Concomitant use of immunomodulators prolonged the effectiveness of pegloticase in patients with uncontrolled gout. Results from a large observational study were consistent with previously conducted smaller trials.1 The combination strategy of pegloticase and immunomodulators did not result in elevated toxicity rates compared with patients who were treated with pegloticase as monotherapy. Medicom interviewed first author of the study, Huifeng Yun, PhD, Associate Professor of Epidemiology at the University of Alabama, who presented the results of the study during the annual American College of Rheumatology Convergence of 2021, held November 3-10.
Pegloticase, a recombinant pegylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, is FDA-approved for the treatment of uncontrolled gout. The development of anti-drug antibodies can, however, result in a reduced efficacy of pegloticase, an increased risk of infusion-related events, and discontinuation of the therapy. It has been suggested that concomitant use of immunomodulatory drugs may enhance the treatment persistence of pegloticase .2,3 In their retrospective analysis, Dr. Yun and colleagues included 700 patients with uncontrolled gout who were treated with pegloticase, 124 of whom received concomitant immunomodulators.
After a median follow-up of 14 months, patients receiving pegloticase plus immunomodulatory therapy were less likely to discontinue therapy than patients who did not receive immunomodulators. This result remained intact after adjustment for potential confounding demographic and medical factors (HR, 0.57; 95% CI, 0.43-0.78). In addition, abnormal laboratory values were reported in less than 5% of the patients, regardless of received therapy.
Medicom’s correspondent interviewed Dr Yun to learn more:
Medicom: What should we tell our patients about pegloticase?
Dr. Yun: Pegloticase is very important, because it is really beneficial for the patients who have previous treatment failure or very severe gout. And in those situations, that’s going to be very important to be able to use pegloticase, because pegloticase just works so dramatically and drops their uric acid immediately. Although I am not a physician, I have seen some really, really huge tophi, but once patients started taking this medication, they just went away.
Note, this is not first-line medication for gout patients, but patients should know there is another option if—for whatever reason—they are not able to use other types of medications, or if other therapies fail to control their symptoms. They should know that there is a safe and effective way to relieve their pain. No one should be suffering from gout anymore. It is also important to tell patients that no matter what medications they use, we should be vigilant that they follow their doctor’s prescriptions and instructions carefully, to make sure these flares or recurrences do not happen as frequently.
For refractory patients, this is an efficient drug, although it’s very expensive. But for individuals who have very high uric acid, for a long time, and despite other therapies their gout persisted or even progressed, watching uric acid levels drop precipitously after just a couple of pegloticase injections is amazing. Their quality of life is simply restored.
However, fewer than half of patients respond adequately to pegloticase monotherapy. We postulated that non-responders probably develop some immunogenicity to pegloticase, by producing anti-drug antibodies, which in turn, nullify the effect of pegloticase. Our rationale was that adding immunomodulatory drugs might help retain the function of pegloticase.
Our data strongly supported that notion; within a month, more than 90% of patients who had 4 weeks of immunomodulation therapy prior to pegloticase dropped to below the 6 mg/dL threshold.
How would you explain the extra effect of immunomodulators when added to pegloticase?
Immunomodulation attenuates anti-drug antibody formation. By using a 4-week run-in period with immunomodulators prior to the first pegloticase infusion, and then continuing immunomodulation during the pegloticase treatment period, we have seen hard numbers that patients are significantly less likely to discontinue treatment, and they are also probably less likely to acquire intolerance.
Does it matter which immunomodulator is added?
All immunomodulatory drugs we have tested to date—including methotrexate, mycophenolate mofetil, leflunomide, and azathioprine—seem to be effective. However, because of the small sample sizes for each of these agents, we were not able to separate differences in the efficacy between them or compare them directly. What was really clear, however, is that when we lumped all these medications together, patients are less likely to discontinue treatment when provided concomitant immunomodulation. Future studies with bigger sample sizes are needed to distinguish the effects of individual immunomodulatory agents.
What are the next steps for research in this area?
We simply need to obtain more data, not only in sample sizes, but also to make sure we get more lab values and report the sequence of the lab results compared with treatment events. It makes it very hard to identify clear patterns when it is not indicated which lab values, such as white blood counts and platelets, were obtained relative to infusion of pegloticase. Sometimes, patients have their blood drawn and analyzed prior to infusion, sometimes afterwards, and that is not usually clearly denoted. When you are trying to develop indicators or markers for efficacy when the total number of outcomes is relatively rare, there can be a lot of data lost due to poorly defined protocols about consistent acquisition of basic lab results. I believe that it is relatively easy to improve the quality of the data we can get by systematically including lab results into our analyses.
Definitely not all patients experience “a miracle” when taking pegloticase, even with immunomodulation. We need to understand who these patients are who do not respond, and how we can further help them. Gout impacts patients so badly, and if by taking immunomodulatory drugs we can delay their intolerance to reduce their blood urate levels and resolve their tophi, we will help patients continue to respond and definitely alleviate their symptoms. The hope is that after induction of response with pegloticase, we will be able to maintain these patients on more standard oral therapies.
