Treat to Target in Gout Management: A Critical Reappraisal of Current Strategies

Abstract

Gout management strategies remain a topic of debate, particularly regarding the efficacy of treat-to-target (T2T) and treat-to-avoid-symptoms (T2S) approaches. T2T, endorsed by major rheumatology societies, involves systematic serum urate (sUA) monitoring and urate-lowering therapy (ULT) dose escalation to maintain sUA below a predefined threshold. In contrast, T2S, which focuses on symptom relief rather than routine sUA monitoring, is supported by alternative guidelines. Despite the widespread adoption of T2T in other chronic diseases, its clinical benefits beyond biochemical parameters, such as serum urate reduction, remain uncertain in gout. This study evaluates current evidence on T2T and T2S, analyzing data from a pragmatic multicenter trial comparing both strategies. Findings suggest that while T2T is effective in reducing sUA levels, its superiority in preventing flares and improving patient-reported outcomes remains inconclusive. Some studies report reduced tophus burden and better adherence with T2T, whereas others find negligible differences in pain relief and functional improvement between the two strategies. The lack of high-quality comparative trials underscores the need for further investigation. Future research should prioritize long-term, patient-centered outcomes and pragmatic implementation strategies.

1. Introduction

Gout results from the deposition of monosodium urate (MSU) crystals in joints and tissues and has become more prevalent due to aging populations and lifestyle changes. [1]. The clinical features include episodic gout flares, deforming gouty arthropathy, tophi, and urolithiasis [2,3]. Effective strategies include frequent serum uric acid(sUA) monitoring and dose adjustments of urate-lowering therapies (ULTs), as the serum urate level is a surrogate marker for all outcomes [4]. The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) support a treat-to-target (T2T) serum urate approach, advocating for sUA levels to be reduced below the physiological threshold of saturation to prevent new crystal formation and dissolve existing deposits over time. To achieve this, sUA levels should be regularly monitored, with treatment intensified to maintain sUA levels <0.36 mmol/L, or even <0.30 mmol/L in severe cases [5,6]. The T2T approach has been highly successful in many areas of medicine, e.g., in treating hypertension [7]. According to the 2020 updated ACR guidelines for gout management, there is moderate to strong evidence from several trials supporting that a T2T management approach yields superior outcomes compared with a fixed dose ULT [8]. An alternative approach advocated by the American College of Physicians (ACP) [9] is the treat-to-avoid symptoms (T2S) strategy, which bases the intensity of treatment on symptom management rather than routine sUA monitoring. This method has been criticized for potentially ignoring ongoing urate deposition until severe manifestations appear [10,11,12]. Despite the lack of high-level evidence directly comparing these strategies, indirect evidence supports the T2T approach’s effectiveness. Patient education, involvement in decision-making, and long-term adherence to urate-lowering therapy are crucial. The treatment targets for gout management include maintaining serum urate levels, reducing inflammation time, decreasing tophi, alleviating pain, preventing attacks, and ensuring medication adherence [13]. Regular assessment of renal function and comorbidities and addressing modifiable risk factors are recommended. The current literature also emphasizes ensuring patients access comprehensive gout management information and developing research protocols to address knowledge gaps.

2. Aim

This article seeks to highlight gaps in gout management strategies, current research, and potential areas for future investigation. General practitioners often view gout as a condition marked by recurrent flares, which leads to a focus on managing acute episodes rather than implementing long-term disease control strategies. The American College of Physicians has recommended a symptom-based approach (T2S), where treatment centers on relieving symptoms. By contrast, rheumatology societies have quickly adopted the treat-to-target (T2T) approach, following the ’dirty dish’ hypothesis proposed by F. Perez Ruiz [14]. The American College of Physicians’ guidelines on gout management agree that there is strong evidence supporting colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids for gout flare treatment, even with limited controlled trials. Gout experts suggest that a reactive “treat-to-avoid-symptoms” approach could be considered a viable strategy with ULT, as the proactive “treat-to-target” method remains insufficiently studied. However, the “treat-to-avoid-symptoms” method hasn’t been rigorously tested either. This approach may lead to treating flares without addressing hyperuricemia, allowing urate deposition and joint damage to worsen. Moreover, issues like starting allopurinol at a high dose, increasing flare risk, and leaving many patients undertreated complicate this strategy, highlighting the need for better monitoring and dosing adjustments [15].

