Pegloticase Benefit Enhanced When Combined With Methotrexate for Patients With Chronic Gout
The addition of methotrexate bolstered responses to pegloticase among patients with chronic, refractory gout, according to study results1 published in Arthritis Research & Therapy.
Approximately 9.2 million people in the United States, or 3.9% of adults, have gout.2 It is more prevalent in older populations and affects men more often than women.2 Gout develops in some patients with hyperuricemia, a condition wherein there is excess uric acid in the body. The uric acid crystallizes and accumulates in joints, tissues, and fluids.3
Although gout flares commonly affect 1 joint, flares can occur in multiple joints at once, usually the big toe, lesser toe joints, ankles, and knees. Symptoms of a gout flare include intense pain, swelling, redness, and heat in affected joints.3
For most patients, gout flares tend to resolve over 2 weeks without treatment. However, repetitive flares can result in permanent joint damage, leading patients to develop chronic gouty arthritis.2 Additionally, chronic high levels of uric acid are associated with the formation of tophaceous deposits or tophi, which are hard deposits under the skin that over time may cause pain, bone and soft tissue damage, and misshapen joints.4
Urate-lowering medications are strongly recommended5 for patients with gout, especially those with tophi, radiographic evidence of gout-related damage, or at least 2 flares per year. Allopurinol, a xanthine oxidase inhibitor, is currently recommended as the first-line therapy for all patients. Other treatment options include febuxostat and probenecid, but guidelines indicate febuxostat should be selected over probenecid for those with moderate-to-severe chronic kidney disease.
If patients fail to reach a target uric acid level of less than 6 mg/dL while on treatment and continue to have flares and tophi, guidelines recommend switching to pegloticase.
Combining Immunomodulators With a Uric Acid Therapy
Pegloticase is an intravenous pegylated uricase enzyme indicated for patients with gout who have received at least 2 prior therapies. Pegloticase functions by converting uric acid to allantoin, a molecule that can then be excreted through the kidneys.1
Clinical research on pegloticase monotherapy shows 42% of patients respond over a 6-month period, and 26% of patients experience infusion-related reactions.1
“Though the initial response to treatment is robust, many patients develop anti-drug antibodies (ADAs) to the therapy and are unable to complete a full course of treatment,” said John K Botson, MD, RPh, CCD, affiliated with Alaska Regional Hospital, and coinvestigators. “Anti-pegloticase antibodies that develop following pegloticase exposure are associated with both loss of urate-lowering effect, through increased pegloticase clearance, and a higher risk of [infusion reactions].”
To curb the development of ADAs, physicians began administering immunomodulators alongside pegloticase, such as methotrexate, leflunomide, and azathioprine. Dr Botson and coinvestigators conducted the open-label MIRROR trial to test the efficacy and safety of methotrexate plus pegloticase.
Key Findings From MIRROR
The MIRROR study1 involved 15 male patients with uncontrolled gout—defined as serum uric acid (sUA) ≥ 6 mg/dL. Patients were eligible for inclusion if they were unable to maintain sUA < 6 mg/dL while taking other therapies, intolerant to their current therapy, or had functionally limiting tophi.
The participants were aged an average 49.3 ± 8.7 years and had an average gout history of 13.8 ± 7.4 years. Almost all (13 of 14; 93%) patients had clinically evident tophi, and their average sUA level was 9.2 ± 2.5 mg/dL.
Patients began a 4-week methotrexate run-in period, during which 1 patient was lost to follow-up. Subsequently, the 14 remaining patients were treated with pegloticase plus methotrexate. Of these, 11 participants completed treatment through week 24, while 3 participants discontinued pegloticase due to a rise in sUA.
Pegloticase initiation was associated with a rapid reduction in sUA. Researchers found sUA was 0.0 ± 0.0 mg/dL at week 24 (change from baseline -9.3 ± 2.8 mg/dL, n = 11) and 1.1 ± 2.5 mg/dL at week 52 (change from baseline -8.2 ± 4.1 mg/dL, n = 10).
Response rates were 76.9% and 69.2% at weeks 36 and 52, respectively. All 8 patients who remained on pegloticase plus methotrexate therapy through week 52 responded during these intervals with sUA levels of 0.0 ± 0.0 mg/dL (change from baseline -9.4 ± 3.3 mg/dL), according to the findings.
“Thirteen patients (92.9%) experienced gout flares during treatment,” two of which were severe, Dr Botson and coauthors reported. “However, both the number of patients on treatment who flared, and the frequency of flares decreased over time.”
In the first 12 weeks of treatment, 13 of 14 patients experienced 4.2 ± 2.3 flares (range 1-8 flares). During weeks 37 through 52, however, flare frequency had dropped to 2.5 ± 0.7 (range 2-3 flares) and occurred in only 2 of the 8 remaining patients.
Regarding safety, 10 patients (66.7%) experienced an adverse event during the methotrexate run-in period, which included gout flare (n = 5), nausea (n = 2), and abdominal discomfort (n = 2). All patients experienced at least 1 adverse event while receiving pegloticase and methotrexate together, the most common of which was gout flare (n = 13), followed by diarrhea (n = 3), nasopharyngitis (n = 3), upper respiratory tract infection (n = 3), muscle strain (n = 3), and arthralgia (n = 3). There was also 1 infusion reaction in which a patient developed a temporary cough after their fifth pegloticase infusion at week 8.
The mean estimated glomerular filtration rate remained stable throughout the study, signaling there was no worsening of hepatic or renal function while patients received treatment, authors said.
Dr Botson and coauthors concluded their data “strongly suggest that methotrexate reduces immunogenicity to pegloticase, allowing more patients to accomplish treatment goals from full courses of therapy with a reduction in previously seen adverse effects.”
Researchers also recommended larger, randomized, placebo-controlled studies be conducted to further investigate the combination therapy’s efficacy and safety.
References:
- Botson JK, Tesser JRP, Bennett R, et al. A multicentre, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase (MIRROR): 12-month efficacy, safety, immunogenicity, and pharmacokinetic findings during long-term extension of an open-label study. Arthritis Res Ther. 2022;24(208). doi:10.1186/s13075-022-02865-z
- Yip K, Berman J. What is gout? JAMA. 2021;326(24):2541. doi:10.1001/jama.2021.19770
- Gout. Centers for Disease Control and Prevention. Reviewed July 27, 2020. Accessed February 2, 2023. https://www.cdc.gov/arthritis/basics/gout.html
- Gout. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Reviewed February 2020. Accessed February 2, 2023. https://www.niams.nih.gov/health-topics/gout
- Guidelines for Treating Gout. Arthritis Foundation. Accessed February 15, 2023. https://www.arthritis.org/diseases/more-about/gout-treatment-guidelines
