The prevalence of gout is skyrocketing all over the world, and although medicine in the pipeline keep promise for strengthening the efficacy and basic safety of procedure, authorities alert that “gout remains suboptimally managed.”
“For a definitely properly-comprehended disorder, gout is remarkably undertreated,” explained Robert A. Terkeltaub, MD, professor of drugs emeritus at the College of California, San Diego. “This is amazing and depressing since allopurinol has been about for about 60 many years or so.”
Randomized, controlled trials clearly show that 80%-90% of clients with gout can be properly addressed to target with existing gout therapies. “Around a calendar year or two, gout flares boost and sufferers do nicely,” Dr. Terkeltaub reported.
By reducing too much concentrations of serum urate, current therapies gradual the formation of soluble monosodium urate crystals that precipitate within just joints and comfortable tissues, inducing a very inflammatory community reaction. These therapies decrease the frequency of excruciatingly agonizing gout flares.
“Quite a few sufferers with gout are not getting urate-lowering treatment at all,” Sara K. Tedeschi, MD, MPH, assistant professor of drugs at Harvard Health-related College, Boston, and head of crystal-induced arthritis ailments at Brigham and Women’s Medical center, also in Boston, mentioned in an interview.
“However, a prevalent problem in gout is treatment method inertia,” explained Tuhina Neogi, MD, PhD, chief of rheumatology at Boston Professional medical Middle.
On a world-wide scale, only a person-3rd of patients with gout are began on urate-reducing treatment, and more than 50% abandon remedy after 1 calendar year. As a consequence, the efficiency of urate-reducing therapies has dropped to very well below 50%, Dr. Terkeltaub said.
“I assume gout has been taken considerably less seriously than it should really be for quite some time,” he spelled out in an job interview. Gout’s influence on health and nicely-remaining is no trivial make a difference. A recent analyze confirmed that a prognosis of gout was related with an enhanced risk of anxiety and depression, and there is new evidence suggesting that gout flares are associated with an amplified hazard of cardiovascular situations, together with lethal myocardial infarction and stroke.
“We need to have medicines that are not just helpful but also risk-free, and we have to have to incorporate true-planet knowledge into our assessment of treatment usefulness, in particular in the existence of comorbidities,” Dr. Terkeltaub claimed.
The prevalence of the “sickness of kings” has increased 100% above the very last 30 several years, outstripping entire world populace advancement and life expectancy. In the United States, an estimated 5% of older people, or 12 million, have gout. Globally, the quantity affected exceeds 50 million.
The patient demographics linked with gout have also expanded. At the time found largely in fleshy, center-aged adult males of privilege, gout impacts a lot more women of all ages, additional older people at either conclude of the age spectrum, and far more individuals in Third Globe international locations than ever right before.
Administration
In the United States, the ideal management of gout remains the matter of discussion, with variations in pro view mirrored in evidence-based clinical tips. “We know that the perception of gout is unique concerning major treatment doctors, sufferers, and rheumatologists,” Dr. Terkeltaub said.
The 2017 American College of Medical professionals rules for the management of gout propose a treat-to-symptom tactic to urate-lowering remedy. Nevertheless, the 2020 American School of Rheumatology rules reinforce a standard deal with-to-target technique to a serum urate goal of < 6.0 mg/dL.
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.
In fact, it can take up to 800 mg a day of allopurinol — less in patients with moderate to severe kidney disease — to reduce the symptom burden in gout. And it can take a year or longer of drug testing and titration to reach the optimal serum urate target. Paradoxically, gout flares usually get worse during this time.
“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.
Practice changes, such as partnering with nursing or pharmacy, may help facilitate in-clinic dose titration, “much like a warfarin clinic,” Dr. Neogi suggested.
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.
The steps involved in the titration of urate-lowering therapy also complicate the treatment of gout, making it impractical for many patients and impossible for others whose access to primary care is limited to one or two visits a year. The process of drug titration, with steadily increasing doses, can make patients anxious about the possibility of being overmedicated. Taking a drug every day, even when joints feel “normal,” can also increase the risk of nonadherence.
“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.
Drugs in the pipeline
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.
