ACR gout guideline: Strong recommendation should be presented as evidence-based discussion
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I applaud the authors of the 2020 American College of Rheumatology guideline for their comprehensive and thoughtful document on the management of gout.
As a participant in the drafting of the previous 2012 version, I fully appreciate the challenges in balancing evidence, well-trod and accepted practice patterns and the directives provided to the committee in the writing of these guidelines. Consistency and transparency are of paramount importance as these are guiding principles in striving to reach consensus recommendations.
It is never a surprise when “conditional recommendations” contained in clinical guidelines provoke discussion and some dissent amongst reasonable experts and practitioners in a specific clinical area. However, it is somewhat surprising when a “strong” recommendation prompts such discussion, particularly regarding issues which reflect an inconsistency with accepted basic principles of clinical management that are strongly supported elsewhere in the guidelines.
Weakness of the Argument
The guideline committee defined a strong recommendation as reflecting “decisions supported by moderate or high certainty of evidence [the bolding is mine] where the benefits consistently outweigh the risks and, with only rare exceptions, an informed patient and his or her provider would be expected to reach the same decision.”
Thus, I am surprised by the guideline authors strongly recommending against switching to pegloticase over continuing current ineffective (“ineffective” is my addition) urate-lowering therapy in patients with gout for whom “XOI treatment, uricosurics, and other interventions have failed to achieve the SU target, but who have infrequent gout flares (<2 flares/year) and no tophi”.
There is no existent evidence supporting this recommendation. There are no data indicating harm in taking the counter approach. Yes, it is certainly more expensive to utilize pegloticase in the short-term as opposed to continuing the previously suboptimal therapy. However, there are no data indicating that the long-term cost of intervening earlier with a potentially effective therapy – for a limited period of time, and then reverting to traditional oral urate lowering therapy – as opposed to continuing with what is clearly stated to be suboptimal therapy, is more expensive.
With continuation of the suboptimal therapy, attacks are likely to increase in number over time as uric acid deposition continues to increase. Thus, this strong recommendation favors waiting until the disease has progressed, as it is expected to do based on previous observational data, prior to introducing potentially effective therapy.
The guideline authors clearly and transparently rationalize their recommendation by stating that the expected improved clinical outcomes with pegloticase come with too “high costs.” Shouldn’t what is characterized as too “high costs” be a topic for shared discussion between patient and physician? An argument for a “conditional recommendation” – predefined by the committee as a scenario “for which the benefits and risks may be more closely balanced and/or only low certainty of evidence or no data are available” – could have been more appropriately considered.
Countering the ACR recommendation
The clinical reasoning provided in support of this strong recommendation is disturbing to me. The expectation that all patients with known hyperuricemia and gouty arthritis having few attacks and no palpable tophi at a given time will continue to have few attacks and remain stable in terms of their uric acid deposition in the future is fallacious.
In fact, this is directly counter to the underpinnings for the accepted concept of treat to target: in patients with uric acid deposition and gout, the uric acid deposition will continue to accrue so long as the serum urate level remains higher than its saturation point (estimated at ~ 6.8mg/dL); successful therapy will maintain a urate level significantly below this. Why should it be strongly recommended that a suboptimal, likely ineffective, therapy be continued, permitting additional deposition to occur, based on the current infrequency of symptoms?
Ironically, an argument against this approach was strongly made by many ACR members in response to a previous conceptually similar recommendation made by the American College of Physicians! From my own experience, dissolution of baseline uric acid deposition with a course of pegloticase has permitted in several patients a successful transition back to traditional urate lowering therapy, at doses that had previously been ineffective. Aggressive urate-lowering therapy is a reasonable and rational therapy to be considered, for some patients with few attacks at the current time, but persistent biological hyperuricemia despite utilizing urate-lowering therapy.
In their Table 5, the recommendation authors again transparently convey their clinical reasoning for this strong recommendation by stating, “for patients with minimal disease activity [the bolding, again, is mine], the smaller potential benefits do not outweigh the harms and costs of the drug”.
I spend hours with gout patients every week decrying this clinical reasoning. The frequency of gout flares does not define disease activity. Having few flares does not equate with minimal disease activity. Disease activity in gout is the deposition of uric acid as tophus in and around soft tissues, including joints, tendons and bursae, even if not easily palpated as “tophi.” A gout flare should be viewed as a symptom, not as the disease.
The active deposition of unstable cholesterol-rich plaque within the coronary arteries is the disease activity of atherosclerosis; an acute coronary event is a symptom. We don't debate the need to treat an elevated LDL because a patient has only had one acute coronary syndrome a year.
I most certainly do not imply that every patient with an above-target serum urate level, despite receiving usual urate-lowering therapy, should receive pegloticase, an expensive and time-intensive treatment, and one that has been associated with described potential side effects.
However, I believe that decision should be made following dialogue between an informed patient, physician and often the patient’s insurance carrier. That dialogue should not be colored by a strong recommendation by the ACR that is not supported by strong evidence or strong consistency with previously identified principles of gout management. For some patients experiencing limited gout symptoms at a given point in time, aggressive intervention consistent with well-established treat-to-target principles does make sense.
References:
- Fitzgerald JD et al. Arthritis Care Res. 2020; doi: 10.1002/acr.24180.
- Shoji A, et al. Arthritis Care Res. 2004; doi: 10.1002/art.20405.
For more information:
- Brian F. Mandell, MD, PhD, FACR, MACP, is professor and chairman of academic medicine in the department of rheumatic and immunologic diseases at the Cleveland Clinic.
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