Vikas Majithia, MD, and Ronald Butendieck, MD, on the Continuing Challenges of Gout

Drs Majithia and Butendieck provide some perspective on the continuing issues surrounding the diagnosis and effective treatment of gout, the most common inflammatory arthritis in the US.

Vikas Majithia, MD, is a senior associate consultant in the division of rheumatology at Mayo Clinic-Florida in Jacksonville. Ronald Butendieck, MD, is a consultant in the division of rheumatology at Mayo Clinic-Florida.

TRANSCRIPT:

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your host, Rebecca Mashaw, and I'm delighted to have here today Dr. Vikas Majithia, who is a senior associate consultant at Mayo Clinic in Florida, and Dr. Ron Butendieck, who's a consultant in the division of rheumatology there. And they're going to be talking with us today about gout, which is, I understand, the most common inflammatory arthritis in the United States. So I'm going to go ahead and turn this over to the experts.

Dr Majithia: Dr Butendieck, I'm glad that you're here and we're talking about gout. That's a topic we don't get to talk a lot about. And one of the things that keeps on bothering me and when I see the literature is somewhat disappointing that, despite having a lot of questions, about 3% or so of patients are achieving the target that is recommended. And so in brief, what are the challenges which are faced by these patients when we are approaching their treatment and what are the reasons for it?

Dr Butendieck: So I think there's quite a few challenges, unfortunately. Patient compliance actually remains a huge challenge in treating gout patients. Gout flares tend to be intermittent, especially in the early stages. So it can be difficult to convince patients to take a daily medication for their gout when they are asymptomatic the majority of the time. Therefore, patient education is extremely important. Now, however, with time constraints on the provider, especially at an urgent care center or an emergency department, it can be challenging to slow down and explain to patients the importance of reducing the uric acid level with long-term medication, not just to treat the flare at hand.

Another challenge is prescriber undertreatment. So prescribers may not initiate urate-lowering therapy due to patient unwillingness to take another medication or fear of conflicting comorbidities. Some providers may start urate-lowering therapy but fail to titrate the dose to achieve a target uric acid level.

Now patient comorbidities can add yet another level of complexity to treatment. For example, dose adjustment of medications may be necessary in patients with chronic kidney disease. Urate levels are increased in patients taking diuretics, tacrolimus, and cyclosporin, such as in our transplant population. Higher doses of allopurinol are needed to achieve target uric acid level in patients with obesity, statins increase the risk of colchicine toxicity, and we have to be judicious with corticosteroid use in patients with diabetes.

Finally, some patients have refractory disease or prominent tophaceous disease requiring more advanced therapy. These are very important and difficult challenges.

Dr Majithia: And I hear you talking about patient being the center, but also education being one of the biggest premises of how we can mitigate this gap between what we need to achieve on the target. One of the things that I do want to ask you is with the currently available urate-lowering therapies and also diet, what is in your experience usually achieved by these patients? The bottom line is how effective are they?

Dr Butendieck: Diet in and of itself can be helpful to reduce the uric acid level a little bit, but it is certainly not sufficient. What's most important actually is avoiding certain foods that have high levels of purines, which are basically the building blocks of proteins and get metabolized throughout the body and kind of lead to development of uric acid, unfortunately which then crystallizes and kind of forms these problems in the joints and other tissues and cause gout flares. So what we really want to educate the patients on is trying to avoid these certain types of foods and drinks such as alcohol, shellfish, red meats, that kind of stuff, because not only do they increase the uric acid level but they can also trigger flares for patients. So diet certainly has a part in treatment but it's not sufficient. So therefore xanthinoxidase inhibitors we have 2: allopurinol and febuxostat are really kind of the cornerstone in trying to get control of the uric acid level and lower it below 6 mg /dL as kind of the target.

And we know that if we're able to do this, then we can effectively start removing the uric acid from the body, remove these crystals, and therefore reduce the patient's risk for developing flares in the future.

Dr Majithia: Frequently, a number of these patients are more difficult to treat despite having access to these medications. What are these medications for these patients who are difficult to treat?

Dr Butendieck: Well, patients who unfortunately either can't tolerate the usual therapies with allopurinol or febuxostat, or if they unfortunately have had those maximized but yet they're still not able to get to target, we do have another option. Pegloticase was actually FDA-approved in 2010, specifically for patients who have had those maximized refractory to conventional therapy. This IV medication is a recombinant, pegylated, porcine uricase that rapidly converts a relatively insoluble urate to highly water soluble allantoin, which is freely excreted in the urine. It's been shown to be very effective, but early trials noted that a portion of patients would fail to respond and be at a higher risk for infusion reactions. Now further investigation found that these failures could largely be attributed to development of high-titer antidrug antibodies to the pegloticase.

Dr Majithia: So are there any interventions where what would need to be taken to mitigate the risk of developing this antidrug antibody and find a way to get these patients to tolerate this seemingly wonderful therapy for gout in difficult to treat cases?

Dr Butendieck: So fortunately, yes. The addition of a concomitant immunosuppressive therapy such as methotrexate, leflunomide, mycophenolate, or azathioprine has been shown to significantly improve responder rate to the pegloticase by reducing the development of these antidrug antibodies. For example, the MIRROR open-label trial showed a 6-month pegloticase plus cotherapy responder rate of 79% compared to an established 42% pegloticase monotherapy responder rate. This led to the FDA approving coadministration of methotrexate with pegloticase in 2022 for these patients. So most people, we would start methotrexate with pegloticase.

Dr Majithia: In the patients who have an issue with methotrexate what is your approach in those patients?

Dr Butendieck: So, alternatives to methotrexate would be things like a leflunamide, azathioprine, or mycophenolate, but again, it really depends; your point is well taken, it depends on the patient's comorbidities of which of these medications you would choose.

Dr Majithia : And in your opinion and experience, they are relatively equally effective?

Dr Butendieck:  They are, they actually do very, very nicely and the trials have shown that.

Dr Majithia: Right, so based on this new data, how do you now approach starting an appropriate patient on pegloticase therapy?

Dr Butendieck: So it is recommended by the label to administer the methotrexate therapy 4 weeks prior to and during the pegloticase therapy. This gives the methotrexate time to kind of calm down and to lower the immune system, reduce the development of these antidrug antibodies to increase the outcomes in these patients. And we also want to make sure that we watch these patients very closely because we have learned through clinical trials and experience that starting these patients on pegloticase does increase their risk for gout attacks. So we have to be very cautious and also be aware so that we're ready to treat the flares of gout when they do occur.

Dr Majithia: We really appreciate this great insight into management of gout in 2024. Is there any final summary statement would you like to make for our listeners?

Dr Butendieck: We really do need to treat gout very seriously; it is, as was brought up, the most common inflammatory arthritis in the United States but also the world and the prevalence and the incidence is increasing globally. There's lots of theories behind this, but also diet plays a part in that as well in lifestyle choices. We really need to take these patients seriously and we really need to get the uric acid level at target for the betterment of these patients and to have long -term good outcomes.

Dr Majithia: Thank you. I could not agree more. We have effective therapies, we just need to make sure we get those to these patients and get them to the target. And again, thank you again for coming on this podcast.

Dr Butendieck: Thank you for having me.