Optimizing Treatment of Refractory Gout · Optimizing Treatment of Refractory Gout CME / ABIM MOC Overview of Gout[1] Let me start with a definition of gout. Many patients and even

$Page 1: Optimizing Treatment of Refractory Gout · Optimizing Treatment of Refractory Gout CME / ABIM MOC Overview of Gout[1] Let me start with a definition of gout. Many patients and even$
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Optimizing Treatment of Refractory Gout CME / ABIM MOC

www.medscape.org/case/refractory-gout

Optimizing Treatment of Refractory Gout

CME / ABIM MOC

Supported by an independent educational grant from Horizon Pharma



Target AudienceThis activity is intended for rheumatologists, nephrologists, and primary care physicians.

Goal The goal of this activity is to update clinicians who manage patients with gout on the latest evidence-based recommendations on the appropriate treatment of this condition, particularly in refractory cases.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the• Available treatments to achieve sufficient gout control, particularly in refractory cases• Approaches to managing safety concerns• Strategies to ensure effective use of urate-lowering therapies

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www.medscape.org/case/refractory-gout



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Disclosures

Moderator

Kenneth G. Saag, MD, MScProfessor of Medicine University of Alabama at Birmingham Birmingham, Alabama

Disclosure: Kenneth G. Saag, MD, MSc, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Horizon Pharma; Sobi, Inc.; Takeda Pharmaceuticals North America, Inc. Received grants for clinical research from: Horizon Pharma; Sobi, Inc.; Takeda Pharmaceuticals North America, Inc.

Panelist

Robert T. Keenan, MD, MPHDuke University School of Medicine Duke University Health System Durham, North Carolina

Disclosure: Robert T. Keenan, MD, MPH, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Dyve Biosciences; Horizon Pharma; Selecta Biosciences, Inc. Served as a speaker or a member of a speakers bureau for: AbbVie Inc.; Janssen Pharmaceuticals; Regeneron Pharmaceuticals, Inc.

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Sara Fagerlie, PhD, CHCPSenior Medical Education Strategic Director, Medscape, LLCDisclosure: Sara Fagerlie, PhD, CHCP, has disclosed no relevant financial relationships.

Emilie McCardellFreelance Medical Education DirectorDisclosure: Emilie McCardell has disclosed no relevant financial relationships.

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Esther Nyarko, PharmDAssociate Clinical CME Director, Medscape, LLCDisclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.



Optimizing Treatment of Refractory Gout

Kenneth G Saag, MD, MSc: Hello. I am Dr Ken Saag, Professor of Medicine in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham. Welcome to this program titled “Optimizing Treatment of Refractory Gout. Joining me today is Dr Rob Keenan, Vice Chief for Clinical Affairs in the Division of Rheumatology at Duke University in Durham North Carolina. Welcome Rob.

Robert T Keenan, MD, MPH: Thank you Ken. It is great to be here.

Dr Saag: Today’s program will include a discussion of data that has been presented in abstract form. These data should be considered preliminary until they have been published in a peer-reviewed journal.



Overview of Gout[1]

Let me start with a definition of gout. Many patients and even for some clinicians consider gout to be a nuisance condition, but we know that it is a progressive debilitating form of arthritis that is caused by an elevation of serum urate (sUA), also known as serum uric acid.[1] Excess sUA can deposit in the joints, leading to painful inflammation that is mediated by interleukin-1 (IL-1).[8,24] People with severe gout describe pain with the a simple bedsheet touching an extremity such as a toe.



Prevalence of Gout[2]

We know that the prevalence of gout has been increasing. Most recent data from the National Health and Nutrition Examination Survey show that the prevalence is approximately 4%, and among men older than 70 years of age, the prevalence may approach 8%.[2] It is the most common form of inflammatory arthritis in men, and indeed gout has a male predominance. We do not commonly see gout in women until after menopause, although it can affect younger women and men, in particular those with genetic abnormalities and urate overproduction. Rob, please begin by discussing how we identify patients as having gout.



Gout: More than Podagra

Dr Keenan: Typically, gout manifests as a swollen, red toe that is extremely painful – as mentioned, it hurts for the bedsheet to touch it. Gout can also affect other joints, however, which can pose additional challenges when a clinician is evaluating a patient with swollen, red, hot knee, elbow, or interphalangeal joint.

Dr Saag: Are there other things that are useful in making the diagnosis? What other approaches have found helpful in classifying someone as having gout?



