LAS VEGAS — In patients with gout, there is indirect evidence that serum urate levels lower than those currently recommended can reduce the risk for flares, which might be even further reduced when treatment is maintained until urate deposits are dissolved, according to an expert who is questioning whether the term “refractory gout” still makes sense.

“Refractory gout is not a good term. I think difficult gout might be better. Although gout can be a challenge, it is not clear that it is refractory if we do what we say we are going to do. It just takes time to resolve uricemia,” reported Brian F. Mandell, MD, PhD, professor and chairman of the Department of Medicine, Cleveland Clinic Lerner College of Medicine in Cleveland.

There is plenty of evidence that the treat-to-target (T2T) strategy is effective. At the recommended serum urate target of < 6 mg/dL, several studies have shown that those who achieve and maintain this level have fewer flares than those who do not, according to Mandell.

T2T Gout Strategy Increased Success by 60%

Of recent examples, the 2026 GO TEST study found that the remission rate, defined as absence of flares, tophi, and pain, increased by more than 60% (39% vs 24%; P = .02) among those randomly assigned to a T2T strategy rather than symptom-driven management.

However, Mandell, who spoke at Perspectives in Rheumatic Diseases (PRD) 2026, said that the traditional serum urate target of < 6 mg/dL, although recommended in the 2020 American College of Rheumatology gout treatment guidelines, “is not necessarily the magic number.”

There are no major trials comparing the effect of achieving or maintaining serum urate levels lower than the current target of < 6 mg/dL, but Mandell provided one piece of indirect evidence that lower is better in at least some patients. In a study published in 2018, 131 asymptomatic sons of patients with gout were evaluated for urate deposits. Imaging to find the deposits was blind to the serum urate levels.

No lesions were seen at a serum urate level of 5 mg/dL, but the proportion of patients with positive images climbed immediately at higher levels. At a serum urate level of 6 mg/dL, nearly 40% had evidence of urate deposits.

These data and others have led Mandell to believe that the current guideline-recommended target of 6 mg/dL might be too high in at least some patients. Yet he acknowledged more aggressive therapy poses its own risks, particularly at the start of treatment. As serum urate levels are lowered, existing monosodium urate crystal deposits in the body begin to dissolve, causing mobilization flares. The speed and depth of serum urate reductions determines the rate of urate crystal dissolution.

Mobilization flares “are not an indication of drug failure,” but they do complicate the picture when trying to separate hyperuricemia resistant to therapy from an increased rate of flares produced by urate crystal dissolution, Mandell said.

As a result, individualized therapies are likely important to avoid lowering urate levels too slowly, prompting a prolonged risk for symptoms, or too quickly, prompting an unacceptable risk for mobilization flares.

Mobilization Flares Are Not Treatment Failures

“There are strategies to limit mobilization flares even if they will not be prevented in all patients,” Mandell said. One is simply to lower serum urate at a slower pace. Another is to add colchicine or another anti-inflammatory agent as a prophylaxis against the symptoms.

“The time it takes to reduce hyperuricemia is often underestimated,” Mandell said. Even if the risk for mobilization flares is reasonably well appreciated among clinicians, the patient-specific risks for recurrent symptoms can be confusing for judging disease control.

Due to flare activity that can recur long after treatment has been initiated, the rate of resistant hyperuricemia relative to late dissolution of urate deposits is unclear, but resistant hyperuricemia “could be and should be infrequent,” according to Mandell, citing data from a T2T trial published in 2018 as an example.

In this study, almost all of the patients in the experimental T2T arm, which involved close monitoring and treatment adjustments by trained nurses, were at goal at 2 years, a target reached by less than a third of patients who were randomly assigned to usual, general practitioner-led care (95% vs 30%; P < .0001).

Putting ‘Difficult Gout’ Into Three Buckets

To provide a systematic approach to retiring the term refractory gout, Mandell placed difficult gout into three buckets.

The first is resistant hyperuricemia, which defines cases in which there is difficulty in lowering the serum urate level even to the traditional target of < 6 mg/dL. The strategy for management typically involves additional therapies, particularly drugs in combination, to reach the treatment goal.

The second is “impatient gout,” which Mandell described as recurrent symptoms that develop as a result of slow dissolution of urate crystal deposits. The strategy for management is simply maintaining treatment adherence at target serum urate levels for long enough — often years — to rid tissues of deposits.

The third is complicated gout. This includes cases in which comorbidities, such as end-stage renal disease, organ transplant, heart failure, or other diseases, limit therapeutic options. It can also include cases of infected tophi or other cases in which higher doses of therapy to more rapidly control hyperuricemia are urgent.

Therapy Adjustments Needed to Avoid Hyperuricemia

Lack of adherence, often a consequence of insufficient patient education, is a common cause of hyperuricemia, but Mandell said inadequate monitoring and dosage adjustments can also play a role.