3. Limited Studies and Varied Interventions in Gout Management Strategies

Although the concept of T2T has gained traction in rheumatology, particularly for conditions like rheumatoid arthritis, the number of studies that specifically evaluate T2T in gout is limited. The existing literature has largely focused on fixed dose/effect studies, with few direct comparisons between treatment strategies. A common pattern across these studies is that there was a significant improvement in patient outcomes when intensive urate-lowering therapies and dose escalation were applied. Across interventions like nurse-led [16] study and dose escalation strategies, patients were more likely to reach serum uric acid targets, exhibit improved adherence and reduce gout flare frequencies. The studies consistently show better outcomes in intervention groups compared to control groups, especially in terms of sUA reduction, progression of tophi, and joint damage control through erosion scores. While these studies typically do not employ the said T2T strategy, they have demonstrated that ULT agents effectively achieve predefined serum urate goals with an acceptable safety profile for many patients. Studies in which T2T principles were applied often evaluate management strategies where T2T principles are embedded, as shown in Table 1. While the T2T principles adopted in these trials might have contributed to improved outcomes for patients, their effects cannot be isolated from other aspects of the intervention that might have also had a positive effect on the outcome. See Table 2 for details on the comparison of clinical outcomes.

4. Lack of Comparisons Between T2T and T2S Approaches

Despite growing support for T2T in gout management, evidence remains limited, and existing studies reveal mixed outcomes.

4.1. Strict Interpretation of T2T

Doherty et al. (2018) [16] showed that T2T, the strict approach, led to superior control of sUA compared to a more fixed-dose approach, where ULT doses were less frequently adjusted.

4.2. Clinical Benefits Besides sUA Reduction

This is a key point, as several studies (e.g., Stamp et al., 2017 and Dalbeth et al., 2022) [17,18] have shown that, although T2T effectively reduces sUA levels, it does not lead to significant improvements in broader clinical outcomes such as pain, joint function, or health-related quality of life. The focus on sUA reduction alone may require additional strategies to enhance broader clinical outcomes, such as pain relief and improved physical function.

5. Outcomes: Focus on sUA as a Proxy Measure

Most studies evaluating T2T in gout have used serum urate (sUA) levels as the primary outcome, aiming to maintain sUA below 6 mg/dL. However, sUA is a surrogate marker and does not always correlate with direct patient benefits, such as reduced pain, fewer flares, or improved quality of life. Recent evidence, including findings from Lisa Stamp and colleagues [19] supports the association between achieving sUA <6 mg/dL and improved clinical outcomes, such as reduced flare frequency and tophus resolution. This reinforces the validity of sUA as a surrogate endpoint in gout. However, despite this association, Stamp et al. acknowledge that prior meta-analyses have struggled to confirm a direct relationship between sUA reduction and flare reduction, highlighting issues such as short trial durations and heterogeneity in outcome reporting. Furthermore, the biochemical target alone does not address real-world treatment challenges, including adherence, patient education, and symptom management. The OMERACT (Outcome Measures in Rheumatology) initiative has underscored the need for standardized patient-centered outcomes beyond sUA, yet many trials continue to focus predominantly on biochemical markers without fully integrating clinical endpoints such as pain, activity limitation, and global health assessment.

Table 1. Treat-to-Target Gout Studies features, and key outcomes of the trials.

First Author, Year	Intervention	Comparator	Treatment Target	sUA Monitoring	Medications	Dosing Strategy	Patient Education	Patient Involvement	Supportive Care	Study Follow-Up Visits
Doherty, 2018 [16]	Nurse-led care	GP-led care	<6 mg/dL	Regular, unspecified frequency	Allopurinol, Febuxostat	Start 100 mg/day, monthly increase	Individualized education	Yes	Nurse follow-ups	Implied regular visits
Mikuls, 2018 [20]	Pharmacist-led intervention	Usual care	<6 mg/dL	Monthly, then every 3 months	Allopurinol	Pharmacist-led dose escalation	Automated phone education	No	Pharmacist follow-ups	Monthly, then every 3 months
Wang, 2024 [21]	mHealth-based care	Routine care	<6 mg/dL	12 and 24 weeks	Not specified	Focus on education/support	Weekly app-based materials	Yes	Continuous app-based care	Baseline, 12, 24 weeks
Stamp, 2017 [17]	Allopurinol dose escalation	Current dose	<6 mg/dL	Monthly during escalation	Allopurinol, Febuxostat	Increase 50–100 mg/monthly	Not mentioned	No	Adverse event monitoring	Monthly, then 3-monthly
Stamp, 2021 [19]	Allopurinol escalation	N/A	<6 mg/dL	Monthly, then 3-monthly	Allopurinol, Febuxostat	Continue as needed	Not mentioned	No	Regular monitoring	3-monthly
Dalbeth, 2022 [18]	Intensive urate lowering	Standard target	<3.36 mg/dL (intensive) vs. <5.04 mg/dL (standard)	Monthly, then 3-monthly	Allopurinol, Probenecid, Febuxostat, Benzbromarone	Max approved dosing	Not mentioned	No	Monthly monitoring, adjustments	3-monthly after target achieved

Table 1. Treat-to-Target Gout Studies features, and key outcomes of the trials.

