Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
AVOIDING MOBILIZATION FLARES WHEN LOWERING URATE: START LOW, GO SLOW
Dr. Mandell: Let’s shift from this focus on the hospital setting as a precipitant for acute gout attacks and recall that the most predictable precipitant is when we pharmacologically reduce the serum urate level in an effort to decrease the total body load. As Larry noted, the down side of this very necessary intervention is that “mobilization flares” of gout are fairly predictable in this setting. While many of us have used prophylaxis to reduce the likelihood of these flares, we hadn’t had much data on duration of prophylaxis prior to some recent trials of urate-lowering therapy.36 So what are your practices now for trying to reduce the chance of acute attacks as you introduce urate-lowering therapy?
Dr. Edwards: A trigger for gouty attacks is the fluctuation of serum urate levels, be it from initiating or discontinuing urate-lowering therapy. So the approach when initiating urate-lowering therapy is to start low and go slow with your dose escalation. Most of us now buy into the notion of trying to lower the serum urate below 6.0 mg/dL for most patients, and perhaps by another 1.5 mg/dL or so for patients with bulky tophaceous disease. To get to that target, however, you should start with a fairly modest dose of whichever urate-lowering therapy you’re using—allopurinol, febuxostat, or (in rare cases) probenecid—and increase it over time. I tend to let several weeks pass between each dose escalation to ensure that the prior escalation has had time to drop the urate to its new nadir, and then I see what that level is. If it’s not at target, I will modestly escalate further.
Dr. Mandell: And we should emphasize that frequent initial monitoring of urate is appropriate to determine whether you’re reaching your target.
Dr. Edwards: That’s a critical element that isn’t done well in this country. Many studies show that regular monitoring of serum urate after initiation of urate-lowering therapy is actually a rarity. The approach to urate monitoring should be the same as for glucose monitoring with oral diabetes medications or blood pressure monitoring with antihypertensives. We should know what impact we’re having on the patient and continue to adjust the dose to find the appropriate level for the individual patient.
As with the therapies for acute gout, there is no onesize-fits-all dose regimen for urate-lowering therapy. A minority of patients will do fine on 100 mg/day of allopurinol. Most patients will still not reach their serum urate target at 300 mg/day of allopurinol, and we should consider gradual escalation to more generous doses as necessary, beyond 400 mg/day and up to the “maximum” recommended dose of 800 mg/day. Monitoring of serum urate should then continue even after we’ve found an appropriate dose to reach the target level since certain factors may change, altering concentrations of any of the urate-lowering therapies. For instance, a new drug may be added, or the patient may develop new comorbidities or a change in renal function. At this point the monitoring need not be as tight as during the initial period, but it should continue on a semiannual or yearly basis.
Dr. Simkin: I completely agree that going slow is desirable, and it’s very important for our patients to understand what we’re doing and what we’re aiming for. Every gout patient should know what his or her last serum urate level was, yet very rarely is that the case.
Dr. Edwards: Not only that, but they should know what the target level is so that they become an equal partner in their treatment plan, just as diabetics might be unsatisfied until their hemoglobin A1c is down to near 6.0%.
WHAT ROLE FOR PROPHYLAXIS DURING URATE LOWERING?
Dr. Mandell: Larry’s point that dropping the serum urate level slowly over time is less likely to induce an attack of gout is something we had suspected for a while and now have some direct trial evidence for. But no matter what we do, there’s always some likelihood of inducing an attack as we lower the urate level. So what do you do, Peter, to prevent those attacks?
Dr. Simkin: I try to get the patient on a regular dosage of colchicine prophylaxis. There’s good evidence that it’s effective. The dose is usually one or two tablets a day, largely depending on GI tolerance. It’s worth noting that more than a few of my elderly patients appreciate colchicine’s GI effects, as they provide some welcome relief from their chronic constipation. While that’s certainly not welcome by everyone, for some patients it makes colchicine prophylaxis an easier sell.
Dr. Sundy: Colchicine is my standard for prophylaxis as well. I think it’s highly effective.
Dr. Edwards: For how and when to start prophylaxis, my general recommendation is that it should precede the start of urate-lowering therapy by about 1 or 2 weeks. I think starting colchicine 2 weeks in advance is probably a good buffer for ensuring that it’s in the system. The urate-lowering therapies have very rapid onset—allopurinol will cause fluctuations in urate levels within a day or two—so the prophylaxis has to be fully on board.
