Robert Keenan, MD: Efficacy of Combination Therapy for Gout

This week Rheumatology Network interviewed Robert Keenan, MD, an adjunct associate professor at Duke University School of Medicine, for his study on “The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review.” A common issue for patients with gout is developing antidrug antibodies, also known as ADAs, which reduces and effectively neutralizes the efficacy of gout therapies. The study found that pegloticase in conjunction with immunomodulator combination therapy significantly increased pegloticase responder rates when compared with pegloticase monotherapy for patients with uncontrolled or refractory gout. The 82 cases studied from 10 different publications showed that the response rate for combination therapy using pegloticase was 82.9%, which was approximately double previous studies examining monotherapy response rates, which were 42%. Pegloticase is the only FDA-approved therapy for uncontrolled gout and the treatment options are quite limited. As the disease can have a severe effect on overall health, including quality of life and morbidity, this current responder rate for combination therapy is promising for patients suffering with more severe symptoms.

Rheumatology Network: Hi, Dr Keenan, thank you for joining me today.

Robert Keenan, MD: Thank you for having me.

RN: So to begin, why do you think there are so few treatment options for uncontrolled or refractory gout?

RK: That's a good question. And probably, while there's multitude of answers, quite honestly, they kind of accumulate to give us the end result. But basically, gout has always kind of been seen as this intermittent kind of comes-and-goes disease state that you can treat kind of intermittently and the patient’s treated and goes away and they feel better. And then a few months later might come back, unfortunately. And some patients will continue to be treated like that for the rest of their lives. And it's not a big deal. But then, there's a lot of patients, unfortunately, who as time goes on, they continue to accumulate those crystals in those joints, because their serum urate is not being adequately controlled and not low enough to prevent that from happening. And you end up with patients who have significant disability and morbidity and possibly mortality. But that's another conversation down the road. So it's kind of had this dogma around it. And unfortunately, it's just been perpetuated over the years and in the medical field in general, in medical education.

RN: Why is this medication so revolutionary for the treatment of gout, and how does it work within the body?

RK: So it basically does what we weren't able to do or stop being able to do back in the [mahcine error]. So it's thought that we lost the ability to break down your uric acid into something called allantoin. Millions of years ago, and us you know, us as humans, are all monkeys, the great apes, and for whatever reason, Dalmatians, lost this ability to break down, as far as mammals go, lost the ability to write down your acid allantoin, which our kidneys get rid of easily just we all get rid of it, excrete it and, and there's no issue with uric acid. And everybody's kidneys kind of handle it differently. Some handle it better than others, some people hold on to more uric acid than others. And over time, especially as we get older, our renal function isn’t as good, obviously, ad so we have a tendency to accumulate or hold on to more of it as we get older as well. And plus, if you have kidney disease of any sort, you're going to hold on to more of it. Certain medications, cause us to hold on to more of it. So what this medication does is put that enzyme back, so we're able to break down that uric acid into allantoin and treat it without any issues.

RN: Why do you believe that combination therapy yields so much better results when compared with monotherapy?

RK: So the Achilles, so to speak, for this medication from the pegloticase is, that some people and most people will develop antibodies against the polyethylene glycol, which it's made from Dr Hershfield, who was at Duke as well, developed this medication around 20 years ago or so. And at the time, used the technology that he had. And it basically required him to use a lot of pig molecules to kind of surrounding uricase, which is an enzyme that will kind of get used up. And he was wanting to make sure it didn't get used up too quickly or the or our immune system didn't go after the enzyme itself. So he pegylated it. And back then to there was a thought that, you know, peg was is relatively inert in our immune system doesn't do much with it or, or go after it, so to speak, which is turns out not to be the case. As we're realizing over the last 5 to 10 years, given all the other pegylated therapies that are out there. And what happens is that some patients will develop high titer antibodies against peg, which basically neutralizes the medication and keeps it from working. So the thought with this study was, and here, again, some of this came from Dr Hershfield, of work when he was trying to find some dosing studies. And he had taken and used a handful, actually 7, transplant patients that were on immunosuppressive therapy and found that most of those patients did really well with it had no issues with it. So that got us thinking a few years ago that maybe if we did the same thing, if we treat some of these patients with some immunosuppressive therapy or immunomodulating therapy, then maybe we could decrease their risk of developing those antibodies, which will increase their chance of success with this with this medication.

