What Gout Research Shows About Uric Acid, Flares and Treatment Adherence

James Mackay discusses difficult-to-treat gout, gaps in disease understanding and why some clinical outcomes may require longer follow-up.

Gout is a common form of inflammatory arthritis caused by excess uric acid in the body. When uric acid builds up, crystals can form in the joints, leading to the sudden pain, swelling and inflammation associated with a gout flare.

Inside the body, however, the process behind gout can continue between those attacks. Uric acid may accumulate over months or years, creating a growing crystal burden that researchers are trying to address through long-term urate control.

The gap between the visible flare and the underlying disease also shapes how patients use treatment, how physicians manage gout and how clinical trials are designed.

In this Xtalks Clinical Edge feature, James Mackay, CEO of Crystalys Therapeutics, discussed what happens in the body during gout, why treatment adherence can be complicated, what “difficult-to-treat” gout can look like and why studying clinical symptoms may require researchers to follow patients for much longer than a single flare.

What Happens in the Body Between Gout Flares?

“Gout honestly is one of the most misunderstood diseases that exists,” James said.

Gout develops when excess uric acid leads to crystals accumulating in the body. Diet can contribute to uric acid production, James explained, particularly foods high in purines. But he said more than 85% of people with gout are what researchers call “under-excreters,” meaning their kidneys do not remove enough uric acid through the urine.

As uric acid builds up, crystals can collect in the joints and contribute to ongoing inflammation.

The familiar swollen, painful joint is an acute gout flare. These attacks can last around 10 to 14 days before the visible symptoms subside. Patients may feel as though the disease has disappeared.

“But all the time these patients have got uric acid buildup and it’s causing damage and inflammation to the body,” James said.

He compared the pattern with high cholesterol: a person may have an underlying biological problem for a long period without feeling it directly. With gout, the flare can be the event that makes the accumulated uric acid visible to the patient.

Researchers need to look at gout over time. A patient may have accumulated a substantial uric acid burden over years or even decades before treatment begins.

“The doctor’s giving you a medicine that tells you that it’s going to make you better. And the first thing that it does is make you worse.”

— James Mackay, CEO, Crystalys Therapeutics

Why Adherence Can Be Difficult During Urate-Lowering Treatment

Long-term treatment introduces another unusual feature of gout: lowering uric acid can initially trigger the symptom patients are hoping to prevent.

Allopurinol, a xanthine oxidase inhibitor, is commonly used to reduce uric acid production. When urate-lowering treatment begins, lowering the uric acid concentration can mobilize existing uric acid deposits. During this early period, patients may experience additional flares.

“The doctor’s giving you a medicine that tells you that it’s going to make you better. And the first thing that it does is make you worse,” James said.

Without an explanation of why this happens, some patients may interpret an early flare as evidence that treatment is failing and stop taking the medication.

The adherence challenge can also appear much later, after a patient has taken treatment for a few years without experiencing a flare. Some patients may feel they no longer need treatment and stop taking it, allowing uric acid to begin building up again.

“If that’s not explained to patients, then a lot of patients actually stop taking the medicine because they think it’s not actually helping them,” James said.

Disease education should become part of long-term gout management. Patients need to understand what can happen during the first months of urate lowering and why treatment may still be needed when they are no longer experiencing attacks.

“They want to have fewer flares and they don’t want to have these disfiguring tophi on their joints.”

— James Mackay, CEO, Crystalys Therapeutics

What Makes Gout Difficult to Treat?

The starting point can look very different from one patient to another.

James said the term difficult-to-treat gout is often used for people who cannot tolerate or have a contraindication to standard-of-care treatment such as allopurinol. Some patients may consequently have relatively few therapeutic options.

Others may have lived with uncontrolled gout for many years, accumulating a large uric acid burden that can eventually form visible masses around the joints called tophi.

These deposits can become painful and disfiguring, and reducing them may take considerable time.

Differences in disease duration and uric acid burden also affect clinical trial design. A study focused on lowering serum uric acid can detect a biochemical response relatively quickly. Showing what that reduction means for flares or tophi can require a much longer observation period.

Crystalys is studying a URAT1 inhibitor, a type of investigational urate-lowering therapy that blocks a kidney transporter involved in reabsorbing uric acid. The approach is intended to increase the amount of uric acid excreted in urine.

James said the company wanted its Phase III program to evaluate clinical symptoms alongside uric acid lowering.

“They want to have fewer flares and they don’t want to have these disfiguring tophi on their joints,” he said of patients.

James said one Phase III trial includes a 15-month treatment period and another runs for 18 months, allowing researchers to examine changes that may take longer to emerge.

The studies are evaluating whether sustained uric acid reduction is accompanied by fewer flares and reductions in tophi over time.

How Gout Stigma Can Affect Patient Care

Some of the challenges surrounding gout begin before a patient enters a clinical study or discusses long-term treatment.

James said one of the most striking lessons from working in the field has been “how misunderstood this disease is and how gout patients are made to feel like it’s their fault that they have gout.”

The long-standing association between gout, rich foods and alcohol can create a simple explanation for a disease with more complex biology.

“How misunderstood this disease is and how gout patients are made to feel like it’s their fault that they have gout.”

— James Mackay, CEO, Crystalys Therapeutics

James recalled a colleague with gout who avoided discussing the disease because conversations about treatment repeatedly returned to diet, despite the colleague being a lifelong vegetarian who did not drink alcohol.

For James, experiences such as these show how stigma can affect whether patients discuss gout openly or seek care.

The condition also frequently occurs in people being treated for other health problems. James noted that patients may also have high blood pressure, diabetes or cardiovascular conditions, which can compete for attention during clinical care.

Comorbidities, limited treatment choices and long symptom-free periods can leave gout lower on the list of issues discussed during routine care.

Emerging Approaches in Gout Treatment Research

James sees several areas of gout research developing in parallel.

URAT1 inhibitors are one area of ongoing gout treatment research.

Other researchers are exploring new uricase-based therapies, which use enzymes to break down uric acid and are generally being investigated for patients with more severe disease. James said newer approaches are being developed to address some of the limitations of existing uricase treatment.

Research is also focusing on acute gout flares. Current management includes anti-inflammatory medicines such as colchicine, which can cause gastrointestinal side effects in some patients, while investigational approaches are being evaluated for controlling acute inflammation.

Gout’s long disease course can also affect how treatment benefits are studied. Lowering uric acid can be measured relatively early, while determining whether this leads to fewer flares and reduced crystal burden may require longer follow-up.