Becky McCall

VIENNA – Naltrexone can be safely administered to patients with alcohol use disorder (AUD) and compensated cirrhosis to help them achieve abstinence and decrease craving, results of the first randomized controlled trial (RCT) show.

After 3 months, 64% of patients who received naltrexone were abstinent from alcohol, compared with 22% of patients who received placebo, Manasa Alla, MD, a hepatologist from the Institute of Liver and Biliary Sciences (ILBS), New Delhi, said at the European Association for the Study of the Liver (EASL) 2023, where she presented the study findings.

Importantly, naltrexone was found to be safe for patients with compensated cirrhosis. “This fragile population of patients has limited drugs to help them quit alcohol. Naltrexone can be a valuable addition to their measures to reduce craving and on their journey to reach de-addiction and abstinence,” Dr. Alla said.

Hepatotoxicity with naltrexone is rare and data are limited. The Food and Drug Administration previously placed a warning on its use for patients with alcoholic liver disease and underlying cirrhosis.

As a clinician constantly challenged with treating patients with AUD and cirrhosis, Dr. Alla wanted to explore the safety of naltrexone and to test its suitability for these patients who struggle to quit alcohol.

“Here we aimed to primarily test the safety of naltrexone in achieving abstinence and reducing alcohol cravings in patients with alcohol-related cirrhosis,” she said, adding, “The FDA black box warning has been removed, but it has never been tested in an RCT in patients with cirrhosis, so this is exactly what we did here.

“Naltrexone is a very good anti-alcohol-craving drug. If we can establish its safety in cirrhotic patients, it may have very good potential in reducing AUD and reducing the related complications of continued alcohol intake,” Dr. Alla said.
 

Safety, abstinence, lapse, and relapse assessed

The prospective, double-blind, single-center study at the ILBS in New Delhi, enrolled 100 patients with alcohol dependence and cirrhosis between 2020 and 2022. Participants were randomly assigned in a 1:1 ratio to receive naltrexone (50 mg/d) or placebo for 12 weeks. All participants attended regular counseling sessions with the resident psychiatrist. At baseline, the biochemical and drinking-related assessment scores between active and placebo groups of patients with compensated cirrhosis were matched.

Abstinence from alcohol was assessed through self-reported mean number of standard drinks (12 g alcohol per day). Findings were corroborated through an interview with a family member. Serum ethyl glucuronide levels were measured in cases of discrepancy. A relapse was considered to be consumption of over four standard alcoholic drinks/month; a lapse was considered any other alcohol drinking event not classified as relapse.

The primary outcome was the proportion of patients who achieved and maintained alcohol abstinence at 12 weeks; secondary outcomes were the proportion of patients who took naltrexone without a liver-related adverse effect compared with placebo at 12 weeks, the number of relapses and lapses, the difference in craving scores on the Obsessive Compulsive Drinking Scale (OCDS) between groups at 4, 8, and 12 weeks and at 6 months and 12 months, and the proportion of patients who achieved and maintained alcohol abstinence at 6 months.
 

Abstinence at 3 months

After 3 months, abstinence was noted in 64% of the study population who received naltrexone, compared to 22% of those who received placebo (P < .001). At 6 months, a higher proportion of patients in the naltrexone group achieved abstinence (22% vs. 8% with placebo; P = .09).

“We still need to look at the longer-term effects of naltrexone,” Dr. Alla said. “Here we gave the drug plus counseling for 3 months only, so despite encouraging findings, we need further studies to understand more.”

The researchers analyzed the predictors of abstinence at 3 months. They found that patients who consumed fewer than 17 drinks per month at baseline were more likely to achieve abstinence (sensitivity, 81%).

“Our study showed that patients who are consuming less alcohol at baseline can quit alcohol if adequately motivated. We need the motivation, as well as the drug,” she said.

Patient counseling was also very important and was provided for the 3 months of the study. “Even in the placebo arm, we had some patients who became abstinent [11/50 patients], but this dropped at 6 months [to 4/50],” Dr. Alla said.

At 12 weeks, 28% in the naltrexone group experienced relapse, vs. 72% in the placebo group (P < .001). Regarding the secondary outcome of craving scores and how they were affected by naltrexone, the mean OCDS-O (obsessive element) scores were 6.63, compared with 9.29 in naltrexone and placebo, respectively (P < .01). The mean OCDS-C (compulsive element) scores were 6.34 and 9.02, respectively (P < .01).

“Most important, was the safety of naltrexone in this study,” she said. There were no significant adverse events in either arm, and only one patient discontinued the drug in the naltrexone arm. Three patients in the naltrexone group who continued alcohol consumption developed jaundice, “so the jaundice can be attributed to continuous alcohol intake and may not be secondary to the naltrexone per se. We concluded that naltrexone is safe in a compensated cirrhotic patient,” Dr. Alla said.

Regarding other adverse events, 13.7% of patients experienced gastritis with naltrexone, vs. 3.7% among patients who received placebo. Nausea was more common in the placebo group, at 11.1% compared with 6.8% among patients who received naltrexone. Vomiting was more common in the naltrexone arm, at 10.3% vs. 7.4% with placebo. None of these differences reached statistical significance.

A longer-term study and comparisons to other drugs would provide valuable insights going forward.

Moderator Aleksander Krag, MD, professor and head of hepatology at the University of Southern Denmark and Odense University Hospital, Denmark, said: “Any intervention that can reduce or stop alcohol use in patients with cirrhosis and more advanced cirrhosis will improve outcome as well as reduce complications and mortality.

“In some cases, alcohol rehabilitation can completely revert the damaged liver. We have lots of data that show that continuous alcohol use at the more advanced stages can be devastating and reduction [in alcohol use] improves outcome. Therefore, any intervention that can help us to achieve this on behalf of all patients is most welcome,” he said.

Naltrexone (ADDTREX) and identical placebos were supplied by Rusan Pharma. Dr. Alla has disclosed no relevant financial relationships. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience and has participated in advisory boards for Norgine and Siemens outside the submitted work. He receives royalties from Gyldendal and Echosens.
 

A version of this article appeared on Medscape.com.

VIENNA – Naltrexone can be safely administered to patients with alcohol use disorder (AUD) and compensated cirrhosis to help them achieve abstinence and decrease craving, results of the first randomized controlled trial (RCT) show.

After 3 months, 64% of patients who received naltrexone were abstinent from alcohol, compared with 22% of patients who received placebo, