2020 American College of Rheumatology Guidelines for the Management of Gout

Introduction

The current American College of Rheumatology (ACR) Guidelines for the Management of Gout were released in 20201 and represent an update on the 2012 ACR guidelines. The new guidelines incorporate the GRADE methodology2 and systematically review recent literature to produce specific recommendations for the management of gout. While the core principles of gout management remain largely unchanged, the 2020 guidelines introduce notable changes in approach, emphasizing patient preferences, treatment costs cardiovascular (CV) safety. Unlike the 2012 guidelines, the 2020 guidelines refrain from specifying serum urate (SU) thresholds for various patient subsets, offering a generalized threshold of <6 mg/dL for severe cases. A significant change is the preference for allopurinol as the first-line urate-lowering therapy (ULT) for all patients, including those with chronic kidney disease (CKD), due to cost considerations and emerging CV safety concerns with febuxostat. The 2020 guidelines offer more focused recommendations based on higher quality studies, with conditional recommendations meant to involve shared decision-making between patients and providers. Additionally, the 2020 guidelines expand the indications for ULT to include individuals with radiographic damage from gout and introduce conditional recommendations for ULT use in patients with infrequent flares or a first flare with high hyperuricemia. The “medication in-pocket” strategy for gout flare management remains a preferred approach.

Indications for Pharmacologic ULT

The 2020 ACR guideline recommendations on the initiation of ULT are shown in Table 13-1.The guidelines advise initiating ULT in patients with subcutaneous tophi, gout-related radiographic damage, or frequent gout flares. Clinical trials have provided high-certainty evidence regarding the effectiveness of ULT in reducing flare frequency, tophi SU concentrations. For those experiencing infrequent flares, ULT can be considered, although the potential clinical benefit may be lower compared to patients with more severe gout manifestations. Notably, one study demonstrated that patients with ≤2 previous flares who received ULT were less likely to experience subsequent flares. Urate lowering therapy is discouraged for patients experiencing their first gout flare, but it may be considered for patients with comorbid moderate-to-severe CKD, elevated SU concentrations, or a history of urolithiasis. In such cases, the prevention of gout progression development of clinical tophi make ULT a viable choice, emphasizing the importance of shared decision-making between patients and their healthcare providers to assess the potential benefits and risks of treatment. For patients with asymptomatic hyperuricemia, including those with MSU crystal deposition, the 2020 ACR guidelines generally do not recommend starting ULT, given that the benefits of ULT may not outweigh potential treatment costs or risks for the majority of patients.

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Recommendations for Choice of Initial ULT for Patients with Gout

The 2020 ACR guideline recommendations on the choice of initial ULT agent are presented in Table 13-2. The guidelines prioritize allopurinol as the preferred initial treatment for all patients due to its effectiveness, tolerability, safety cost-efficiency. Conversely, initiating pegloticase as a first-line therapy is strongly discouraged. For individuals with moderate-to-severe CKD, the guidelines recommend choosing either allopurinol or febuxostat over probenecid. When initiating ULT, the guidelines advise a cautious approach by starting with a lower dose and gradually increasing it. This method aims to minimize the risk of gout flares associated with the initiation of ULT. The guideline patient panel emphasizes a preference for safer prescribing regimens, that begin with lower doses and gradually escalate, even if they require more monitoring and provider visits. Furthermore, the guidelines recommend administering anti-inflammatory prophylaxis therapy concurrently with ULT to prevent gout flares. Continuing the prophylaxis therapy for 3–6 months is preferred over shorter durations, with ongoing evaluation and further prolongation as necessary if gout flares persist. This comprehensive approach aims to optimize gout management and enhance patient outcomes.

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Recommendations for All Patients Receiving ULT

The 2020 ACR guidelines present 4 specific recommendations applicable to all patients on ULT (Table 13-3). Focusing on a strategic and patient-centered approach, the guidelines emphasize the treat-to-target strategy, characterized by ULT dose titration to achieve a target SU (<6 mg/dL). Robust evidence demonstrates enhanced adherence, reduced SU concentrations, fewer tophi decreased gout flares compared to fixed-dose ULT regimens. Moreover, the delivery of an augmented ULT dose management protocol by non-physician providers and incorporating patient education and shared decision-making is advised to optimize the treat-to-target strategy. However, the guidelines recognize that the availability of such resources may vary in different healthcare settings.

Starting ULT during a flare, rather than after its resolution, should be considered as this approach offers practical advantages, such as time efficiency and increased patient motivation due to acute symptoms. However, there are concerns about potential flare worsening and information overload for patients, though the evidence is limited. For patients on ULT, even those in remission for a year with no tophi, continuing ULT indefinitely should be considered due to noted instances of flare recurrence and a general patient preference for ongoing treatment, provided that it is well-tolerated.

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Recommendations for the Use of Specific ULT Agents

In addition to the general recommendations applicable to all patients on ULT, the 2020 ACR guidelines also contain specific recommendations for patients on allopurinol, febuxostat uricosurics (Table 13-4). Before initiating allopurinol, genetic testing for the HLA–B*5801 allele is advised, especially for patients of East Asian, Southeast Asian African American descent. This recommendation is based on the significantly elevated risk of allopurinol-induced severe hypersensitivity syndrome (AHS) associated with the HLA–B*5801 allele. Due to higher prevalence in these populations, testing is crucial to identify individuals at greater risk. However, for patients from other ethnic backgrounds with lower allele prevalence, the necessity and cost-effectiveness of universal testing are less evident. For those with a prior allergic response to allopurinol, who cannot be treated with other oral ULT agents, allopurinol desensitization should be considered, with the recognition that desensitization protocols are not commonly used and that many rheumatologists may have limited experience with them.

For patients taking febuxostat who have a history of cardiovascular disease (CVD) or a new CVD-related event, switching to an alternative oral ULT is advisable, if available and consistent with other treatment recommendations. This recommendation aligns with the FDA prescribing information black box warning for febuxostat and takes into account data from clinical trials and observational studies. While there is no clear difference in the primary composite CVD outcome between febuxostat and allopurinol, febuxostat has been associated with a higher risk of CVD-related death and all-cause mortality. However, interpretation of these data is complex due to high dropout rates and lack of an untreated control group. In this context, the guidelines emphasize shared decision-making, especially for high-risk CVD patients.

For patients being considered for or already receiving uricosuric treatment, checking urinary uric acid and alkalinizing the urine are not encouraged. This is due to the challenges associated with 24-hour urine collection and nomogram-based testing (which can be influenced by diet and may not provide substantial clinical benefit) a lack of supporting evidence, respectively. While the use of uricosurics remains infrequent, the 2020 ACR guidelines align with the previous guidelines in stating that add-on therapy to partially responsive xanthine oxidase inhibitor (XOI) treatment can result in improved SU control. However, the guidelines support the standard best practice that patients with known renal calculi or moderate-to-severe CKD should not be treated with uricosurics.

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When to Consider Changing ULT Strategy

The 2020 ACR guidelines also offer three recommendations on when to consider switching to other ULT agents (Table 13-5). For patients experiencing persistently high SU concentrations despite maximum-tolerated or FDA-indicated XOI dose frequent gout flares or non-resolving subcutaneous tophi, the guidelines suggest switching to a second XOI instead of adding a uricosuric agent. Although several studies have demonstrated the benefit of adding a uricosuric medication to XOI treatment, the guidelines lack direct evidence for this choice. If the patient has not achieved the SU target and continue to experience frequent gout flares or non-resolving subcutaneous tophi despite XOI, uricosurics and other interventions, the guidelines emphasize a switch to pegloticase over continuing current ULT. Clinical trials have shown improved SU concentrations, reduced flare frequency diminished tophi among patients receiving pegloticase, although this approach involves higher costs and potential allergic reactions. However, for patients with infrequent gout flares and no tophi, a switch to pegloticase is discouraged, as the potential benefits do not outweigh the harms and costs associated with this treatment.

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Gout Flare Management

For the treatment of gout flares, the 2020 ACR guidelines offer 5 recommendations (Table 13-6). They emphasize the use of well-established medications with proven efficacy, cost-effectiveness tolerability as the primary approach. These first-line therapies include colchicine, NSAIDs (nonsteroidal anti-inflammatory drugs), or glucocorticoids. Within the category of colchicine, it is advisable to opt for a low-dose rather than a high-dose regimen, since the lower doses can provide the desired therapeutic effect while reducing the risk of potential side effects associated with higher doses. In addition to these pharmacological agents, the use of topical ice as a complementary treatment during gout flares should be considered. While this approach may not be as robustly supported by clinical trials, it can provide some relief to patients, especially when used in combination with other treatments.

In cases where first-line treatments prove ineffective, are poorly tolerated, or are medically contraindicated, healthcare providers may consider the use of IL-1 inhibitors, although this recommendation comes with concerns over patient access due to cost. However, if a patient is unable to take oral medications, intramuscular, intravenous, or intraarticular glucocorticoids are preferred over IL-1 inhibitors. Note that the 2020 ACR guidelines predate the approval of the IL-1β inhibitor canakinumab for the treatment of acute gout attacks (August 2023).

