Gout

The U.S. Food and Drug Administration has approved canakinumab (Ilaris) for the treatment of gout flares in adults who cannot be treated with NSAIDs, colchicine, or repeated courses of corticosteroids. The drug is also indicated for people who could not tolerate or had an inadequate response to NSAIDs or colchicine.

The drug, a humanized anti–interleukin-1 beta monoclonal antibody, is the first and only biologic approved in the United States for the treatment of gout flares, according to Novartis. It is administered in a single, subcutaneous injection of 150 mg.

“At Novartis, we are committed to bringing medicines that address high unmet needs to patients. We are proud to receive approval on our eighth indication for Ilaris in the U.S. and provide the first biologic medicine option for people with gout flares to help treat this painful and debilitating condition,” the company said in a statement to this news organization.

Canakinumab was first approved in the United States in 2009 for the treatment of children and adults with cryopyrin-associated periodic syndrome (CAPS). Since then, it has been approved for the treatment of several other autoinflammatory diseases, including Still’s disease and recurrent fever syndromes.

In 2011, an FDA advisory panel voted against the approval of canakinumab to treat acute gout flares refractory to NSAIDs, colchicine, or repeated courses of corticosteroids, while in 2013, the European Medicine Agency approved the drug for this treatment indication.

Since that FDA advisory committee meeting and the FDA’s subsequent rejection letter, “[Novartis] has conducted additional studies in patients with gout flares and other related populations to further characterize the short- and long-term safety of canakinumab supporting the current application. To further support the benefit-risk [profile of the drug], the indication is for a more restricted population than initially proposed in 2011,” the FDA’s Center for Drug Evaluation and Research said in a statement to this news organization. “Given these considerations and the available safety information, the Agency determined that canakinumab, at the recommended dosage, has a favorable risk-benefit profile” in the specified patient population.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved canakinumab (Ilaris) for the treatment of gout flares in adults who cannot be treated with NSAIDs, colchicine, or repeated courses of corticosteroids. The drug is also indicated for people who could not tolerate or had an inadequate response to NSAIDs or colchicine.

The drug, a humanized anti–interleukin-1 beta monoclonal antibody, is the first and only biologic approved in the United States for the treatment of gout flares, according to Novartis. It is administered in a single, subcutaneous injection of 150 mg.

“At Novartis, we are committed to bringing medicines that address high unmet needs to patients. We are proud to receive approval on our eighth indication for Ilaris in the U.S. and provide the first biologic medicine option for people with gout flares to help treat this painful and debilitating condition,” the company said in a statement to this news organization.

Canakinumab was first approved in the United States in 2009 for the treatment of children and adults with cryopyrin-associated periodic syndrome (CAPS). Since then, it has been approved for the treatment of several other autoinflammatory diseases, including Still’s disease and recurrent fever syndromes.

In 2011, an FDA advisory panel voted against the approval of canakinumab to treat acute gout flares refractory to NSAIDs, colchicine, or repeated courses of corticosteroids, while in 2013, the European Medicine Agency approved the drug for this treatment indication.

Since that FDA advisory committee meeting and the FDA’s subsequent rejection letter, “[Novartis] has conducted additional studies in patients with gout flares and other related populations to further characterize the short- and long-term safety of canakinumab supporting the current application. To further support the benefit-risk [profile of the drug], the indication is for a more restricted population than initially proposed in 2011,” the FDA’s Center for Drug Evaluation and Research said in a statement to this news organization. “Given these considerations and the available safety information, the Agency determined that canakinumab, at the recommended dosage, has a favorable risk-benefit profile” in the specified patient population.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved canakinumab (Ilaris) for the treatment of gout flares in adults who cannot be treated with NSAIDs, colchicine, or repeated courses of corticosteroids. The drug is also indicated for people who could not tolerate or had an inadequate response to NSAIDs or colchicine.

The drug, a humanized anti–interleukin-1 beta monoclonal antibody, is the first and only biologic approved in the United States for the treatment of gout flares, according to Novartis. It is administered in a single, subcutaneous injection of 150 mg.

“At Novartis, we are committed to bringing medicines that address high unmet needs to patients. We are proud to receive approval on our eighth indication for Ilaris in the U.S. and provide the first biologic medicine option for people with gout flares to help treat this painful and debilitating condition,” the company said in a statement to this news organization.

Canakinumab was first approved in the United States in 2009 for the treatment of children and adults with cryopyrin-associated periodic syndrome (CAPS). Since then, it has been approved for the treatment of several other autoinflammatory diseases, including Still’s disease and recurrent fever syndromes.