RN: The FDA indicated that this drug is seen as a “last hope” method for patients with severe gout. As it's been proven to be such an effective medication with a solid therapeutic response rate of almost 83%, why do you think it's seen as a last resort therapy?

RK: Well, it kind of speaks to the first question you asked me, unfortunately, and how and why are there any was seen as it is now? And why are there so few treatments for refractory gout, it that is the perspective that most providers in general in the medical field, and most people in general, feel that gout is “not that big a deal, quote.” And there's only a handful of patients, they get so bad, where they're having significant, morbidity and disability and a decreased quality of life from it, which is quite not true. There's probably a whole lot more folks out there than than that that have gout and it just kind of suffer in silence, basically. And because of that, you know, here again, is that dogma in how gout is perceived that the FDA kind of made that statement, where, I think a lot of those who a lot of us who have an interest in gout and kind of do gout research and are kind of goutologists, so to speak. We like to treat gout a little more aggressively and make sure people don't get to that point where they're having significant morbidity and a significant decrease quality life. We want to make sure they're not they're able to put on normal shoes, we want to make sure they're able to pick up a cup of coffee, we're going to make sure they can. I had a patient the other day that came in, and he said he's having trouble writing because the tophi on his hand were so large, he couldn't grip a pencil anymore. So his goal was to be able to write again, and those are kind of things that, you know, these patients should never get to that point. But unfortunately, they are and that's just due to the the treatment out there is sometimes limited for one reason or another.

RN: Can you briefly discuss the limitations of the study?

RK: Yeah, so, just like any, any other systematic literature review, retrospective study is going to have some limitations, especially with publication bias. We're looking at, you know, doctors like to publish what was successful not so much what was not successful. So that's kind of inherent in the study. But what we try to do to kind of look at it, and basically see how much that influenced our results, that 82.9%. We took out 2 trials that were clinical trials. There was 1 that was a randomized control trial, and then we took out another one's open label trial. And what we found was it went from 82.9% to 82.6%. And to further aim, looking at the look at that potential bias, we took out a single case reports and we only went down to 82.3%. So, it illustrates to me that even though there's that inherent bias in this study, I think this still illustrates some real-world data that can be kind of taken to the bank, so to speak.

RN: Absolutely. Are you planning on doing any further research for this medication specifically, or combination therapy for the treatment of gout?

RK: Yeah, definitely. Right now, there's actually an ongoing randomized clinical trial comparing monotherapy pegloticase With pegloticase plus methotrexate, so we'll hopefully have results in data from that trial by the end of the year, if not before.

RN: Awesome. Is there anything else that you'd like to add before we wrap up?

RK: Yeah, I mean, the biggest thing is I just want to, you know, I think this publication adds to the literature that emphasizes that gout is not just a disease of intermittent flares, and it's not just only worthy of intermittent management with nonsteroidals or colchicine, short bursts of prednisone, but rather it's a disease that requires significant, usually long term, ulrate lowering therapy and should be treated to having a target urate level. And that it's in some patients treating requires aggressive therapy. And I think that's important to remember, just like some rheumatoid arthritis patients and some psoriatic arthritis patients need more than 1 drug to get their disease state or the control, they might need a DMARD (disease modifying antirheumatic drug) plus a biologic, for example. And I think that a good analogy is look at some of these patients with gout. We're going to treat them the same way.

RN: I agree. Thank you so much for speaking with me today. I really appreciate it.

RK: You’re welcome and I appreciate you letting me talk about my favorite subject here.

Reference:

Keenan RT, Botson JK, Masri KR, et al. The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review [published online ahead of print, 2021 Jan 27]. Semin Arthritis Rheum. 2021;51(2):347-352. doi:10.1016/j.semarthrit.2021.01.005