Dr. Pile: Do you have a sense of how much more effective twice-daily dosing of colchicine is compared with once-daily dosing?
Dr. Edwards: I don’t have a good sense of it, but I tend to use twice-daily dosing unless renal function is a concern—specifically, if the patient’s GFR is between 50 and 60 mL/min/1.73 m2. And in such cases, you’re not really diminishing the dose with a once-daily regimen because the patient is keeping more of the drug around, in light of the renal insufficiency. That hearkens back to Peter’s earlier comments about baseline therapy with statins, some calcium channel blockers, and other drugs that will also require dose modification.
Dr. Mandell: The point is that we want to maintain a certain level of colchicine in all our patients for prophylaxis. It’s not clear that the blood level matters as much as the intracellular level, but we can’t routinely measure either. I think the answer to Jim’s question is that we don’t have data on whether once daily, twice daily, or even three times daily is the right regimen for colchicine prophylaxis; patients differ. I believe many of us start with twice-daily dosing on an empirical basis. If it’s not tolerated, typically for GI reasons, we’ll go down to once a day. If it’s tolerated but ineffective from the point of view of having flares, we may try to go to three times a day, assuming the patient’s not on other medications that would preclude that and doesn’t have chronic kidney disease or hepatobiliary disease.
WHAT ABOUT ALTERNATIVE PROPHYLAXIS OPTIONS?
Dr. Mandell: If a patient is truly intolerant of colchicine but has a reasonable GFR and no comorbidities, what about alternative prophylactic agents? The class to think about would seem to be NSAIDs, but we have no trial data to guide us with their use for prophylaxis. What’s been your experience with NSAIDs for prophylaxis of gout flares during the urate-lowering process?
Dr. Sundy: My experience is that NSAIDs are effective for this. I don’t have a notion of comparative effectiveness relative to colchicine, but I will use an NSAID in this setting when there has been GI intolerance to colchicine. The trick is the added responsibility of monitoring toxicity in terms of blood pressure, renal function, and hyperkalemia, as well as offering gastric protection, but I certainly have patients on NSAID prophylaxis.
Dr. Mandell: Do you feel compelled to use the same very high doses that we talked about for treating acute attacks of gout?
Dr. Sundy: No. I tend to use doses in more of a midrange area and make adjustments based on how the patient is doing. For example, I might increase the dose if a patient has a breakthrough flare.
Dr. Simkin: A situation where I’ve more often seen NSAIDs used for prophylaxis is in patients who have gout but are also taking NSAIDs on a regular basis for osteoarthritis. In that setting I’d be less inclined to add colchicine.
Dr. Pile: And I guess cost becomes an issue now, with the advent of branded colchicine, in a way that it hadn’t been before. At my local retail pharmacy generic naproxen costs 6 cents per 200-mg tablet, so some NSAIDs are very inexpensive.
Dr. Mandell: Colchicine used to have a similar cost invisibility as well. As Peter said before, our ability to provide cost-efficient prophylaxis is disappearing, and this may affect our ability to provide prophylaxis to some patients.
Dr. Sundy: I agree. Many times patients will stop taking drugs that are too expensive for them without telling their doctor. I sense that not using prophylaxis is a major impediment to adherence with urate-lowering drugs as well, as patients will stop those drugs because they sense appropriately that their gout has gotten worse without having been adequately educated about this risk. At the end of the day, we’re trying to eliminate gout as a medical issue for our patients, and anything that makes nonadherence more likely can be a big impediment to this goal.
Dr. Edwards: Patient education is absolutely crucial in this regard. We should step back and appreciate that these regimens can be very complicated and not terribly obvious from the patient’s perspective. First you have the disease gout, for which the treatment is allopurinol. You take that treatment and then your gout gets worse. Without good education to prepare patients for that, how can we expect them to respond, other than wanting to stop the allopurinol and probably thinking poorly of their doctor? Physicians have to educate patients on what to expect and how to stay the course. We must make clear from the start that the treatment of gout is a long-term process. We must explain that when acute flares occur the emphasis is on getting rid of the pain quickly but that the larger job of getting their disease under control by lowering their uric acid levels over time is a long haul. Both patient and physician have to be patient, go slowly, and make sure they don’t disrupt therapy just because symptoms are occurring.
Dr. Sundy: It sounds funny, but sometimes I’ve taken to congratulating patients whose gout flares after they start urate-lowering therapy. I say, “This is great—it means the drug is working, even if it doesn’t seem like it.”
