Gout: Suboptimal Management a Continuing Problem

“For a really well-understood disease, gout is remarkably undertreated,” said Robert A. Terkeltaub, MD, professor of medicine at the University of California, San Diego, and chief of rheumatology at the VA Medical Center in San Diego. “This is amazing and depressing because allopurinol has been around for about 60 years or so.”

Randomized, controlled trials show that 80%-90% of patients with gout can be effectively treated to target with existing gout therapies. “Over a year or two, gout flares improve and patients do well,” Dr. Terkeltaub said.

By lowering excessive levels of serum urate, current therapies slow the formation of soluble monosodium urate crystals that precipitate within joints and soft tissues, inducing a highly inflammatory local response. These therapies reduce the frequency of excruciatingly painful gout flares.

“Many patients with gout are not taking urate-lowering therapy at all,” Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, Boston, and head of crystal-induced arthritis diseases at Brigham and Women’s Hospital, also in Boston, said in an interview.

“Unfortunately, a common problem in gout is treatment inertia,” said Tuhina Neogi, MD, PhD, chief of rheumatology at Boston Medical Center.

“I think gout has been taken less seriously than it should be for quite some time,” he explained in an interview. Gout’s impact on health and well-being is no trivial matter. A recent study showed that a diagnosis of gout was associated with an increased risk of anxiety and depression, and there is new evidence suggesting that gout flares are associated with an increased risk of cardiovascular events, including fatal myocardial infarction and stroke.

“We need drugs that are not just effective but also safe, and we need to incorporate real-world data into our assessment of treatment effectiveness, especially in the presence of comorbidities,” Dr. Terkeltaub said.

The patient demographics associated with gout have also expanded. Once seen primarily in fleshy, middle-aged men of privilege, gout affects more women, more adults at either end of the age spectrum, and more people in Third World countries than ever before.

Management

In the United States, the optimal management of gout remains the subject of debate, with differences in expert opinion reflected in evidence-based clinical guidelines. “We know that the perception of gout is different between primary care physicians, patients, and rheumatologists,” Dr. Terkeltaub said.

In their report, the ACR guidelines’ authors stated that the use of urate-lowering therapy for gout has not increased in the last decade. Research shows that adherence to treatment for gout continues to be the lowest among seven common chronic medical conditions, including hypertension and seizure disorders, they said.

Some physicians don’t recommend urate-lowering medication to their patients with gout, and others don’t up-titrate it sufficiently to meet the recommended serum urate target, said Dr. Tedeschi. The latter “can require increasing the dose of allopurinol well beyond the 300 mg that often seems the landing point for many patients with gout,” she pointed out.

“We need to reduce the time it takes to get the patient to the serum urate target, and simplify regimens with once-a-day dosing,” Dr. Terkeltaub said. “We also need greater precision so that we can get a home run, hitting the serum urate target the first time, with zero titration.”

Clinician education is important, but education alone is not enough, Dr. Neogi emphasized. “Just as clinicians treat-to-target in other conditions such as hypertension and diabetes, or titrate warfarin to maintain a certain level of anticoagulation, gout must be monitored and treatments adjusted accordingly,” she said.

That’s exactly what Dr. Terkeltaub has done. Overwhelmed by the number of gout consults, Dr. Terkeltaub and his team set up a pharmacist-managed, rheumatology-supervised clinic to care for gout patients remotely. The model has been very successful, he said. Nurses and clinical pharmacists educate the patients and manage their lab testing and prescriptions, all according to ACR guidelines.

The treatment of gout has become more complex, with a greater risk of drug complications and interactions, particularly in older patients with comorbid diabetes, chronic kidney disease, and heart disease. Many of the patients he sees are already on “10, 15, or 20 other medications,” Dr. Terkeltaub noted.

“In our conversations with patients with gout, it’s extremely important that we counsel them about the need to take urate-lowering therapy on an ongoing basis to reduce the risk of a gout flare,” said Dr. Tedeschi. “Patients need to have prescription refills available and know to contact the doctor before they run out, so that the chances of having a gout flare are reduced.”

Current drugs

Although urate-lowering drugs form the cornerstone of gout therapy, there are only three oral medications available in the United States currently, and all have significant limitations. “We need more drugs, basically,” Dr. Terkeltaub said.

New drugs in the pipeline offer treatment options that are not only effective but also safe. “This will be important in clinical practice, especially for patients in whom existing medications are contraindicated or there is an increased risk of side effects,” Dr. Neogi said.

Most of these investigational drugs are uricosuric agents that increase the renal excretion of uric acid, reducing serum levels. “The pipeline of new drugs is rich,” Dr. Terkeltaub said. “These drugs are very selective and really work well and they appear to be safe.”

AR882, an inhibitor of selective uric acid transporter 1 (URAT1), is shaping up to be one of them. In July, results from a phase 2b study of AR882 were presented at the annual European Congress of Rheumatology in Milan. They showed that in the intent-to-treat population, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy. In the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” said Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, who presented the results.

“More efficacious URAT1 inhibitors that are safe and have a reduced pill burden will be useful additions to current urate lowering options,” Dr. Neogi said.

The recent phase 3 DISSOLVE I and II trials of the investigational uricase-based infusion therapy SEL-212 in refractory gout have also demonstrated encouraging results, particularly in older patients. In DISSOLVE I, a response rate of 65% was observed in patients 50 years of age and older at least 80% of the time during month 6 of treatment. In DISSOLVE II, a response rate of 47% was reported in older patients.

SEL-212, which is made up of PEGylated uricase (pegadricase) coadministered with sirolimus (Rapamycin), will be submitted for U.S. regulatory approval in the first half of 2024.

In the management of gout flares, interleukin (IL)-1beta and inflammasome inhibitors, both of which target specific inflammatory pathways, could also provide attractive additions to urate-lowering therapies. Other agents commonly used in the treatment of flares, such as NSAIDs, steroids, and colchicine (Colcrys), are not as specific, and have side effects that often limit their usability, Dr. Neogi said.

In the meantime, new research indicates that an inflammasome inhibitor that has already been approved for use in diabetes may provide distinct benefits for the management of gout. An analysis of data from 15,067 adults with both gout and type 2 diabetes showed that when a sodium-glucose cotransporter 2 (SGLT-2) inhibitor was added to urate-lowering therapy, the symptoms of gout, including flares, were significantly reduced, resulting in fewer emergency department visits and hospitalizations.

“SGLT-2 inhibitors have anti-inflammatory activity that limits the progression of kidney failure, heart failure, and will also lower the serum uric acid,” said Dr. Terkeltaub. “That’s a major development.”

Dr. Neogi disclosed relationships with Novartis, Pfizer/Lilly, and Regeneron, Dr. Terkeltaub reported relationships with Dyve, Fortress, and Atom, and Dr. Tedeschi reported a relationship with Novartis.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Taken from Medscape , by Kristin Jenkins