In 2011, an FDA advisory panel voted against the approval of canakinumab to treat acute gout flares refractory to NSAIDs, colchicine, or repeated courses of corticosteroids, while in 2013, the European Medicine Agency approved the drug for this treatment indication.

Since that FDA advisory committee meeting and the FDA’s subsequent rejection letter, “[Novartis] has conducted additional studies in patients with gout flares and other related populations to further characterize the short- and long-term safety of canakinumab supporting the current application. To further support the benefit-risk [profile of the drug], the indication is for a more restricted population than initially proposed in 2011,” the FDA’s Center for Drug Evaluation and Research said in a statement to this news organization. “Given these considerations and the available safety information, the Agency determined that canakinumab, at the recommended dosage, has a favorable risk-benefit profile” in the specified patient population.

A version of this article first appeared on Medscape.com.

The prevalence of gout is skyrocketing worldwide, and while drugs in the pipeline hold promise for improving the efficacy and safety of treatment, experts warn that “gout remains suboptimally managed.”

“For a really well-understood disease, gout is remarkably undertreated,” said Robert A. Terkeltaub, MD, professor of medicine emeritus at the University of California, 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 monosodium urate crystals that precipitate within joints and soft tissues, inducing a highly inflammatory local response with superimposed systemic inflammation. 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.

On a global scale, only one-third of patients with gout are started on urate-lowering therapy, and more than 50% abandon treatment after 1 year. As a result, the effectiveness of urate-lowering therapies in reality is well below 50%, Dr. Terkeltaub said.

“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 prevalence of what used to be thought of as the “disease of kings” has increased 100% over the last 30 years, outstripping world population growth and life expectancy. In the United States, an estimated 5% of adults, or 12 million, have gout. Globally, the number affected exceeds 50 million.

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.

The 2017 American College of Physicians guidelines for the management of gout recommend a treat-to-symptom approach to urate-lowering therapy. However, the 2020 American College of Rheumatology guidelines reinforce a standard treat-to-target strategy to a serum urate target 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 or second visit, with minimal dose 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.

• Allopurinol (Zyloprim, Aloprim), an inexpensive xanthine oxidase inhibitor (XOI), is still considered a first-line treatment, but is associated with allopurinol hypersensitivity syndrome. In select patients of Asian, African, and Arab descent, this adverse drug reaction can be life-threatening, and is associated with a mortality rate of 20%-25%.
• Febuxostat (Uloric), another XOI, is considered a second-line drug in the treatment of gout, but has carried a boxed warning from the Food and Drug Administration since 2019. It is associated with a significantly increased risk of cardiovascular death.
• Probenecid (Probalan), a uricosuric agent that increases renal uric acid excretion, is associated with an increased risk of drug interactions and kidney stones, and is rarely used.

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 story was updated on August 14, 2023.

The prevalence of gout is skyrocketing worldwide, and while drugs in the pipeline hold promise for improving the efficacy and safety of treatment, experts warn that “gout remains suboptimally managed.”

“For a really well-understood disease, gout is remarkably undertreated,” said Robert A. Terkeltaub, MD, professor of medicine emeritus at the University of California, 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 monosodium urate crystals that precipitate within joints and soft tissues, inducing a highly inflammatory local response with superimposed systemic inflammation. 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.

On a global scale, only one-third of patients with gout are started on urate-lowering therapy, and more than 50% abandon treatment after 1 year. As a result, the effectiveness of urate-lowering therapies in reality is well below 50%, Dr. Terkeltaub said.

“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 prevalence of what used to be thought of as the “disease of kings” has increased 100% over the last 30 years, outstripping world population growth and life expectancy. In the United States, an estimated 5% of adults, or 12 million, have gout. Globally, the number affected exceeds 50 million.

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.

The 2017 American College of Physicians guidelines for the management of gout recommend a treat-to-symptom approach to urate-lowering therapy. However, the 2020 American College of Rheumatology guidelines reinforce a standard treat-to-target strategy to a serum urate target 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 or second visit, with minimal dose 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.