ACR Gout Classification Criteria[3,4]

Dr Keenan: Definitely. Needle aspiration can be used to test for monosodium urate crystal depositions.[3] In addition, the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) have developed a gout classification criteria.[4] The criteria involve a point system that requires ≥8 points to establish a classification of gout. For example, elevated sUA will be designated 4 points if it is >10 mg/dL, and if it is <4 mg/dL, the scoring system calls for minus 4 points. The classification criteria can be helpful in trying to establish a diagnosis of gout without drawing fluid from the joint.



Imaging in Gout

Dr Saag: Should clinicians rely on the criteria to diagnose gout or is it more commonly used in conducting studies?

Dr Keenan: It is used more as criteria for research, but it can be used to help confirm diagnoses.

Dr Saag: It lays out the key criteria that you should be considering, including imaging.

Dr Keenan: Exactly. Dual energy computed tomography, for example, can be extremely helpful.

Dr Saag: Yes. It is an impressive technique that shows depositions of urate in the soft tissues and around the joints. Ultrasound is also useful.

Dr Keenan: Ultrasound is able to show microtophi, or small depositions of crystals in the joint, that might not be visible on clinical examination.

Dr Saag: When I see a patient with a bunion who has a history of gout or is having acute gout, I typically order radiographs of the feet, and I am surprised by how many times I see subtle changes in the first metatarsophalangeal (MTP) joint that ultimately are consistent with the classic radiographic appearance of gout. Early on it may be subtle, but later it is possible to see the typical overhanging edge, the absence of significant joint space narrowing, and some soft tissue haziness consistent with tophi.

Dr Keenan: Sometimes early changes will be determined to be an early bone cyst from osteoarthritis, which can be accurate, but it also may be gout. Over time, as the degradation of bone continues, the patient’s joints may take on a “rat bite” appearance, which is a classic sign of gout.

Dr Saag: I encourage all my fellows to look at radiographs because I find that sometimes the radiologists do not always pick up the subtle findings that we may see.



Dr Keenan: Yes, they do not have the advantage of the clinical examination as we do.

Dr Saag: Exactly. Let us talk more about refractory gout. How do you identify a patient as having treatment-refractory gout?

Identifying Patients With Severe or Refractory Gout[1,5]

Dr Keenan: Treatment refractory gout is a term that does not necessarily refer to patients who are refractory to treatment. It can also refer to patients who have been undertreated for years and have developed significant morbidity and disability from gout.[1] Patients may have multiple flares over months and years or just 1 flare a year but they have a draining tophus that it will not heal, which makes them susceptible to infection. Patients with severe gout can have significant disability: They cannot put on a normal shoe because they cannot put their foot inside, or they cannot pick up a cup of coffee or hold a pen. This represents severe or refractory gout.[5]

Dr Saag: Yes. A variety of types of refractory patients are seen: some have severe gout, and existing therapies have been inadequate; some patients may not be able to get access to therapy or may be nonadherent to therapy; and some patients are not well served by clinicians who do not manage the disease adequately. These are all problem patients that we see.

Dr Keenan: With respect to adherence, patients’ lack of understanding may be the biggest issue. They do not always fully appreciate why they should remain on a medication, the purpose of the medication, and the medication’s potential adverse events.

Dr Saag: Well it is a challenging disease initially. Patients may have a couple of attacks a year before you think about starting uric lowering therapy. Patients can then occasionally experience disease flares before they get better, which emphasizes the need to maintain the urate lowering therapy and to prophalax appropriately with colchicine or occasionally a nonsteroidal anti-inflammatory drug (NSAID) to help prevent flares that can occur as you lower serum urate levels.



Characteristics of Severe Gout[5,6]

Dr Keenan: Exactly. The ACR defines refractory severe gout as >4 tophi or a draining tophus and multiple flares per year.[6] I tend to be a little more aggressive in managing gout: just because a patient can have 1 flare a year for many years, the disease can suddenly result in significant disability from the accumulation of the crystals, not only in the joints but along the tendon sheaths and other uncommon locations.[5,7]

Dr Saag: It is progressive, and the increase in prevalence of obesity and associated cardiovascular disease, and chronic kidney disease (CKD)are conditions that predispose to hyperuricemia; these are part of the epidemic of gout. More often, patients first present with severe refractory gout that often manifests with tophi at the rheumatology clinic.

