Pegloticase Alongside Methotrexate Improves Uncontrolled Gout in MIRROR Trial

The MIRROR trial showed pegloticase treatment with or without methotrexate co-therapy led to meaningful clinical and quality of life improvements in uncontrolled gout.1

“The data presented here reflect both patient-reported and clinical benefits of rapid urate depletion in patients with uncontrolled gout,” wrote investigators, led by John Botson, MD, from Rheumatology and Bone Health Management at Orthopaedic Physicians Alaska. “Patients randomized to receive [methotrexate] vs. [placebo] co-therapy had greater improvements in some measures, likely related to the increased rate of sustained urate-lowering in those co-treated with [methotrexate].”

Anti-drug antibodies make it harder for pegloticase to lower serum urate. The co-administration of methotrexate increases the urate-lowering response rate and reduces infusion reaction risk.2

Investigators sought to assess the quality of life and clinical assessment outcomes of pegloticase treatment with or without methotrexate among patients with gout.1 Participants were included if they had uncontrolled gout, defined as serum urate ≥ 7 mg/dl, urate-lowering therapy failure or intolerance, and the presence of ≥ 1 of the following: ≥ 1 tophus, ≥ 2 gout flares in the prior year, or chronic gouty arthritis.

The MIRROR trial randomized 152 patients 2:1 to receive pegloticase treatment (8 mg biweekly infusion) with either oral methotrexate (15 mg/week) (n = 100) or placebo (n = 52) as co-therapy over 52 weeks. After a 2-week methotrexate tolerance period and a 4-week blinded methotrexate or placebo period, participants started pegloticase alongside methotrexate or pegloticase alongside placebo. Day 1 was considered the first day of pegloticase infusion.

Pre-specified exploratory quality of life and clinical measure outcomes included change from baseline in Physical Global Assessment of Gout, tender joint count, and swollen joint count at weeks 14, 24, 36, and 52. Investigators examined the proportion of participants meeting gout chronic response criteria, looking for a 50%/70% reduction in exploratory outcomes at weeks 14, 24, 30, 44, and 52.

At baseline, clinical and quality of life assessments showed patients with gout had poor overall health, heavy gout burden, some disability, high pain levels, and high level of joint involvement. Pegloticase improved quality of life and clinical assessment measures in both the methotrexate and placebo groups; the assessments HAQ-DI (−0.35 ± 0.05 vs. −0.31 ± 0.07; P = .63], HAQ-Pain (−31.0 ± 2.2 vs. −22.6 ± 3.2; P = .03], and HAQ-Health (−28.9 ± 2.5 vs. −18.7 ± 3.7; P = .02] all meaningfully improved in both arms by week 52.

However, the change from baseline in HAQ-DI was not significantly different between patients receiving pegloticase plus methotrexate and those receiving pegloticase plus placebo. Investigators did observe participants on methotrexate had greater improvements in HAQ-Pain and HAQ-Health at week 52, with differences apparent at weeks 14 and 20 (P < .05).

Furthermore, the PhGA score improved in both groups, with a mean change from baseline at week 52 of −4.2 ± 0.2 in participants on methotrexate (6.0 at baseline to 1.0 at week 52) and −3.8 ± 0.3 in participants on placebo (5.0 at baseline to 1.0 at week 52) (P = .18). Investigators saw PhGA was significantly greater in the methotrexate group by week 14, with improvement differences through week 36 (P < .05).

Additionally, the study saw that the number of swollen or tender joints reduced during pegloticase treatment, with no significant differences between groups (P > .05). By week 52, tender joint count reduced from 6.7 ± 8.4 at baseline to 1.4 ± 4.6 in the methotrexate group and 11.0 ± 15.9 at baseline to 0.6 ± 1.0 in the placebo group. Moreover, the swollen joint count reduced from 5.4 ± 7.8 at baseline to 1.4 ± 4.5 in the methotrexate group and from 8.3 ± 12.2 at baseline to 1.1 ± 2.9 in the placebo group.

The study saw both treatment groups had a large increase in the number of patients meeting GCR, but more patients in the methotrexate group versus the placebo group had met GCR20, GCR50, and GCR70 by week 20. GCR response rates were greater in the methotrexate group, but by week 24 only the GCR20 response rate stayed significantly different (61% vs 42.3%; P = .03). At week 52, GCR50 (58% vs 38.5%; P = .03) and GCR70 (52% vs 30.8%; P = .01) response rates were significantly greater in the methotrexate group versus the placebo group.

“As gout therapeutic discussions and goals continue to work towards remission, which includes a treat-to-target [serum urate] approach, the patient perspective on both gout treatments and the [quality of life] impacts of gout become increasingly more important,” investigators concluded.

References

1. Botson J, Obermeyer K, LaMoreaux B, Padnick-Silver L, Verma S, Weinblatt ME, Peterson J. Quality of life and clinical gout assessments during pegloticase with and without methotrexate co-therapy: MIRROR randomized controlled trial exploratory findings. Rheumatol Adv Pract. 2024 Nov 29;8(4):rkae145. doi: 10.1093/rap/rkae145. PMID: 39678124; PMCID: PMC11646119.
2. Botson JK, Saag K, Peterson J, Parikh N, Ong S, La D, LoCicero K, Obermeyer K, Xin Y, Chamberlain J, LaMoreaux B, Verma S, Sainati S, Grewal S, Majjhoo A, Tesser JRP, Weinblatt ME. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings. Arthritis Rheumatol. 2023 Feb;75(2):293-304. doi: 10.1002/art.42335. Epub 2022 Dec 16. PMID: 36099211; PMCID: PMC10107774.