• Allopurinol (Zyloprim, Aloprim), an inexpensive xanthine oxidase inhibitor (XOI), is still considered a first-line treatment, but is associated with allopurinol hypersensitivity syndrome. In select patients of Asian, African, and Arab descent, this adverse drug reaction can be life-threatening, and is associated with a mortality rate of 20%-25%.
• Febuxostat (Uloric), another XOI, is considered a second-line drug in the treatment of gout, but has carried a boxed warning from the Food and Drug Administration since 2019. It is associated with a significantly increased risk of cardiovascular death.
• Probenecid (Probalan), a uricosuric agent that increases renal uric acid excretion, is associated with an increased risk of drug interactions and kidney stones, and is rarely used.

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 story was updated on August 14, 2023.

The prevalence of gout is skyrocketing worldwide, and while drugs in the pipeline hold promise for improving the efficacy and safety of treatment, experts warn that “gout remains suboptimally managed.”

“For a really well-understood disease, gout is remarkably undertreated,” said Robert A. Terkeltaub, MD, professor of medicine emeritus at the University of California, 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 monosodium urate crystals that precipitate within joints and soft tissues, inducing a highly inflammatory local response with superimposed systemic inflammation. 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.

On a global scale, only one-third of patients with gout are started on urate-lowering therapy, and more than 50% abandon treatment after 1 year. As a result, the effectiveness of urate-lowering therapies in reality is well below 50%, Dr. Terkeltaub said.

“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 prevalence of what used to be thought of as the “disease of kings” has increased 100% over the last 30 years, outstripping world population growth and life expectancy. In the United States, an estimated 5% of adults, or 12 million, have gout. Globally, the number affected exceeds 50 million.

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.

The 2017 American College of Physicians guidelines for the management of gout recommend a treat-to-symptom approach to urate-lowering therapy. However, the 2020 American College of Rheumatology guidelines reinforce a standard treat-to-target strategy to a serum urate target 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 or second visit, with minimal dose 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.

• Allopurinol (Zyloprim, Aloprim), an inexpensive xanthine oxidase inhibitor (XOI), is still considered a first-line treatment, but is associated with allopurinol hypersensitivity syndrome. In select patients of Asian, African, and Arab descent, this adverse drug reaction can be life-threatening, and is associated with a mortality rate of 20%-25%.
• Febuxostat (Uloric), another XOI, is considered a second-line drug in the treatment of gout, but has carried a boxed warning from the Food and Drug Administration since 2019. It is associated with a significantly increased risk of cardiovascular death.
• Probenecid (Probalan), a uricosuric agent that increases renal uric acid excretion, is associated with an increased risk of drug interactions and kidney stones, and is rarely used.

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 story was updated on August 14, 2023.

TOPLINE:

Treatment of adults with type 2 diabetes and gout with a sodium-glucose cotransporter 2 (SGLT2) inhibitor was significantly linked with fewer gout flares, compared with matched patients treated with a dipeptidyl peptidase–4 (DPP-4) inhibitor.

METHODOLOGY:

• The study used observational data collected from the entire population of British Columbia that included 15,067 adults with both gout and type 2 diabetes in 2014-2020.
• The group included 8,318 patients who initiated an SGLT2 inhibitor and 6,749 patients who initiated a DPP-4 inhibitor during the study period after at least 1 year of continuous enrollment.
• Using propensity-score matching, 4,075 matched pairs were identified, where one person initiated an SGLT2 inhibitor and the other started a DPP-4 inhibitor.
• Primary outcome was recurrent gout flare counts during follow-up that required an ED visit, hospital admission, or an outpatient visit for a gout flare coupled with appropriate treatment, tallied from the first day of drug receipt until June 30, 2022, with an average follow-up of 1.6 years.
• Secondary endpoints included the incidence of myocardial infarction and stroke.

TAKEAWAY:

• Total gout-flare rates after SGLT2 inhibitor initiation were 52.4/1000 person-years and after DPP-4 inhibitor initiation were 79.7/1,000 person-years, an adjusted rate ratio of 0.66, a reduction significantly linked with SGLT2 inhibitor use.
• For flares that required an ED visit or hospitalization, initiation of an SGLT2 inhibitor was linked with a significant, reduced aRR of 0.52, compared with DPP-4 inhibitor initiation.
• The flare-rate reduction linked with SGLT2 inhibitor use was consistent regardless of sex, age, baseline diuretic use, prior treatment with a urate-lowering agent, and baseline gout intensity.
• SGLT2 inhibitor initiation was also significantly linked with an adjusted reduced hazard ratio of 0.69 in the incidence of myocardial infarction, compared with DPP-4 inhibitor initiation, but stroke incidence was not significantly different between the groups.