Dr Keenan: By the time we see patients most have a tophus or tophi.



Implications of Uncontrolled Gout[5,7,8,22]

Dr Saag: Let me move on to discuss some of the concerns about hyperuricemia and associated comorbidities. The literature is growing that shows relationships with hypertension, heart disease, kidney disease, stroke, metabolic syndrome, diabetes, and nonalcoholic fatty liver disease and hyperuricemia.[5,7,8,22]

Often, we are posed with a chicken and egg-type conundrum. For example, we know that if you treat a patient with hypertension with a diuretic, the patient is more likely to develop gout. Studies of gout pathophysiology in laboratory animals, however, shows that you can induce glomerular hypertension by inhibiting the uricase that is normally produced in rats and that causes hyperuricemia.[25] Data also show that, particularly in adolescence, early hypertension may be responsive to urate lowering.[26]

Let us turn now to just reviewing treatment in general. What are your treatment goals?



Treatment Goals in Gout[5,6,9]

Dr Keenan: The first step is to speak with the patient about his or her preferences: what does the patient want out of this? Does the patient want to be gout-free, gout flare-free, or improve any comorbidities or combination thereof? Most patients never want to have another flare again.

Next I help them understand how we get to a flare-free state. I will discuss how we are going to do it, target a urate level of <6 mg/dL or sometimes <5 mg/dL,[6] depending on how fast we want flush out deposits of urate crystals, whether it is the joint or soft tissue, and how severe the disease may be based on morbidity and number of flares per year.

Dr Saag: What do you see as the primary target for urate lowering therapy? What do you aim for?

Dr Keenan: In the general gout population, you aim for <6 mg/dL. I tend to shoot for <5 mg/dL, as do the British Society of Rheumatology.[27]

Dr Saag: If the patient has major deposits, tophi, and imaging evidence of joint damage, that is a target we have embraced in rheumatology.[5,6,9] Debate about this treat-to-target-strategy is ongoing, nevertheless. Our colleagues in general medicine have questioned this strategy, but in my view are misinterpreting some of the data from pegloticase studies, for example, or some of the follow-ons to some of the large randomized controlled trials. Many observational studies show that as we reduce serum urate we decrease flares and reduce tophi burden. We see this clearly with some of our more powerful therapies.

We do need a well done treat-to-target versus treat-to-symptom strategy study. As rheumatologists, given the absolute essential component of urate and the pathophysiologic process of gout, it seems logical that you would want to lower serum urate levels much like you treat high glucose levels in patients with diabetes or lower blood pressure levels to prevent strokes in patients with hypertension. It is clearly in the causal pathway to the gouty outcome.



Dr Keenan: I agree. In a handful of patients, it may be acceptable to treat the symptoms only, but only a handful. In fact, it may be considered unethical to design a study assessing a treat-to-target arm versus a symptomatic treatment arm, because over time the patients receiving treatment for symptoms only are going to develop severe disease.

Dr Saag: We have talked a little bit about who you treat. Do you have particular criteria that you use? You mention that you tend to be a little more aggressive in using urate-lowering therapy. Are there certain rules that you follow?

ACR Management Guidelines: Use of Pharmacologic ULT[6]

Dr Keenan: The ACR guidelines recommend pharmacologic urate-lowering therapy in patients with tophus or tophi, frequent attacks consisting of ≥2 or more a year.[6] We will also treat patients with CKD stage 2 or worse, even if they had only 1 flare. Treatment is also appropriate in patients with a history of urolithiasis, especially urate stones.



ACR/EULAR Treatment Recommendations[6,8,10]

Dr Saag: Let’s review the standard therapies. When we think about acute management, we are talking about 3 groups of agents: NSAIDs, colchicine, and glucocorticoids. Rarely, I might add a fourth agent, an IL-1 inhibitor. Although IL-1 inhibitors are not currently approved in the United States to treat gout flare, it has been used off-label in patients who are treatment refractory.[8,24]

A lot of the patients I see have contraindications to the use of NSAIDs, such as heart failure, hypertension, or an increased risk for gastrointestinal bleeding, so we are often limited to colchicine and steroids. Colchicine works well, especially if it is used early. Steroids are also effective, but it is often necessary to use a higher dose than the traditional dose-pack strategy. In addition, it may be necessary to continue the steroid regimen longer. Steroids can be especially effective when injected into the affected area, but this can be difficult when a tendon sheath or an MTP joint is involved. The midfoot is especially difficult, but ultrasound may help in that regard.

