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Full results from the so-called have now been published and suggest the FDA made the right decision this summer to approve methotrexate as an add-on to pegloticase (Krystexxa) for patients with uncontrolled gout.

Among patients assigned to the combination in the randomized trial, 71.0% met the primary endpoint of serum urate below 6 mg/dL after 6 months, versus 38.5% for those receiving placebo plus pegloticase (difference of 32.3 percentage points, 95% CI 16.3-48.3), according to Michael E. Weinblatt, MD, of Brigham & Women's Hospital in Boston, and colleagues.

Rates of adverse events were similar in the two arms, but methotrexate seemed to suppress one common type of pegloticase side effect: reactions to the infusion. Just 4.2% of patients receiving the combination therapy had such reactions, compared with 30.6% in the placebo-pegloticase group, the researchers .

MIRROR was the study underpinning the of the methotrexate-pegloticase combination treatment for gout patients not responding to conventional therapy such as allopurinol. includes a summary, of course, but the new journal publication is the first full peer-reviewed accounting of the study's efficacy and safety results.

Why methotrexate? It's not primarily because the drug can limit inflammation, though that is the reason for its use in rheumatoid arthritis and other autoimmune conditions. Rather, pegloticase's effectiveness is often thwarted by development of anti-drug antibodies, and methotrexate has appeared to be effective in preventing this. Weinblatt and colleagues cited small prospective trials that have shown dramatically improved response rates when moderately potent immunosuppressants including methotrexate or mycophenolate mofetil were added to pegloticase therapy. has backed the approach too.

Pegloticase's manufacturer, Ireland-based Horizon Therapeutics, saw that FDA approval of the combination could be a good business move, and therefore sponsored MIRROR. The trial randomized 152 patients in a 2:1 ratio to methotrexate or placebo, both in combination with pegloticase infusions. Methotrexate was given orally at 15 mg/week. 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 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. Body mass index 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%.

About 35% of patients receiving the combination had complete resolution of at least one tophus, compared to 14% of the placebo group (P=0.04). Also, half the placebo-pegloticase group had two consecutive serum urate readings above 6 mg/dL at some point during the trial, whereas this occurred in only 18% of the methotrexate-pegloticase arm.

Adverse events of any kind were recorded for 81% of the combination arm and 96% of controls. Infusion reactions accounted for most of the difference. The most common event was gout flare, and these were seen in about two-thirds of both groups. (Weinblatt and colleagues did not, however, report numbers of gout flares.)

As the researchers had hoped, methotrexate did seem to suppress development of anti-pegloticase antibodies. By week 24, more than half of the placebo group tested positive for these antibodies, versus less than 25% of the methotrexate arm. Maximal and especially trough concentrations of pegloticase in blood were also higher with concomitant methotrexate.

However, one patient receiving methotrexate in MIRROR developed anaphylaxis after his or her first pegloticase infusion, indicating that the combination did not eliminate this type of risk. Pegloticase's label still includes a boxed warning about anaphylaxis. At least partly because of this risk, pegloticase remains a treatment of last resort for gout, and the FDA has stipulated that the drug is not to be used to reduce serum urate in patients without gout symptoms.

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