IN PRACTICE:

These findings suggest that SGLT2 inhibitors could have a much-needed ability to simultaneously reduce the burden of recurrent gout flares and coronary sequelae in patients with gout and type 2 diabetes, indicating that “SGLT2 inhibitors may offer distinct benefits,” making the drug class “a particularly attractive addition to current urate-lowering therapies,” the researchers write.

SOURCE:

The study was primarily conducted by researchers at Massachusetts General Hospital in Boston. The study was published online July 24 in Annals of Internal Medicine.

LIMITATIONS:

The data used in the study did not include gout flares that did not require medical attention and did not include laboratory findings for study participants. Because the data were observational the findings may be susceptible to unmeasured confounding.

DISCLOSURES:

The study received no commercial funding. One author has reported receiving consulting fees from ANI and LG Chem.

A version of this article first appeared on Medscape.com.

TOPLINE:

Treatment of adults with type 2 diabetes and gout with a sodium-glucose cotransporter 2 (SGLT2) inhibitor was significantly linked with fewer gout flares, compared with matched patients treated with a dipeptidyl peptidase–4 (DPP-4) inhibitor.

METHODOLOGY:

• The study used observational data collected from the entire population of British Columbia that included 15,067 adults with both gout and type 2 diabetes in 2014-2020.
• The group included 8,318 patients who initiated an SGLT2 inhibitor and 6,749 patients who initiated a DPP-4 inhibitor during the study period after at least 1 year of continuous enrollment.
• Using propensity-score matching, 4,075 matched pairs were identified, where one person initiated an SGLT2 inhibitor and the other started a DPP-4 inhibitor.
• Primary outcome was recurrent gout flare counts during follow-up that required an ED visit, hospital admission, or an outpatient visit for a gout flare coupled with appropriate treatment, tallied from the first day of drug receipt until June 30, 2022, with an average follow-up of 1.6 years.
• Secondary endpoints included the incidence of myocardial infarction and stroke.

TAKEAWAY:

• Total gout-flare rates after SGLT2 inhibitor initiation were 52.4/1000 person-years and after DPP-4 inhibitor initiation were 79.7/1,000 person-years, an adjusted rate ratio of 0.66, a reduction significantly linked with SGLT2 inhibitor use.
• For flares that required an ED visit or hospitalization, initiation of an SGLT2 inhibitor was linked with a significant, reduced aRR of 0.52, compared with DPP-4 inhibitor initiation.
• The flare-rate reduction linked with SGLT2 inhibitor use was consistent regardless of sex, age, baseline diuretic use, prior treatment with a urate-lowering agent, and baseline gout intensity.
• SGLT2 inhibitor initiation was also significantly linked with an adjusted reduced hazard ratio of 0.69 in the incidence of myocardial infarction, compared with DPP-4 inhibitor initiation, but stroke incidence was not significantly different between the groups.

IN PRACTICE:

These findings suggest that SGLT2 inhibitors could have a much-needed ability to simultaneously reduce the burden of recurrent gout flares and coronary sequelae in patients with gout and type 2 diabetes, indicating that “SGLT2 inhibitors may offer distinct benefits,” making the drug class “a particularly attractive addition to current urate-lowering therapies,” the researchers write.

SOURCE:

The study was primarily conducted by researchers at Massachusetts General Hospital in Boston. The study was published online July 24 in Annals of Internal Medicine.

LIMITATIONS:

The data used in the study did not include gout flares that did not require medical attention and did not include laboratory findings for study participants. Because the data were observational the findings may be susceptible to unmeasured confounding.

DISCLOSURES:

The study received no commercial funding. One author has reported receiving consulting fees from ANI and LG Chem.

A version of this article first appeared on Medscape.com.

TOPLINE:

Treatment of adults with type 2 diabetes and gout with a sodium-glucose cotransporter 2 (SGLT2) inhibitor was significantly linked with fewer gout flares, compared with matched patients treated with a dipeptidyl peptidase–4 (DPP-4) inhibitor.

METHODOLOGY:

• The study used observational data collected from the entire population of British Columbia that included 15,067 adults with both gout and type 2 diabetes in 2014-2020.
• The group included 8,318 patients who initiated an SGLT2 inhibitor and 6,749 patients who initiated a DPP-4 inhibitor during the study period after at least 1 year of continuous enrollment.
• Using propensity-score matching, 4,075 matched pairs were identified, where one person initiated an SGLT2 inhibitor and the other started a DPP-4 inhibitor.
• Primary outcome was recurrent gout flare counts during follow-up that required an ED visit, hospital admission, or an outpatient visit for a gout flare coupled with appropriate treatment, tallied from the first day of drug receipt until June 30, 2022, with an average follow-up of 1.6 years.
• Secondary endpoints included the incidence of myocardial infarction and stroke.