What are your approaches to urate lowering therapy? How do you pick between the standard drugs that we have available?

Dr Keenan: Typically, I use allopurinol first because it has been around a long time, is relatively inexpensive, and covered by most payers. It is also effective if it is titrated appropriately and the patient does not have any early signs of adverse events. When a patient has issues with allopurinol, whether it is a rash or nausea, I may switch to febuxostat, which also works well but is more expensive and more difficult to get. If the patient’s disease is not adequately controlled with allopurinol or febuxostat, I have titrated one or the other up to maximum dose.

Dr Saag: That is an important point. Quality indicators in gout stipulate that clinicians must ensure that the dose of whatever urate lowering therapy is used is appropriately titrated to achieve target.[6,28]



Allopurinol[6,11]

Dr Keenan: Clinicians might start with 50 mg or 100 mg allopurinol based on renal function and then slowly titrate up.[6] Clinical practice and the literature show that if you start low and go slow, the patient is less likely to develop adverse events, in particular, allopurinol hypersensitivity syndrome.

Dr Saag: In contrast, a study conducted in New Zealand showed that titrating allopurinol slowly, particularly in patients with CKD, may not be necessary.[11] What about the testing for HLA-B*5801? Are you doing that routinely in your practice?

Dr Keenan: Only if patients have the right background. In patients who are of Han Chinese or Korean descent, I screen for HLA-B*5801. If also screen patients of Korean descent who have CKD.

Dr Saag: HLA-B*5801 is a marker that is strongly associated in the correct at-risk population with a higher rate of allopurinol hypersensitivity.



Febuxostat[6,12,13]

Let us talk more about febuxostat, because it has been in the news lately regarding cardiovascular safety. A large study comparing febuxostat with alopurinol was mandated by the FDA based on early safety signals associated with febuxostat.[12,13] It is interesting that the primary endpoint did not show a difference in terms of cardiovascular events, but there was a greater rate of cardiovascular and all-cause mortality. How have you put that into context? I know that it has led to some changes in the labeling of febuxostat,[12] and it has raised some questions in our dialogue both with patients who are on the drug as well as those who were thinking about starting on it.

Dr Keenan: So far it has not changed my practice much, because the data are a bit muddy. The day after the updated label was announced, I saw a patient who was on febuxostat 80 mg who had a myocardial infarction (MI) between the time I saw him last and that day. He came to my office and reported that he did not want to discontinue the febuxostat. He said, “Well, I’m being monitored now, so I’m good. I don’t want to stop taking the drug.”

Dr Saag: The study did have some problems, such as a high rate of losses to follow up and there was no placebo control group. Is it possible that allopurinol is slightly more protective against cardiovascular events than febuxostat? A large European study is expected to add to this and provide more data.



Pegloticase for Refractory Gout[7,15-17]

Next I want to discuss pegloticase, a drug that we have had some experience with in managing patients with severe gout who are treatment refractory. Data show that it has resulted in profound reductions in serum urate. We know that humans do not naturally produce uricase, so the idea is to provide replacement therapy with this enzyme, but because it is an enzyme it has to be pegylated to allow it to have biological persistence, which creates some issues related to its administration. What does your typical pegloticase patient look like?



Pegloticase for Refractory Gout: Tophi, Uric Acid Reductions[7,16]

Dr Keenan: My typical patient is the patient with significant disability whether it is a hand or both hands, a foot or both feet, or the knees. These patients will have significant tophus or tophi and elevated sUA. I have also used it in a patient with 1 draining tophus who was at risk for an infection because of this open wound. These are the patients in whom I typically use pegloticase. I describe it to patients as similar to a debulking agent used in patients with cancer.

Dr Saag: It is akin to induction chemotherapy. We want to treat these patients with severe gout with something that is going to work fast to reduce the tophi burden, and there is no other way to do that rapidly to the degree that we see with this therapy.



Pegloticase for Refractory Gout: Safety[18,19]

The pegloticase molecule is large, and as a result it is immunogenic and patients may experience a rise in sUA over time.[19] Typically, when pegloticase is used, sUA drops to undetectable levels -- our lab reports levels of <1.5 mg/dL. Sometimes, however, particularly in younger patients and patients with stronger immune systems, we see a rise in sUA. In some circumstances, it may be appropriate to stop the drug to avoid infusion reactions. What can we do to counter immunogenicity?



