Clinician Q&A: Can Immunomodulators Improve the Effect of Pegloticase in Uncontrolled Gout?

Medical vials for injection with a syringe
Robert T. Keenan, MD, discusses the role of co-treatment with immunomodulators and pegloticase in patients with uncontrolled gout.

Pegloticase, a recombinant form of uricase that converts insoluble uric acid to allantoin, which is more easily excreted by the kidneys, is one of the few treatment options available for patients with uncontrolled gout. However, as a biologic, the efficacy of pegloticase is limited by the development of antidrug antibodies.1

There is growing evidence that co-treatment with pegloticase and an immunomodulatory agent attenuates antidrug antibody formation and greatly improves the efficacy of pegloticase. In a systematic review recently published in Seminars in Arthritis and Rheumatism, Keenan et al found that the pegloticase response rate was nearly twice as high (82.9%) with the concomitant use of an immunomodulator,2 compared with previous clinical trials that reported a 42% response rate with pegloticase alone.3

Pegloticase: “Last Hope” Medication for Uncontrolled Gout

There are approximately 9.2 million people in the United States with gout.4 Although the majority of patients with gout achieve a response to conventional therapies, there is a subset of this population in whom traditional treatments cannot be tolerated or fail, thus progressing to an uncontrolled disease state.5

Refractory or uncontrolled gout is characterized by serum uric acid (SUA) levels above 6 mg/dL. At these levels, urate deposits in the joints and soft tissues cause recurrent disease flares, progressive physical disability, and poor health-related quality of life, along with comorbidities such as diabetes, cardiovascular disease, and chronic kidney disease.6

Pegloticase is the only biologic therapy approved for refractory gout. Keenan et al explained, “By virtue of its [Food and Drug Administration] (FDA) indication, pegloticase is often administered as a ‘last hope’ medication for individuals with severe gout [in whom] traditional therapies [have failed].”2

“Some physicians have begun to try immunomodulation prior to and/or in conjunction with pegloticase in patients with uncontrolled gout, with the goal of minimizing antidrug antibody development and increasing the number of patients who fully benefit from pegloticase therapy,” they added.2

The formation of antidrug antibodies in response to biologic medications is not unique to gout. In patients with other autoimmune diseases, disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and mycophenolate mofetil, are commonly co-administered with biologics to minimize immunogenecity.7 However, the use of immunomodulators in patients with uncontrolled gout has not been well studied.

Immunomodulation and Pegloticase: A Systematic Review

In their systematic review, Keenan et al searched PubMed and the 2012 to 2020 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual meeting abstract databases.2 A total of 144 articles were identified in PubMed using the following search terms: “immunomodulator and pegloticase,” “immunomodulation and pegloticase,” “pegloticase and antidrug antibodies,” “pegloticase and DMARD,” and “methotrexate or mycophenolate or azathioprine or cyclosporin or tacrolimus or leflunomide or sulfasalazine or rapamycin and pegloticase.” An additional 87 meeting abstracts were found in the annual meeting databases using “pegloticase” as a search term.2

After eliminating duplicates, review papers, sources with insufficient information, and cases of off-label pegloticase treatment, and including 1 article found in an abstract that did not appear in the PubMed search, the researchers reviewed 7 articles and 3 abstracts describing 82 cases.2

The cases included the use of the following immunomodulators administered either before or during pegloticase treatment: oral methotrexate (n=31), subcutaneous methotrexate (n=9), leflunomide (n=6), azathioprine (n=11), and cyclosporin (n=1). In 2 cases, more than 1 immunomodulator was used.2

A double-blind randomized controlled trial that assessed pegloticase efficacy with mycophenolate mofetil immunomodulation was also included in the systematic review. This was the largest group of cases reviewed from a single source (n=22) and included a placebo group of 10 participants.8

The definition of a responder varied with each study, but generally required SUA levels to remain below 6 mg/dL for the entire study or a proportion of the study period.

Overall, the pegloticase response rate was 82.9%. Among the immunomodulators used, the response rates were 90.0% for oral methotrexate, 78.0% for subcutaneous methotrexate, 66.7% for leflunomide, and 63.6% for azathioprine. One patient who received cyclosporin was considered a responder, along with 2 patients who received multiple immunomodulators.2

In the mycophenolate mofetil trial, the response rate was 86% at week 12 and 68% at week 24 compared with 40% and 30% in the pegloticase plus placebo group at weeks 12 (P =.02) and 24 (P =.03), respectively.8

To gain further insight into the effect of immunomodulators on the efficacy and tolerability of pegloticase, and their clinical implications, in patients with uncontrolled gout, we interviewed the lead author of the systematic review, Robert Keenan, MD, adjunct clinical professor at Duke University School of Medicine, Durham, North Carolina, and rheumatologist at Florence Rheumatology Center, Articularis Healthcare, South Carolina.