TAKEAWAY:

• Total gout-flare rates after SGLT2 inhibitor initiation were 52.4/1000 person-years and after DPP-4 inhibitor initiation were 79.7/1,000 person-years, an adjusted rate ratio of 0.66, a reduction significantly linked with SGLT2 inhibitor use.
• For flares that required an ED visit or hospitalization, initiation of an SGLT2 inhibitor was linked with a significant, reduced aRR of 0.52, compared with DPP-4 inhibitor initiation.
• The flare-rate reduction linked with SGLT2 inhibitor use was consistent regardless of sex, age, baseline diuretic use, prior treatment with a urate-lowering agent, and baseline gout intensity.
• SGLT2 inhibitor initiation was also significantly linked with an adjusted reduced hazard ratio of 0.69 in the incidence of myocardial infarction, compared with DPP-4 inhibitor initiation, but stroke incidence was not significantly different between the groups.

IN PRACTICE:

These findings suggest that SGLT2 inhibitors could have a much-needed ability to simultaneously reduce the burden of recurrent gout flares and coronary sequelae in patients with gout and type 2 diabetes, indicating that “SGLT2 inhibitors may offer distinct benefits,” making the drug class “a particularly attractive addition to current urate-lowering therapies,” the researchers write.

SOURCE:

The study was primarily conducted by researchers at Massachusetts General Hospital in Boston. The study was published online July 24 in Annals of Internal Medicine.

LIMITATIONS:

The data used in the study did not include gout flares that did not require medical attention and did not include laboratory findings for study participants. Because the data were observational the findings may be susceptible to unmeasured confounding.

DISCLOSURES:

The study received no commercial funding. One author has reported receiving consulting fees from ANI and LG Chem.

A version of this article first appeared on Medscape.com.

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

A European Alliance of Associations for Rheumatology task force has released new guidance on imaging of crystal-induced arthropathies (CiA). The document provides recommendations for using imaging for diagnosis and monitoring of these types of diseases.

“These are the first-ever EULAR recommendations on imaging in this group of diseases. In fact, we are not aware of any similar international recommendations which provide guidance on which imaging technique, when, and how [they] should be used for crystal-induced arthropathies,” lead author Peter Mandl, MD, PhD, of the division of rheumatology at the Medical University of Vienna, told this news organization. Dr. Mandl presented the new recommendations at the annual European Congress of Rheumatology.

While some rheumatologists very familiar with crystal-induced arthropathies already regularly use imaging with these patients, these formal recommendations could highlight to wider audiences that “these imaging modalities can be very sensitive and specific for CiA,” said Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School and head of crystal-induced arthritis diseases at Brigham and Women’s Hospital in Boston. She was not involved with the work.

The document included general recommendations for imaging in CiA as well as specific recommendations for gout, basic calcium phosphate deposition disease (BCPD), and calcium pyrophosphate deposition disease (CPPD). Across all disease types, performing imaging on symptomatic areas as well as disease-specific target sites should be considered, the recommendations state. This includes the first metatarsophalangeal joint in gout, the wrist and knee in CPPD, and the shoulder in BCPD.

Both ultrasound (US) and dual-energy CT (DECT) are the recommended imaging modalities in gout. If imaging reveals characteristic features of monosodium urate (MSU) crystal deposition, synovial fluid analysis is not necessary to confirm a gout diagnosis. The volume of MSU crystals on imaging can also be used to predict future disease flares.

Showing imaging and explaining imaging findings may help patients understand their condition and adhere to treatment regimens, the recommendations state. “I think it’s a very powerful way to counsel patients,” Dr. Tedeschi said in an interview.

Imaging is necessary in the diagnosis of BCPD, and clinicians should use either conventional radiography or US. These imagining modalities are recommended for CPPD, and clinicians can use CT if they suspect axial involvement. The document does not recommend serial imaging for either BCPD or CPPD unless there has been an “unsuspected change in clinical characteristics.”

These recommendations highlight how imaging can have a “powerful impact on patient counseling and diagnosis,” said Dr. Tedeschi. She emphasized the importance of US training in rheumatology fellowship programs.

