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Gout: Combining 2 existing drugs doubles treatment success in new study

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New research examines a potential new approach to treating severe gout. Boy_Anupong/Getty Images
  • Gout is a form of arthritis that results from excess uric acid in the bloodstream and causes intense pain, swelling, and stiffness around a joint.
  • Doctors often treat severe gout with pegloticase (Krystexxa), a medication that reduces uric acid levels, but the body’s immune response to the drug limits its effects.
  • By combining Krystexxa with an immunosuppressant, researchers doubled the percentage of people with gout who achieved target levels of uric acid.
  • This drug combination offers a new solution for people who are not able to control their gout with conventional treatment.

Intense joint stiffness, severe pain, and hot, discolored, swollen skin around the affected area characterize gout attacks. These attacks arrive without warning — often in the middle of the night — and can last for up to 2 weeks.

Gout is a common form of inflammatory arthritis, which, according to the National Health and Nutrition Examination Survey, affected about 9.2 million adults in the United States between 2015 and 2016.

“I’ve been shot, beat up, stabbed, and thrown out of a helicopter, but none of that compared to the gout.”

A veteran visiting a hospital in Birmingham, AL

Despite gout’s high prevalence, the options for treating it are limited compared with other types of arthritis.

Due to the slow timeline for getting new drugs on the market, Dr. Puja Khanna, a clinical associate professor at the medicine department of the University of Michigan, and her colleagues decided to optimize treatment by combining two existing therapies.

“Getting a new medication from inception to [Food and Drug Administration (FDA)] approval can take anywhere from 10 to 20 years. Gout is a challenge to treat, and because we have limited options, we are always looking for innovative ideas,” she told MNT.

The team’s research features in Arthritis & Rheumatology.

Gout occurs due to excess uric acid in the bloodstream. The symptoms result from uric acid crystals forming in the joints and the body’s inflammatory response to them.

Krystexxa is a biologic drug that doctors prescribe to people with severe, treatment-resistant gout to reduce uric acid levels in the body. Krystexxa, which doctors deliver as an intravenous infusion, metabolizes uric acid into a harmless chemical that the body then expels in the urine.

However, as a stand-alone treatment, Krystexxa triggers an immune response against itself. The body produces antibodies that remove Krystexxa molecules, limiting the drug’s effectiveness.

“This has been a dilemma,” explained Prof. Herbert Baraf, a clinical professor of medicine at George Washington University in Washington, D.C., “because it tends to be the last thing you do for the patients with the most desperate cases of gout.”

“This is the last hurrah for these patients,” Prof. Baraf, who was not involved in the study, told Medical News Today.

Dr. Khanna’s team wanted to explore whether the oral immunosuppressant drug mycophenolate mofetil (CellCept) could limit antibody production and improve Krystexxa’s ability to sustain a low uric acid level.

The phase II clinical trial included 32 participants who received either CellCept or a placebo pill before beginning treatment with Krystexxa infusions, which they received every 2 weeks for 6 months. After 3 months, the study participants stopped receiving the oral medication but continued Krystexxa infusions.

Of the participants who received CellCept and Krystexxa in combination, 86% reached the therapeutic target level — less than 6 milligrams per deciliter (mg/dl) — of uric acid in the blood serum at 12 weeks. However, this reduced to 68% of participants at 24 weeks.

In comparison, 40% of the participants who only took Krystexxa reached the therapeutic target.

A previous phase II randomized trial that investigated the effectiveness of Krystexxa on its own had similar results: Only 42% of participants achieved serum uric acid levels of less than 6 mg/dl.

However, Dr. Khanna believes that an even higher success rate could be possible with combination therapy under different conditions:

“This was a proof-of-concept study,” she said. “It’s quite possible that if we had continued to administer the [CellCept] for another couple of weeks, would we have seen a 100% response rate?”

Although the study’s sample size was very small, Prof. Baraf believes that the “very impressive” results fit into a wider pattern that researchers have seen with other immunomodulatory and biologic drugs.

“I think the data is becoming fairly robust,” he said.

“When you look at the effects of all that has been published, controlled and uncontrolled, […] it may be reasonable to expect that with a little bit of immunosuppression, you can get that response rate up above 80%.”

Gout can be tricky for patients and healthcare providers to recognize, as the symptoms come and go over time.

“Because the disease is so episodic, what usually happens is most patients don’t get a diagnosis of gout for close to a decade [or] even longer,” Dr. Khanna noted.

What’s more, relatively few healthcare professionals are well-educated in treating gout, especially in primary care settings. They may not consistently follow a “treat-to-target” approach, which involves gradually increasing a uric acid-lowering therapy to reach a target therapeutic level.

“There are many physicians who may give the right drug but in the wrong dose. They don’t give enough, and they don’t monitor it closely enough,” said Prof. Baraf.

“It means that [many] patients are flirting with a 6 mg/dl target but not achieving it consistently.”

The precise dose requirements to achieve therapeutic targets will be a focus of Dr. Khanna’s future work.

As well as a larger scale trial, the researchers will explore how long people need to take immunosuppressants before and after starting Krystexxa infusions. They also hope to determine the most effective dosages of both medications in combination.

“We know immunomodulation needs to stay on; it just depends on how strongly the patients respond,” Dr. Khanna says. “Gout is severely underdiagnosed, and if you treat it earlier and more aggressively, you can control symptoms and limit long-term damage to the joints.”

“This therapy offers a solution for patients who are not able to control their gout on oral therapy,” she told MNT. “[Our] findings suggest that there is hope.”

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