For example, inadequate uptitration of initial therapy or failure to move to combination therapy is often mislabeled as refractory gout. This might be more appropriately labeled resistant gout requiring higher doses of monotherapy or drugs in combination.

Not uncommonly, clinicians may fail to optimize doses. Although 800 mg is the maximum dose in FDA-approved labeling, Mandell suggested higher doses might be warranted. At higher doses, he advised moving to split doses taken twice daily rather than a single dose taken once daily to improve tolerance.

Combining first-line xanthine oxidase inhibitor therapies with a uricosuric therapy is also an effective strategy to push patients to target serum urate levels. Although probenecid is the only uricosuric therapy currently available in the United States, Mandell said others are likely to come. Other strategies such as diet changes to lower risk for elevated serum urate can also be incorporated to help move patients to the treatment goal.

But with all forms of difficult gout, there is a balance between adequate therapy to control disease and aggressive therapy that risks mobilization flares, Mandell reiterated. Many strategies have been evaluated to address this balance, but patient responses vary. Mandell cited another study published in 2018 showing that a stepwise increase in the dose of febuxostat was about as effective as initiating febuxostat with colchicine in preventing gout flares. He suggested some patients might respond better or better tolerate one than the other.

Yet any strategy to reduce risk for mobilization flares must be implemented for an extended period. Based on a meta-analysis of studies evaluating the risk for flares after stopping anti-inflammatory prophylaxis provided with serum urate lowering, Mandell recommended 6 months of prophylaxis, but again, this should be individualized.

“Be aware that flares may occur after stopping colchicine even after 6 months,” he said. He warned that in addition to evidence that greater drops in serum urate are associated with more flares, such factors as a high flare rate before start of therapy can help predict when to consider longer periods of prophylaxis.

Pegloticase Effective in Difficult-to-Treat Gout

Conversely, more aggressive serum urate lowering might be needed to address persistent and extensive tophi. He gave an example in which a patient with extensive tophi of the hands had severely impaired activities of daily living. When given pegloticase, an intravenous uricase enzyme, on an every-2-week but off-label schedule, resolution of the complaint was relatively rapid.

For “complicated gout,” pegloticase is also an option to reduce urate crystal deposits quickly before resuming more traditional treatments. Mandell described a case in which a finger amputation was being considered to treat an infected tophus. With intravenous pegloticase, the finger was preserved.

Although effective, Mandell warned that antihistamine and steroids should be administered with pegloticase infusions for at least 3 months to reduce the risk for infusion reactions and the development of anti-drug antibodies. Based on evidence that immunosuppression with such agents as methotrexate and mycophenolate mofetil can improve the response to pegloticase, he said these might be considered in selected patients.

Cautioning that these types of strategies are generally considered in patients “that really are with limited options,” Mandell said that kidney function, liver function, and alcohol use are all variables to consider before embarking on aggressive regimens with pegloticase used with adjunctive methotrexate.

For all of the reasons he listed, difficult gout is common, but Mandell is not convinced that there is a substantial risk for gout refractory to treatment. Within the three buckets of difficult gout, there are generally solutions for most. As a general rule, “all of these types of gout can be controlled,” he said.

Mandell is not the first to question the value of the term refractory gout. In a presentation at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting, Thomas Bardin, MD, PhD, of the Department of Medicine, Institut Mutualiste Montsouris, and Paris-Cité University, Hôpital Lariboisière, Paris, called refractory gout a “myth.”

In a subsequent interview, published in The Rheumatologist, he was quoted as saying, “The cause of refractory gout is obviously mismanagement.”

The reality, however, might be more complex, according to Angelo L. Gaffo, MD, who is section chief of rheumatology at the Birmingham VA Medical Center in Birmingham, Alabama.

Refractory Gout May Reflect Knowledge Gaps

Some clinicians might call gout refractory when disease persists despite standard therapy, but Gaffo agreed that is the wrong term for challenging cases.

“Most often, uncontrolled or refractory cases are those in which urate-lowering therapy, such as allopurinol or febuxostat, have not been maximized or combined with uricosurics,” said Gaffo, who was the senior author of a 2025 review article on gout flare management.

Yet he is reluctant to call refractory gout a myth.

“There are cases of complete intolerance to conventional therapies,” he said, citing “well-documented” cases of resistance to allopurinol mediated by the ABCC4 gene. He also pointed out that comorbidities, such as tophaceous disease with advanced chronic kidney disease, can complicate therapy.

“An experienced rheumatologist can control these cases with a lot of effort, but they certainly can come across as refractory to first-line therapies,” Gaffo said.

Mandell reported having financial relationship with Arthrosis, Amgen, and Sobi. Gaffo reported having financial relationships with Atom Therapeutics, Avalo Therapeutics, PK MED, Scilex, and Sobi.

Ted Bosworth, a career medical writer based in New York City, has been covering advances in clinical medicine, including rheumatology, for several decades.