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Management of Lifestyle Factors

The recommendations on lifestyle management from the 2020 ACR guidelines are shown in Table 13-7. The guidelines advise limiting alcohol, purine high-fructose corn syrup intake, as these can lead to an increase in uric acid levels and/or promote gout flares. Lower alcohol consumption has been linked with lower uric acid levels, while higher alcohol consumption, especially in heavy drinkers, has been associated with up to 51% higher risk of gout flares, even in patients receiving ULT. Limiting purine intake is advised due to the observed dose-response relationship between increased purine consumption and the risk of gout flares. However, it is worth noting that an educational intervention focusing on low purine intake did not result in lower uric acid concentrations in a small RCT, despite improved patient dietary knowledge. Additionally, studies indicate that fructose ingestion can significantly raise uric acid levels. While research has shown associations between high-fructose corn syrup consumption and higher uric acid levels, there is a lack of specific data on patients with existing gout.

For gout patients with overweight or obesity, considering a weight loss program is advised, although the evidence supporting this recommendation is rated as very low in terms of uric acid levels and flare prevention. Modest weight loss has been shown to reduce uric acid levels changes in body mass index over time can impact the risk of recurrent gout flares. Additionally, bariatric surgery or dietary interventions resulting in weight loss may also reduce gout flare frequency, though some transient increase in flares may occur after surgery.

Vitamin C supplementation for gout patients is not encouraged, as the evidence supporting its use is insufficient.

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Management of Concurrent Medications

Finally, the 2020 ACR guidelines present 4 recommendations on the management of concurrent non-gout medication (Table 13-8). In situations where patients with gout are also managing hypertension, the guidelines advise switching hydrochlorothiazide to an alternative antihypertensive and preferably choosing losartan when feasible. The preference for losartan aligns with its potential urate-lowering effects and relatively lower risk profile. The guidelines also discourage discontinuing low-dose aspirin when used for urate reduction due to limited practical alternative options advise against adding or switching cholesterol-lowering medications to fenofibrate, considering the potential risks and side effects.

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The Treat-to-Target Divergence between the 2020 ACR Guidelines and the 2016 American College of Physicians (ACP) Guidelines

Theoretically, gout management presents two contrasting approaches: the treat-to-target (T2T) approach, in which a specific SU target is chosen and the treatment subsequently tailored to achieve and maintain that target; and the treat-to-avoid-symptoms approach, in which anti-inflammatory therapy in the context of flares of chronic inflammation is employed to treat symptoms. The 2020 ACR guidelines for the management of gout, supported by the 2016 EULAR evidence-based recommendations for the management of gout, emphasize the T2T approach characterized by gradual ULT adjustments to maintain SU concentrations below 6.0 mg/dl. In contrast, the 2016 ACP guidelines for the management of gout, citing a lack of robust evidence to support this approach, advocate for the treat-to-avoid-symptoms strategy. The ACP highlights the uncertainty surrounding whether achieving specific urate levels through T2T justifies the potential drawbacks of frequent monitoring and medication adjustments. However, it is essential to note that the treat-to-avoid-symptoms strategy also lacks direct experimental support. Patients not receiving adequate ULT may suffer ongoing urate deposition, leading to progressive joint damage and functional limitations. Such cases necessitate more aggressive and costly treatment than if SU levels had been appropriately targeted from the start. Finally, while no randomized, double-blind, controlled trials directly tested the T2T approach, indirect evidence from clinical practice and post-hoc analyses of trials amply supports its clinical effectiveness. For example, structured nurse-led and pharmacist-led gout care programs which explicitly included a T2T approach both resulted in numerically lower gout flares. A meta-analysis of 8 articles on gout incidence and 18 articles on gout recurrence showed that incidence, recurrence flare risk all have an inverse relationship with SU levels, with the lowest rates among patients with SU ≤6 mg/dL. Finally, a 2022 analysis of pooled data from two randomized ULT trials (one of which was the abovementioned nurse-led intervention trial) revealed that patients who maintained an average SU level <6 mg/dL at 6, 9 12 months after baseline had a significantly lower number of flares (27%) at 12-24 months after baseline compared to patients whose average SU level was higher (64%; P <0.0001). Thus, modern gout management continues to rely on the best available evidence, which currently favors a TTT strategy, leaving room for further refinement in the future.

Comparison of the 2020 ACR Guidelines with the 2016 EULAR Guidelines

The 2020 ACR Guidelines are in broad accordance with the 2016 EULAR guidelines in most recommendations concerning ULT, acute gout treatment gout attack prophylaxis; however, minor differences do exist. The EULAR guidelines list “recurrent flares” a strong indication for ULT, while the ACR guidelines specify the flare frequency (2 or more per year). Both guidelines consider allopurinol and pegloticase as the first- and third-line options for ULT, but for second-line therapy the EULAR guidelines lists febuxostat, uricosuric agent, or allopurinol with a uricosuric agent, while the ACR guidelines recommend another xanthine oxidase inhibitors over a uricosuric. Finally, the two guidelines differ slightly in the recommendations on prophylaxis: EULAR recommends colchicine as first-line therapy and NSAIDs are second line therapy, while ACR considers colchicine, NSAIDs, or prednisone/prednisolone all equally appropriate as first-line therapy.