During his presentation at EULAR 2023, Dr. Mandl also highlighted a robust research agenda to further investigate how imaging can aid in the diagnosis and treatment of CiA. “It would be great to have an imaging modality someday that would help us differentiate between various types of calcium crystal,” he said.

Dr. Mandl has financial relationships with AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Roche, and UCB. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article first appeared on Medscape.com.

A European Alliance of Associations for Rheumatology task force has released new guidance on imaging of crystal-induced arthropathies (CiA). The document provides recommendations for using imaging for diagnosis and monitoring of these types of diseases.

“These are the first-ever EULAR recommendations on imaging in this group of diseases. In fact, we are not aware of any similar international recommendations which provide guidance on which imaging technique, when, and how [they] should be used for crystal-induced arthropathies,” lead author Peter Mandl, MD, PhD, of the division of rheumatology at the Medical University of Vienna, told this news organization. Dr. Mandl presented the new recommendations at the annual European Congress of Rheumatology.

While some rheumatologists very familiar with crystal-induced arthropathies already regularly use imaging with these patients, these formal recommendations could highlight to wider audiences that “these imaging modalities can be very sensitive and specific for CiA,” said Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School and head of crystal-induced arthritis diseases at Brigham and Women’s Hospital in Boston. She was not involved with the work.

The document included general recommendations for imaging in CiA as well as specific recommendations for gout, basic calcium phosphate deposition disease (BCPD), and calcium pyrophosphate deposition disease (CPPD). Across all disease types, performing imaging on symptomatic areas as well as disease-specific target sites should be considered, the recommendations state. This includes the first metatarsophalangeal joint in gout, the wrist and knee in CPPD, and the shoulder in BCPD.

Both ultrasound (US) and dual-energy CT (DECT) are the recommended imaging modalities in gout. If imaging reveals characteristic features of monosodium urate (MSU) crystal deposition, synovial fluid analysis is not necessary to confirm a gout diagnosis. The volume of MSU crystals on imaging can also be used to predict future disease flares.

Showing imaging and explaining imaging findings may help patients understand their condition and adhere to treatment regimens, the recommendations state. “I think it’s a very powerful way to counsel patients,” Dr. Tedeschi said in an interview.

Imaging is necessary in the diagnosis of BCPD, and clinicians should use either conventional radiography or US. These imagining modalities are recommended for CPPD, and clinicians can use CT if they suspect axial involvement. The document does not recommend serial imaging for either BCPD or CPPD unless there has been an “unsuspected change in clinical characteristics.”

These recommendations highlight how imaging can have a “powerful impact on patient counseling and diagnosis,” said Dr. Tedeschi. She emphasized the importance of US training in rheumatology fellowship programs.

During his presentation at EULAR 2023, Dr. Mandl also highlighted a robust research agenda to further investigate how imaging can aid in the diagnosis and treatment of CiA. “It would be great to have an imaging modality someday that would help us differentiate between various types of calcium crystal,” he said.

Dr. Mandl has financial relationships with AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Roche, and UCB. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article first appeared on Medscape.com.

A European Alliance of Associations for Rheumatology task force has released new guidance on imaging of crystal-induced arthropathies (CiA). The document provides recommendations for using imaging for diagnosis and monitoring of these types of diseases.

“These are the first-ever EULAR recommendations on imaging in this group of diseases. In fact, we are not aware of any similar international recommendations which provide guidance on which imaging technique, when, and how [they] should be used for crystal-induced arthropathies,” lead author Peter Mandl, MD, PhD, of the division of rheumatology at the Medical University of Vienna, told this news organization. Dr. Mandl presented the new recommendations at the annual European Congress of Rheumatology.

While some rheumatologists very familiar with crystal-induced arthropathies already regularly use imaging with these patients, these formal recommendations could highlight to wider audiences that “these imaging modalities can be very sensitive and specific for CiA,” said Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School and head of crystal-induced arthritis diseases at Brigham and Women’s Hospital in Boston. She was not involved with the work.

The document included general recommendations for imaging in CiA as well as specific recommendations for gout, basic calcium phosphate deposition disease (BCPD), and calcium pyrophosphate deposition disease (CPPD). Across all disease types, performing imaging on symptomatic areas as well as disease-specific target sites should be considered, the recommendations state. This includes the first metatarsophalangeal joint in gout, the wrist and knee in CPPD, and the shoulder in BCPD.