What are the current gaps in treating patients with refractory gout?

Current and emerging data are beginning to amplify the systemic nature of gout and the extent of the burden that urate deposition can cause throughout the body. In fact, chronically elevated SUA levels that lead to gout can have serious and long-term consequences, like permanent damage to not only the bones and joint, but also in the organs. For example, in multiple studies, gout has been shown to be an independent risk factor for cardiovascular disease.9

As clinicians, we need to be adopting a more comprehensive and aggressive approach to treating uncontrolled gout – shifting the mindset of just addressing the acute pain of the condition – to address the pathophysiology of uncontrolled gout, working to urgently remove uric acid deposits from the body, and maintaining uric acid levels at a target level to avoid uric acid crystals from forming and redepositing.

How is the use of immunomodulators in combination with biologics unique to the treatment of patients with gout?

Co-treatment with immunomodulators is not a new concept in rheumatology. When we think of the way other inflammatory conditions, like rheumatoid arthritis, are treated, many approaches leverage DMARDs to prevent immunogenicity and mitigate the formation of antidrug antibodies for patients.

Immunogenicity has many potential consequences, including lower clinical responses and an increased risk for infusion reactions. However, real-world and clinical studies evaluating DMARDs in combination with urate-lowering therapies are not as well established, which is why this study2 is so important.

This is the first comprehensive look at publications and cases on the use of immunomodulation with pegloticase, and the conclusion is that numerous immunomodulatory agents could effectively improve response rates for pegloticase and provide patients and clinicians new options for treating uncontrolled gout.

What are the mechanisms by which immunomodulators increase the response rates of biologics?

Immunomodulators work by modifying a patient’s immune system and decreasing the production of serum antibodies. They allow for additional treatment options for diseases where immune functions may cause the formation of antidrug antibodies and limit response to treatment and long-term effectiveness of drugs, like pegloticase.

Assessing the use of immunomodulators in combination with pegloticase allows us to determine if they attenuate immune response and increase durability of response for patients with uncontrolled gout.

In the systematic analysis, you noted that co-prescriptions of immunomodulators with pegloticase have increased between 2016 and 2019. What are the next steps for more widespread co-treatment in patients with uncontrolled gout?

As we look to treat uncontrolled gout with the urgency that the condition requires, we should be compelled to understand which patients may benefit from co-treatment with an immunomodulator and pegloticase to help them achieve a complete response and their treatment goals.

There is currently a randomized trial underway evaluating pegloticase monotherapy vs pegloticase plus methotrexate of which preliminary results have been promising.10 Data from this large trial will give clinicians the additional evidence needed to use a co-treatment approach and for it to become the standard of care when using pegloticase.

Disclosure: Dr Robert Keenan has declared affiliations with the pharmaceutical industry.


  1. Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9(11):1319-1323. doi:10.1517/17425247.2012.720969
  2. Keenan RT, Botson JK, Masri KR, et al. The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review. Semin Arthritis Rheum. 2021;51(2):347-352. doi:10.1016/j.semarthrit.2021.01.005
  3. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720. doi:10.1001/jama.2011.1169
  4. Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999. doi:10.1002/art.40807
  5. Brook RA, Forsythe A, Smeeding JE, Edwards NL. Chronic gout: epidemiology, disease progression, treatment and disease burden. Curr Med Res Opin. 2010;26(12):2813-2821. doi:10.1185/03007995.2010.533647
  6. Francis-Sedlak M, LaMoreaux B, Padnick-Sillver L, Holt RJ, Bello AE. Characteristics, comorbidities, and potential consequences of uncontrolled gout: an insurance-claims database study. Rheum Ther. Published online December 7, 2020. doi:10.1007/s40744-020-00260-1
  7. Jani M, Barton A, Warren RB, Griffiths CEM, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). Published online August 14, 2013. doi:10.1093/rheumatology/ket260
  8. Khanna P, Khanna D, Cutter G, et al. Reducing immunogenicity of pegloticase (RECIPE) with concomitant use of mycophenolate mofetil in patients with refractory gout – a phase II double blind randomized control trial [abstract 0952]. Arthritis Rheumatol. 2020;72(suppl 10).
  9. Kaul S, Gupta M, Bandyopadhyay D, et al. Gout pharmacotherapy in cardiovascular diseases: a review of utility and outcomes. Am J Cardiovasc Drugs. Published online December 28, 2020. doi:10.1007/s40256-020-00459-1
  10. Botson JK, Tesser JRP, Bennett, R, et al. Pegloticase in combination with methotrexate in patients with uncontrolled gout: a multicenter, open-label study (MIRROR). J Rheum. Published online February 15, 2021. doi:10.3899/jrheum.200460