First Author, Year	Intervention	Comparator	Treatment Target	sUA Monitoring	Medications	Dosing Strategy	Patient Education	Patient Involvement	Supportive Care	Study Follow-Up Visits
Doherty, 2018 [16]	Nurse-led care	GP-led care	<6 mg/dL	Regular, unspecified frequency	Allopurinol, Febuxostat	Start 100 mg/day, monthly increase	Individualized education	Yes	Nurse follow-ups	Implied regular visits
Mikuls, 2018 [20]	Pharmacist-led intervention	Usual care	<6 mg/dL	Monthly, then every 3 months	Allopurinol	Pharmacist-led dose escalation	Automated phone education	No	Pharmacist follow-ups	Monthly, then every 3 months
Wang, 2024 [21]	mHealth-based care	Routine care	<6 mg/dL	12 and 24 weeks	Not specified	Focus on education/support	Weekly app-based materials	Yes	Continuous app-based care	Baseline, 12, 24 weeks
Stamp, 2017 [17]	Allopurinol dose escalation	Current dose	<6 mg/dL	Monthly during escalation	Allopurinol, Febuxostat	Increase 50–100 mg/monthly	Not mentioned	No	Adverse event monitoring	Monthly, then 3-monthly
Stamp, 2021 [19]	Allopurinol escalation	N/A	<6 mg/dL	Monthly, then 3-monthly	Allopurinol, Febuxostat	Continue as needed	Not mentioned	No	Regular monitoring	3-monthly
Dalbeth, 2022 [18]	Intensive urate lowering	Standard target	<3.36 mg/dL (intensive) vs. <5.04 mg/dL (standard)	Monthly, then 3-monthly	Allopurinol, Probenecid, Febuxostat, Benzbromarone	Max approved dosing	Not mentioned	No	Monthly monitoring, adjustments	3-monthly after target achieved

Table 2. OMERACT Domains Comparison.

First Author, Year	Primary Outcome of the Study	Pain	Patient Global Assessment	Activity Limitation	Serum Urate Levels	Gout Flares	Tophi	HR-QoL	Physical Function
Doherty, 2018 [16]	% of patients sUA < 6 mg/dL at 2 years	Yes (VAS)	Yes	Yes (HAQ)	Yes	Yes	Not reported	Not reported	Yes (HAQ)
Mikuls, 2018 [20]	Adherence and sUA goal attainment at 1 year	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Wang, 2024 [21]	Gout knowledge, treatment compliance, and sUA levels	Yes (VAS)	Not reported	Yes (HAQ-II)	Yes	Yes	Not reported	Not reported	Not reported
Stamp, 2017 [17]	% achieving sUA < 6 mg/dL at 12 months	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Stamp, 2021 [19]	Maintenance of sUA < 6 mg/dL at 24 months	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Dalbeth, 2022 [18]	Change in CT bone erosion score at 2 years	Yes	Yes	Yes (HAQ-II)	Yes	Yes	Yes	Yes	Yes (HAQ-II)

Table 2. OMERACT Domains Comparison.

First Author, Year	Primary Outcome of the Study	Pain	Patient Global Assessment	Activity Limitation	Serum Urate Levels	Gout Flares	Tophi	HR-QoL	Physical Function
Doherty, 2018 [16]	% of patients sUA < 6 mg/dL at 2 years	Yes (VAS)	Yes	Yes (HAQ)	Yes	Yes	Not reported	Not reported	Yes (HAQ)
Mikuls, 2018 [20]	Adherence and sUA goal attainment at 1 year	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Wang, 2024 [21]	Gout knowledge, treatment compliance, and sUA levels	Yes (VAS)	Not reported	Yes (HAQ-II)	Yes	Yes	Not reported	Not reported	Not reported
Stamp, 2017 [17]	% achieving sUA < 6 mg/dL at 12 months	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Stamp, 2021 [19]	Maintenance of sUA < 6 mg/dL at 24 months	Not reported	Not reported	Not reported	Yes	Yes	Not reported	Not reported	Not reported
Dalbeth, 2022 [18]	Change in CT bone erosion score at 2 years	Yes	Yes	Yes (HAQ-II)	Yes	Yes	Yes	Yes	Yes (HAQ-II)

6. Patient Benefits

Interventions such as nurse-led care and mHealth-based continuous support significantly enhanced patient knowledge, adherence, and compliance, leading to more effective gout management. Improved adherence to urate-lowering therapy (ULT) translated into better health-related quality of life. Among these, Doherty’s (2018) nurse-led care study was the only trial closely resembling a real-world treat-to-target (T2T) strategy, where dose escalation was based on individual biochemical markers (sUA) and clinical indicators, such as ongoing flares. In contrast, most studies—including Mikuls (2018) [20] and Wang (2024) [21] compared fixed doses of urate-lowering therapies rather than a protocolized escalation approach based on treatment failure.