Both ultrasound (US) and dual-energy CT (DECT) are the recommended imaging modalities in gout. If imaging reveals characteristic features of monosodium urate (MSU) crystal deposition, synovial fluid analysis is not necessary to confirm a gout diagnosis. The volume of MSU crystals on imaging can also be used to predict future disease flares.

Showing imaging and explaining imaging findings may help patients understand their condition and adhere to treatment regimens, the recommendations state. “I think it’s a very powerful way to counsel patients,” Dr. Tedeschi said in an interview.

Imaging is necessary in the diagnosis of BCPD, and clinicians should use either conventional radiography or US. These imagining modalities are recommended for CPPD, and clinicians can use CT if they suspect axial involvement. The document does not recommend serial imaging for either BCPD or CPPD unless there has been an “unsuspected change in clinical characteristics.”

These recommendations highlight how imaging can have a “powerful impact on patient counseling and diagnosis,” said Dr. Tedeschi. She emphasized the importance of US training in rheumatology fellowship programs.

During his presentation at EULAR 2023, Dr. Mandl also highlighted a robust research agenda to further investigate how imaging can aid in the diagnosis and treatment of CiA. “It would be great to have an imaging modality someday that would help us differentiate between various types of calcium crystal,” he said.

Dr. Mandl has financial relationships with AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Roche, and UCB. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

A version of this article first appeared on Medscape.com.

Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.

“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.

“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.

“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.


 

Links between gout and neurodegenerative diseases debated in earlier studies

Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.

Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
 

A novel approach that analyzes brain structure and genetics

In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.

Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
 

MRI shows brain changes in patients with gout

In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.

They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.

Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.

Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).

In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.

Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
 

Genetic analyses reinforce MRI results

Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.

They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.

In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.

Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
 

A novel approach that suggests further related research

Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.

Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.

“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.

Early diagnosis benefits patients

Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.

“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”

Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.

The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.

Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.

“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.

“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.

“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.


 

Links between gout and neurodegenerative diseases debated in earlier studies

Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.

Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
 

A novel approach that analyzes brain structure and genetics

In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.

Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
 

MRI shows brain changes in patients with gout

In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.

They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.

Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.

Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).

In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.

Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
 

Genetic analyses reinforce MRI results

Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.

They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.

In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.

Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
 

A novel approach that suggests further related research

Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.

Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.

“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.

Early diagnosis benefits patients

Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.

“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”

Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.

The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.

Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.

“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.

“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.

“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.


 

Links between gout and neurodegenerative diseases debated in earlier studies

Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.

Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
 

A novel approach that analyzes brain structure and genetics

In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.

Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
 

MRI shows brain changes in patients with gout

In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.

They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.

Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.

Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).

In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.

Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
 

Genetic analyses reinforce MRI results

Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.

They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.

In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.

Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
 

A novel approach that suggests further related research

Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.

Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.

“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.

Early diagnosis benefits patients

Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.

“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”

Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.

The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – Serum uric acid of less than 6 mg/dL was achieved and maintained for a substantial period of time with a once-monthly infusion of SEL-212 in patients with refractory gout, according to results of the two phase 3 DISSOLVE I and II trials.

Both trials met their primary endpoints. In DISSOLVE I – the U.S. study – 56% of patients on SEL-212 at 0.15 mg/kg (high dose) achieved a response, defined as achievement and maintenance of a reduction in serum urate to less than 6 mg/dL for at least 80% of the time during month 6 of treatment. In DISSOLVE II – the global study – 46% of patients on SEL-212 on the 0.15-mg/kg dose achieved response.

In participants aged 50 years or older, there was a statistically significant higher response rate at the high dose of SEL-212 in both DISSOLVE I and II of 65% and 47%, respectively, compared with placebo.

Herbert S.B. Baraf, MD, clinical professor of medicine at George Washington University, Washington, and principal investigator of the DISSOLVE program, presented results of the two phase 3 trials during a late-breaking session at the annual European Congress of Rheumatology.

Arthritis Foundation

“The top-line data from the two SEL-212 phase 3 studies are encouraging. They show that induction of immunotolerance with an infusion of a rapamycin-containing nanoparticle (SEL-110), followed immediately by an infusion of pegadricase, a potent but immunogenic uricase, allows for a strong and sustained uric acid–lowering effect without the development of anti-drug antibodies,” Dr. Baraf said in an interview.

SEL-212 is a monthly two-part infusion therapy – a combination of Selecta Biosciences’s ImmTOR immune tolerance platform, and a therapeutic uricase enzyme (pegadricase), designed to treat refractory gout. SEL-110 (ImmTOR) is an immune-tolerizing, nanoencapsulated rapamycin administered 30 minutes before pegadricase and inhibits anti-pegadricase antibodies. SEL-37 is a pegylated uricase (pegadricase) that converts uric acid to excretable allantoin.