Limiting Risk for Pegloticase Immunogenicity[19,23]

Dr Keenan: We can do a couple of things. To decrease the risk of adverse events, we can follow sUA levels, and if it goes >6 mg/dL, it is appropriate to consider discontinuing pegloticase. Again, I am more aggressive and I have a lot of experience with the medication, so I might push it above 6 mg/dL to see whether the patient is truly developing antibodies and resistance.

Another useful strategy is to add methotrexate before starting the pegoticase[19,23] or add azathioprine, which we reported on as well.[29]



Investigational Agents for Refractory Gout[20,21]

Dr Saag: Studies are underway that are looking at that. A uricase is currently under investigation that is combined with rapamycin. Have you seen the data?

Dr Keenan: Yes. The data are promising.[20,21] This is pegadricase plus synthetic vaccine particle bound to rapamycin, called mTOR. The idea is that the rapamycin product will decrease the immunogenicity of pegadricase.

Dr Saag: Rheumatologists are not particularly familiar with that drug but we certainly do have experience using drugs such as methotrexate, azathioprine, and mycophenolate with other biologic agents to prevent immunogenicity. This could be a strategy that might help temper an issue that, in my view, is one of the few things that limit the use of this therapy.

Dr Keenan: I recently put a patient on pegloticase who developed whose sUA level rose to >6 mg/dL after his second infusion, but he still seemed to be at least a partially responding, so we continued the drug. I recently started him on methotrexate to see if we could get an improved response.



Limiting AEs in the Management of Gout[6,10,13,18,19]

Dr Saag: We talked about adverse events with pegloticase and febuxostat. I think it is fair to say that all of our therapies in gout, like drugs used in other diseases, have the potential for adverse events. This is particularly so with some of our acute therapies, NSAIDs, steroids, and colchicine. You have to always balance risk and benefit.

Dr Keenan: It is important to explain these issues to patients. Most, especially if they have severe gout, are willing to take the risks to achieve the benefit.

Dr Saag: It has been great reviewing all of this information with you and hearing how you manage difficult-to-treat gout patients. Let me spend a minute and just summarize.



Concluding Remarks

We have talked a bit about refractory gout and highlighted that the prevalence of gout is growing. Patients seen at our medical centers in areas where gout is highly prevalent will often have refractory gout. We have newer data on some of our older therapies, and we have some newer therapies such as pegloticase that are being used successfully in patients with severe gout.

Safety issues exist. For example, new questions have emerged around febuxostat. Ultimately, we have to figure out who is best suited for a given therapy. We must try whenever possible and with the patient’s input to optimize therapy and to manage the risk and benefits.



Thank You

Rob, it has been great having a chance to hear your expertise today, and I look forward to discussing gout with you more in the near future.

Dr Keenan: I appreciate the opportunity. Thank you, Ken.

Dr Saag: Thank you for participating in this important educational activity.



Abbreviations

ACR = American College of RheumatologyAE = adverse eventBL = baselineCKD = chronic kidney diseaseCV = cardiovascularEULAR = European League Against RheumatismFDA = US Food and Drug AdministrationFU = follow-upHRQoL = health-related quality of lifeIL = interleukinmTOR = mechanistic (mammalian) target of rapamycinNHANES = National Health and Nutrition Examination SurveyNSAID = nonsteroidal anti-inflammatory drugPPI = proton pump inhibitorRCT = randomized controlled trialsUA = serum uric acidULT = urate-lowering therapyXOI = xanthine oxidase inhibitor

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23. Botson J, Peterson J. Pretreatment and Coadministration with Methotrexate Improved Durability of Pegloticase (Krystexxa) Response: A Prospective, Proof-of-Concept, Case Series [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/pretreatment-andcoadministration-with-methotrexate-improved-durability-of-pegloticase-krystexxa-response-aprospective-proof-of-concept-case-series/. Accessed April 29, 2019.

24. So A, Dumusc A, Nasi S. The role of IL-1 in gout: from bench to bedside. Rheumatology (Oxford). 2018;57(suppl_1):i12-i19. 25. Lu J, Hou X, Yuan X, et al. Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia

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Optimizing Treatment of Refractory Gout · Optimizing Treatment of Refractory Gout CME / ABIM MOC Overview of Gout[1] Let me start with a definition of gout. Many patients and even