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PHILADELPHIA -- Previous findings that adding methotrexate to pegloticase (Krystexxa) in patients with gout was more effective than pegloticase alone have now been extended to a full year of treatment.

At month 12 in the randomized, 152-patient , 60% of patients receiving the combination had serum urate levels below the target of 6 mg/dL, the primary efficacy endpoint, compared with 30.8% of those assigned to pegloticase plus placebo, reported John Botson, MD, of Orthopedic Physicians Alaska in Anchorage.

Both figures were a bit lower than were seen at the trial's primary evaluation at 6 months, which helped underpin the FDA's of the combined approach (and were subsequently reported in ). However, the difference in response rates was nearly identical at 29.1 percentage points at month 12 versus 32.3% at month 6, Botson reported at the American College of Rheumatology (ACR) annual meeting.

Encouragingly, the combination's clinical efficacy appeared to increase with continued treatment. The percentage of patients seeing complete resolution of at least one tophus grew markedly, to 53.8% at month 12 from 34.6% at the 6-month evaluation. Both were significantly greater than in the control group receiving pegloticase plus placebo.

Why add methotrexate, a somewhat toxic drug, to pegloticase? Botson explained that the latter's efficacy can be severely compromised by development of anti-drug antibodies, which occurs in close to 90% of patients with regular dosing. Pegloticase is an enzyme formulated with polyethylene glycol, and as such the immune system may recognize it as foreign. Methotrexate limits this effect.

Indeed, rates of infusion reactions were much lower, even among those who developed anti-pegloticase antibodies despite the methotrexate add-on. Botson reported that about 30% of the pegloticase-alone group experienced infusion reactions; but for those receiving the combination, just 13% of those still developing anti-drug antibodies had reactions. Among those in the combination group who never showed anti-drug antibodies, none had infusion reactions.

Rates of adverse events were generally similar between groups. One patient receiving the combination did have a nonfatal anaphylactic reaction, demonstrating that methotrexate doesn't abolish all reactivity to pegloticase. The drug's label carries a boxed warning about potential anaphylaxis and cautions against prescribing the drug to patients without overt gout symptoms.

Following Botson's presentation, an ACR attendee questioned the choice of methotrexate to suppress pegloticase immunogenicity, given that kidney disease is common with gout and methotrexate is contraindicated for patients with serious renal impairment. He responded that the researchers and pegloticase's manufacturer believed that treating physicians would be more comfortable with methotrexate, as an agent they understand well and prescribe all the time, than other immunosuppressants. He noted that about one-third of participants had estimated glomerular filtration rates less than 60 mL/min/1.73 m² but above the study's cutoff for exclusion of 40 mL/min/1.73 m².

"Could other medications be used? Probably," he said, but the study findings do "cover most of the patients that we treat."

A related question centered on whether methotrexate's potential toxicity could be reduced by dosing it less often (it was 15 mg weekly in the trial). Botson was not enthusiastic, saying that less frequent dosing would mean deeper troughs in blood levels that might allow anti-drug antibodies to gain traction.

The trial randomized 152 patients in a 2:1 ratio to methotrexate or placebo, both in combination with pegloticase infusions. Pegloticase was administered in 8-mg doses every 2 weeks. To be eligible, patients had to have serum urate levels of at least 7 mg/dL and to have either failed, or proven unable to take, conventional oral urate-lowering agents. Other inclusion criteria were the presence of at least one tophus and two or more gout flares in the previous year, or else a diagnosis of gouty arthritis. Patients with serious renal deficiency or who were using immunosuppressants were excluded.

About 90% of patients were men; mean age was 54. Some 70% of participants were white. BMI values averaged about 33. Mean duration of gout symptoms was about 14 years, and participants had averaged about 11 flares in the previous year. Serum urate at baseline averaged roughly 9 mg/dL. Drugs tried without benefit included allopurinol in three-quarters of patients, febuxostat (Uloric) in 17%, and probenecid in about 4%.

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