SEL-212 was originally developed by Selecta. Swedish Orphan Biovitrum (Sobi) licensed SEL-212 from Selecta in June 2020 and is responsible for development, regulatory, and commercial activities in all markets outside of China. Selecta is responsible for ImmTOR manufacturing. The phase 3 program for SEL-212 was run by Selecta and funded by Sobi.

It is understood that a biologic license application will be submitted to the Food and Drug Administration, most likely next year, and if approved, “the SEL-212 two-component infusion treatment would provide a monthly alternative to twice-monthly pegloticase, for patients with refractory gout,” Dr. Baraf added.
 

Details of the trials

The two DISSOLVE studies replicate double-blind, placebo-controlled trials in patients with chronic refractory gout. DISSOLVE I was carried out in 112 patients across 29 sites in the United States, and DISSOLVE II tested the two-part treatment in 153 patients across 37 sites in the United States, Russia, Ukraine, Georgia, and Serbia.

Both studies randomized patients 1:1:1 to a high dose (SEL-110 of 0.15 mg/kg plus SEL-037 of 0.2 mg/kg), low dose (SEL-110 of 0.1 mg/kg plus SEL-037 of 0.2 mg/kg), or placebo (saline) infused every 28 days for 6 months. Prophylaxis against infusion reactions and gout flares were given to all participants.

Adult patients had a 10- to 14-year history of symptomatic gout, with three or more flares over the 18 months prior to screening, or one or more tophus, or a diagnosis of gouty arthritis. They were also required to have chronic refractory gout with a failure to normalize serum uric acid with any xanthine oxidase inhibitor (for example, allopurinol) and to have not been previously exposed to uricase-based therapy. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, body mass index, and sex across treatment groups. Gout severity was greater in DISSOLVE II, Dr. Baraf reported.

Both studies treated patients for 6 months, but DISSOLVE 1 continued with a 6-month, blinded safety extension. The primary endpoint in both studies was serum urate control during month 6, and secondary endpoints included tender and swollen joint counts, tophus burden, patient-reported outcomes of activity limitation, quality of life, and gout flare incidence.

In DISSOLVE I, patients on SEL-212 had a statistically significant higher response rate during month 6 of 56% with the high dose (P < .0001) and 48% with the low dose (P < .0001), compared with 4% of patients randomized to receive placebo. In DISSOLVE II, participants on SEL-212 had a statistically significant higher response rate during month 6 of 46% with the high dose (P = .0002) and 40% with the low dose (P = .0008), compared with 11% of patients randomized to receive placebo.

“We also saw significant reductions in serum uric acid for all treatment groups, compared with placebo,” Dr. Baraf reported. Mean percentage change was –62.3% and –58.3% in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1% and –52.2% in DISSOLVE II, respectively.

SEL-212 had a favorable safety profile with adverse events as expected across both doses, including mild to moderate stomatitis (3.4% in the low-dose group and 9.2% in the high-dose group versus 0% in the placebo group), and a greater number of infusion reactions at 24 hours and 1 hour after drug administration in both treatment groups versus placebo. Six patients had treatment-related serious adverse events, including two cases of anaphylaxis and one gout flare in both the high- and low-dose treatment groups. The 6-month extension period in the DISSOLVE I trial showed that the majority (75%) of patients who completed 6 months of SEL-212 treatment as a responder continued to be successfully treated through 12 months with no infusion reactions or safety signals.

“I expect more data will be forthcoming on the important clinical secondary endpoints targeted by SEL-212 therapy,” Dr. Baraf noted.
 

Need control arm taking allopurinol?

Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas, commented on the study methods after the presentation. “The major problem with this study is that they say the patients had had insufficient response to allopurinol, and my guess is most had received 100-200 mg of allopurinol but were not titrated up to the maximum tolerated dose,” he said, adding: “they should have had a control arm of patients on allopurinol and titrated to the maximum tolerated dose. So, I don’t know what this is really telling us with respect to allopurinol, which is a relatively cheap drug.”

Dr. Baraf reported consulting with Horizon, Sobi, and Selecta; serving on Horizon’s speakers bureau, and receiving grant/research support from Horizon and Sobi. Dr. Fleischmann reported no financial relationship of relevance to this study.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

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

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

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

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

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

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

A version of this article first appeared on Medscape.com.