Home > Rheumatology > Adding methotrexate to pegloticase nearly doubles gout response rate

Adding methotrexate to pegloticase nearly doubles gout response rate

Dr John K Botson, Orthopedic Physicians Alaska, Anchorage
ACR 2021
MIRROR RCT (NCT03994731) phase III data support the combination of immunosuppression with pegloticase treatment for uncontrolled gout in all patients, raising the response rate from 40-42% to 71%. Medicom spoke with Dr John K Botson, (Orthopedic Physicians Alaska, Anchorage), which was highlighted at the annual American College of Rheumatology Convergence of 2021, which was held from 3 to 10 November.

Medicom: How did you think about combining immunomodulation agents to improve response with pegloticase? 

“This is a great story, a real journey. About 3 years ago, we were trying to treat these most refractory gout cases and really thing about how to do it better so that patients benefit and they can stay on therapy and things. Gout is a disease that has been around forever, and contrary to popular belief, it is largely determined by genetic factors, not only lifestyle choices. The burden on quality of life that gout imposes is substantial, and beyond gout itself, it is even associated with higher morbidity and mortality in patients with cardiovascular disease, it is associated with higher risk of metabolic syndrome and diabetes. Relieving patients of gout has both short-term and long-term benefits.

“We considered that the underlying pathophysiology driving uncontrolled gout is likely a chronic inflammatory process, perhaps similar to rheumatoid arthritis or lupus or other diseases that we deal with daily in rheumatology. It occurred to me and my colleagues that gout is actually a systemic problem that we need to treat better. You can tip the scale one way or the other either, by decreasing nitrogen input through reduced dietary protein intake, but that is riddled by variables you can’t control, such as the patient’s genetic makeup. Ultimately it is probably a better idea to get rid of the excess uric acid that is causing the problem.

“Pegloticase is given as an infusion every 2 weeks in later-line therapy to patients with terrible refractory gouts, where every oral medicine that we give does not work sufficiently. Quite frankly, the oral agents that we use are not that good. The cut-off for acceptable serum uric acid is 6 mg/dL, but we prefer to get gout patients under 5 mg/dL. If you have a patient with a serum uric acid of 11 mg/dL and they have tophi coming out of their fingers and toes, you are not going to be able to bring them below the cut-off with oral medication at that point. Remember, it takes years, even decades, for these folks to build up that much uric acid. You cannot turn that off overnight, essentially, with our oral agents.

“These the rare and extreme cases, people who are so burdened by gout that they have to call off a lot of days of work. These are the folks who are miserable, literally in bed-ridden from the disease.

“What really got us thinking about new approaches was that we have this great medicine, pegloticase. It literally dissolves the uric acid away and the medication has been around now about 9 years. However, it works effectively for less than half of patients. The clinical trials data inform us that as a monotherapy, pegloticase is roughly 42% efficacious. We know that even good responders may need 6-9 months of this treatment to achieve the threshold levels of serum uric acid because their disease can be so extensive.

“More than half, the other 58%, of the patients in those trials would get 1 or 2 doses of pegloticase, and we observed some consequent improvement. But then, by golly, the medication would just stop working. Those people are stuck at that point because they have no other treatments. We would have to say, Mr. Smith, I'm sorry. That is it. We do not have anything else.

“Dr Jeff Peterson in the Seattle area in Washington and myself asked ourselves about 3 years ago whether we could add other medicines onto pegloticase to improve outcomes. Immunomodulation, for example using methotrexate, is a standard practice in rheumatology, and we decided to try a pilot. We agreed that the next 10 patients we put on pegloticase, we would start them with a run-in period of methotrexate before their first pegloticase treatment, and keep them on methotrexate during the course of their treatment. At the end of 6 months after we met each other every month to check in on all the patients. We were amazed. All of the patients responded; it was 10 out of 10 patients [1].

“This initial data led up to the MIRROR trial. MIRROR was an open-label study combining methotrexate treatment with a 1-month run-in period to pegloticase, and 79% of the patients had a response [2]. Although this data was certainly promising, we really needed data from the gold standard, a randomised controlled trial, to change the recommendations is.

“We just got the results from MIRROR-RCT in the last 2 weeks; 71% had a response. Compared to pegloticase monotherapy, you are looking at nearly twice as many patients who responded. The placebo arm showed a response of 40%, which is exactly what we see in everyday patients on pegloticase monotherapy. We therefore are really confident that these data really represent real-world patients, these numbers are really solid and consistent across all studies.”

Medicom: With regard to safety, was the most common adverse event in the RCT as well, was it gout flares? 

‘’Yes, absolutely. Gout flares happen all the time, and even in these in these trials about 71% or so of patients have gout flare, generally in the first 3 months. We observed that the longer the subject stayed on the medication, the gout flare significantly reduced. We do things to try to help prevent flares, such as prophylaxis anti-inflammatories, corticosteroids or colchicine. Some patients also received IV steroids, such as methylprednisolone at the time of their infusion. In the old days we were using that to prevent infusion reactions, but currently, we think of it more of a gout flare prophylaxis or gout flare treatment, because that is probably really where it is most efficacious.”

Medicom: Once normal serum uric acid levels have been achieved after induction therapy with pegloticase, can you re-challenge with an oral drug for maintenance therapy? 

“That is exactly right. We are not curing gout. I wish we were, but we are not, the body is still going to probably accumulate uric acid. Depending a lot on the patient's genetics, they will eventually raise their serum uric acid again, because they are making more than they can get rid of, quite simply.

“I use a cooking metaphor: if you have salt and you are pouring it into the water, eventually the salt is going to sit down on the bottom of the pan. And that water will never be unsalted unless you get the salt out of the bottom of the pan. Pegloticase can get all that extra deposited salt out of the pan, but removing the immune response to pegloticase works even better. At that point we can keep up with the rest of the body processes, and an oral uric acid agent can now adequately keep their serum uric acid at goal. Sometimes it the same oral agent that failed the patient previously, now works better, and we can halve the dose. Patients get their life back.

“Going forward, to treat uncontrolled gout, we will be using methotrexate with pegloticase. We may be able to tweak the immunomodulatory agent to improve the response rate incrementally. We also are going to want to see the patient experience get better. Pegloticase is given over 2 hours by IV infusion, every 2 weeks. We are looking to see if we can speed that up, do it 30 minutes, or alternatively reducing the frequency. I think that is going to be the exciting part as we go forward.”

  1. Botson JK, Peterson J. Pretreatment and Coadministration With Methotrexate Improved Durability of Pegloticase Response: An Observational, Proof-of-Concept Case Series. J Clin Rheumatol. 2020 Oct 10.

  2. Botson JK, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021 May;48(5):767-774.

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