Notably, none of these studies explicitly addressed the clinical decision-making process between escalating xanthine oxidase inhibitor (XOI) doses or adding uricosurics in patients with low urate excretion, likely because urate excretion was not systematically measured. As a result, most trials focused on dose escalation or switching between XOIs, with only one study including patients who received additional uricosuric therapy.

Interestingly, both nurse-led care (Doherty, 2018) and mHealth-based continuous care (Wang, 2024) outperformed standard therapeutic approaches, raising important questions about the effectiveness of conventional rheumatology practices in gout management. Wang’s study, in particular, utilized mobile health (mHealth) [21] interventions, which refer to the use of smartphone applications, text messaging, and remote patient monitoring tools to provide ongoing disease management. Patients received monthly app-based education, reminders, and feedback to support medication adherence and lifestyle modifications over a two-year period. The success of mHealth in improving serum urate control and adherence suggests that digital health solutions could complement traditional clinical follow-ups, offering a scalable and accessible approach to long-term gout management.

The rheumatology community continues to face challenges in improving standard practices for treating gout and advancing study designs that implement a more individualized treat-to-target (T2T) strategy. Improved adherence and effective urate-lowering therapy also enhanced patients’ health-related quality of life. However, achieving lower sUA targets often required higher doses and/or combination therapy, increasing the burden of treatment. These findings emphasize the need for consistent patient adherence and innovative approaches, like mHealth applications, to support treatment regimens.

In summary, recent studies have demonstrated the effectiveness of urate-lowering therapy in achieving serum urate goals, both with fixed doses and through a treat-to-target approach. In a few long-term studies (over 12 months), treat-to-target interventions have been shown to help reduce tophi, decrease gout flare frequency, and improve MRI-detected synovitis. These findings build a compelling case for adopting a treat-to-target serum urate strategy to optimize patient outcomes in gout management. Managing severe gout cases requires more stringent sUA targets and complex treatment regimens, which adds to implementation challenges. The studies highlight the necessity for adaptable and scalable treatment strategies that comply with guidelines. Key factors influencing treatment effectiveness and adherence include the frequency of monitoring, dose adjustments of urate-lowering therapies, and adherence assessment methods. The scoping review we conducted underscores the importance of setting target sUA levels and applying stringent targets for severe gout cases. Proactive management of acute flares, comprehensive comorbidity assessments, and patient education on lifestyle modifications are also essential.

7. The GO TEST Overture Trial and TRUST Trial: Addressing Shortcomings in the Literature

The GO TEST Overture trial aims to fill some of these gaps by comparing T2T and T2S strategies in a real-world setting. Patients in the T2T arm are treated with escalating doses of urate-lowering therapy (ULT) based on regular sUA monitoring, while those in the T2S arm are managed with symptomatic relief and lower ULT doses. The trial incorporates a broader set of outcomes, including sUA and patient-reported outcomes like flare frequency, pain, and health-related quality of life. The study’s approach is designed to yield valuable insights into the comparative benefits of T2T and T2S strategies for gout patients, guiding optimal treatment choices in clinical practice.

The TRUST (Treat-to-Target Serum Urate vs. Treat-to-Avoid Symptoms in Gout) Trial is a randomized clinical study comparing two distinct strategies for managing gout. The Treat-to-Target Serum Urate (T2T-SU) approach focuses on maintaining serum urate levels below 6.0 mg/dL through urate-lowering therapy, while the Treat-to-Avoid Symptoms (TTASx) strategy prioritizes symptom management without targeting specific urate levels. The primary objective of the trial is to determine whether achieving target serum urate levels leads to better patient-centered outcomes compared to a symptom-driven management approach.

8. Conclusions

Future research should focus on larger trials to validate findings and, evaluate the long-term sustainability of interventions, assess cost-effectiveness, and examine interventions across diverse populations, shifting the focus toward strategy studies to optimize gout management that reflect a real world setting which requires a more pragmatic approach given that in daily clinical practice, physicians do not always strictly follow either T2T or T2S but often use hybrid approaches that combine symptom control with gradual urate-lowering therapy (ULT) titration. Despite the lack of high-level evidence directly comparing these strategies, indirect evidence supports the effectiveness of the T2T approach (a few trials are already on-going as mentioned). Patient education, shared decision-making, and long-term adherence to ULT are crucial. The key treatment targets in gout management include maintaining serum urate levels, reducing inflammation duration, shrinking tophi, alleviating pain, preventing attacks, and ensuring medication adherence. Regular assessment of renal function and comorbidities and addressing modifiable risk factors are also recommended. Current literature further emphasizes the importance of providing patients with comprehensive gout management information and developing research protocols to fill knowledge gaps.