.
Patients with tophaceous gout undergoing combination therapy with lesinurad and febuxostat showed a greater degree of symptom resolution than with febuxostat monotherapy.

Patients with tophaceous gout had significantly lower serum urate levels and reduced tophi when taking combination lesinurad and febuxostat, compared with patients receiving only febuxostat, according to recent research from a phase 3 trial published in Arthritis & Rheumatology.

“For patients [with tophaceous gout] uncontrolled on an appropriate dose of a xanthine oxidase inhibitor (XOI) for whom a uricosuric is recommended, there is a need for additional treatment options,” Nicola Dalbeth MD, FRACP, from the University of Auckland in New Zealand and colleagues wrote in their study.

“Lesinurad 200 mg is a novel selective uric acid reabsorption inhibitor approved for treatment of gout in combination with an XOI for those not at target serum uric acid (sUA) on an XOI alone. Combination therapy with lesinurad and febuxostat provides a dual mechanism, addressing both uric acid excretion and urate production, and may represent a treatment option for patients with tophaceous gout on febuxostat who warrant additional therapy.”

Dr Dalberth and colleagues enrolled 324 patients (mean age 54.1, body mass index <45 kg/m2) with tophaceous gout who received daily febuxostat 80 mg for 3 weeks followed by being randomly assigned to receive daily lesinurad (200 or 400 mg) or placebo in addition to febuxostat. Patients were included in the trial if they had sUA levels ≥8 mg/dl or ≥6 mg/dl under urate-lowering therapy and at least one tophus on the feet, ankles, hands, or wrists between ≥5 mm and ≤20 mm in diameter.

The researchers found 76.1% of patients in the lesinurad 400-mg group reached target sUA levels (P <.0001) at 6 months compared with 56.6% of patients in the 200-mg group (P =.13) and 46.8% of patients in the placebo group. However, patients in the 200-mg lesinurad group were significantly more likely to reach target sUA levels at 1 through 5 months, 8 months, 10 months, and 12 months compared with the 400-mg and placebo groups (P ≤.0281), with sUA <5 mg/dL reached at 4 months through 6 months as well as a median sUA <5 mg/dL and an sUA <4 and <3 mg/dl at 6 months and 12 months.

Regarding tophus resolution, 52.9% of patients in the lesinurad 400-mg group and 50.1% of patients in the lesinurad 200-mg group had reduced target tophi area compared with 28.3% of patients in the placebo group (P <.05). Dr Dalbeth and colleagues noted that apart from reversible elevated serum creatinine levels 1.5 or 2 times higher than baseline in the lesinurad groups, the safety profile for lesinurad was comparable to febuxostat alone.

The researchers recommended monitoring clinical signs typically associated with these patients when treating tophaceous gout.

“When prescribing lesinurad, physicians should take into consideration that patients with gout typically present with comorbidities, may also be taking other renal-acting medications, and may be poorly hydrated,” Dr Dalberth and colleagues wrote.

“The prescribing information recommends patients take lesinurad with food and water and maintain appropriate hydration via daily water intake. It also states that physicians should monitor renal function before starting and during lesinurad therapy, particularly in patients with estimated creatinine clearance (eCrCl) of <60 mL/min — using the Cockcroft-Gault equation — or with serum creatnine (sCr) elevations 1.5 to 2 times the starting value, and evaluate for signs and symptoms of acute uric acid nephropathy. Lesinurad should not be started in patients with eCrCl <45 mL/min.”

Limitations & Disclosures

Researchers noted limitations in the study included the short study length, small number of women, and a high number of patients with sUA <5 mg/dl at 3 weeks after randomization in the febuxostat alone group.

Dr Dalbeth received grant support from AstraZeneca; is on the speaker's bureau for Menarini, AstraZeneca, Takeda; and is on the advisory board for AstraZeneca, Fonterra, Takeda, Pfizer, Cymabay, and Crealta. Dr Jones received grant support from Abbvie, Ardea, Novartis, Auxilium; is on the advisory board for Pfizer, Roche, Hospira, and Jannsen; and is on the speaker's bureau for UCB, Roche, Jannsen, Abbvie, Novartis, Mundipharma, Amgen, BMS, and Pfizer. Dr Terkeltaub is a consultant for AstraZeneca, Takeda, Revive, Relburn, and UCB. Dr Khanna received a research grant from AstraZeneca and is a consultant for AstraZeneca, and Takeda. Dr Perez-Ruiz received grant support from the Spanish Health Ministry, Spanish Rheumatology Foundation, and Cruces Hospital Rheumatologists Association; is on the speaker's bureau for AstraZeneca and Menarini; and is on the advisory board for AstraZeneca, Menarini, Metabolex, Novartis, Pfizer, and SOBI. Dr Bhakta is an employee of Ardea Biosciences, Inc. Dr Adler is an employee of AstraZeneca. Fung, Kopicko, Storgard, and Baumgartner are former employees of Ardea Biosciences, Inc.

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Reference 

Dalbeth N, Jones G, Terkeltaub R, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: a phase III clinical trial [published online June 9, 2017]. Arthritis Rheum. doi:10.1002/art.40159

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