Background to Gout

Orrin M. Troum, MD: Hello, and welcome to a Rheumatology Network™ Between the Lines program [titled “New Treatment Paradigms in Gout”]. Today’s featured article is about pegloticase in combination with methotrexate in patients with uncontrolled gout, in a multicenter open-label study called the MIRROR RCT trial. I’m Dr Orrin Troum, a clinical professor of medicine and voluntary faculty member at the division of rheumatology at the Keck School of Medicine at the University of Southern California [USC, in Los Angeles]. I’m in practice in Santa Monica, affiliated with the Providence health care system. I’m joined by Dr Jeff Peterson, a rheumatologist specialist in Bothell, Washington, associated with the University of Washington Medical Center. In today’s discussion we’ll review the practical and clinical implications of the MIRROR RCT study and discuss the impact of pegloticase combined with an immunomodulator.

In this first part of the program, I want to get into the background to gout. I’m going to ask you if you can discuss the burden of gout on patients’ quality of life. I’ll ask 3 other questions, and then we’ll return to discuss, the treatment landscape of gout treatment, which urate-lowering therapies are available, how the treatment landscape has evolved over the past few years, which treatment options are available for patients who have failed to achieve target urate levels, and recent advances in the treatment of gout and what unmet needs remain. Let’s start with the beginning and talk about the burden of gout on the patients’ quality of life.

Jeff R. Peterson, MD: Thanks, Orrin. When patients have a flare of gout, they describe it as if somebody was tearing off their skin and putting acid on. I can imagine how terrible it is. I know it’s completely incapacitating to most patients during the flare. What we don’t recognize is that in chronic or uncontrolled gout, the tophaceous material builds up over time. That leads to many other disabilities, so patients don’t want to go for a walk with their family, play with their children, or even go to work because their hand hurts too much. Many patients become disabled because of this. The quality-of-life issue is dramatic. I’ve seen it. When we treat patients well, they get their life back, and they’re so happy.

Orrin M. Troum, MD: As rheumatologists, and for other health care providers taking care of patients with gout, we’ve found that when their gout is controlled, they lead an otherwise normal life—other than other comorbidities, which we’ll get into later. The landscape regarding treatment of gout hasn’t changed much over the decades since I started at USC in 1980. I remember some of the therapies we had available to us then. Things haven’t changed much. What urate therapies are available that you use? I’d suggest what I’m using, but it can’t be much different because there aren’t that many.

Jeff R. Peterson, MD: You’re absolutely right, Orrin. There are very few choices. They talk about using probenecid, which is a uricosuric agent. But we rheumatologists almost never use the drug. Most of our patients have renal insufficiency. Uricosurics usually causes kidney stones, which is probably as bad or worse than gout, so we don’t use it. There are also a lot of drug interactions with probenecid. In Europe they have other uricosuric agents available. They probably don’t have them here because it causes liver issues, so we don’t see a lot of the uricosuric agents.

Allopurinol is the classic 1 we always use. It’s inexpensive and generally well tolerated, but often primary care doctors, or even rheumatologists, don’t push the dose up enough to get adequate treatment from it. However, there are patients who don’t respond or who have adverse effects. We also have febuxostat, or Uloric, which is the other medication we use. That’s our cadre of medications. In the last 10 years we’ve had Krystexxa, or pegloticase. That’s been a game changer, especially now that we’re using immunomodulation.

Orrin M. Troum, MD: We’ll be talking more about that. Some of the other caveats about what you brought up were about using allopurinol, which is the first xanthine oxidase inhibitor that we used. We typically start at 100 mg, and may go up to 200 or 300 mg. Most of the patients I’ve seen that are referred to me have started on 300 mg, and most physicians and other health care providers don’t push the dose. I’ve had several patients that are on 800, 900 mg of allopurinol. Once you get past 300 mg, you’re supposed to split the dosing [to twice a day].

There’s 1 caveat about that in patients who may not be able to tolerate it, especially certain genetic components of having the specific HLA gene, [particularly] in the Han Chinese, Korean, or some Asian populations. Those patients should be screened prior to starting allopurinol or febuxostat. We’re going to talk a lot more about pegloticase, or Krystexxa. In fact, that comes up in our next question: what treatment options are available for those who have failed to achieve their target urate level? This is going to be the meat of our discussion. You already brought up pegloticase for patients with uncontrolled gout and tophaceous gout.

The last part of this is about the unmet needs that remain. I’d like to get your thoughts. You see certain populations—in Washington, on the West Coast, in Hawaii—where other patients have a significant unmet need. Can you talk a little about that?

Jeff R. Peterson, MD: You’re absolutely right, Orrin. Many patients aren’t being treated, and the unmet need is getting them to us or to somebody who has comfort in treating gout. We have medications that can work. Especially now that we have pegloticase, we can debulk these patients and get their uric acid levels low, get rid of the tophaceous burden, and reinitiate oral therapy at a much lower dose—a more tolerable dose. As you know, allopurinol has a ceiling effect. You can go only so high before it stops working and you don’t get any more bang for your buck.

Even though the insurance companies would like us to keep pushing it up to as high a level as we can, it stops working. Studies have shown that of patients taking adequate doses of allopurinol or Uloric, about half achieved serum uric acid with less than 6 mg/dL. I don’t know about you, but I try to cheat my patients down to 4.5 mg/dL or lower because that’s going to help get rid of the sodium urate burden quicker. The lower the uric acid, the faster the crystals will dissolve. It increases risk for infusion reactions, gout flares, etc, but we can talk about that later. Now that Krystexxa is out there and we’re using immunomodulation, we’re getting a dramatic improvement in the response rate. That’s where the unmet need lies: getting those patients to us.

Orrin M. Troum, MD: That’s a critical point. If it’s not a rheumatologist, the only other folks who feel comfortable utilizing this medicine are nephrologists. There may be others who are the only doctor in town who knows about Krystexxa, so fortunately those patients are able to get to them. It’s an urgent need to have these patients recognized with uncontrolled gout so that they can get it under control. We’re not going to talk too much about the comorbidities surrounding gout, but there are plenty. There are increased incidences of cardiovascular disease, heart attacks, and even death around having uncontrolled gout.

You mentioned something very important. You’ve talked about once they’re off the Krystexxa, which in my experience is between 9 and 12 months—I have several patients who have gone longer and a few who have gone shorter. Hopefully you’re going to make the point about this being a last resort for some patients. They’re urged to stay on the medicine if they can and then go back on urate-lowering therapy because this is a lifelong disease. That’s important. The other important aspect is, as they go on to Krystexxa, they should have stopped their xanthine oxidase inhibitors prior to initiation of pegloticase.

Transcript edited for clarity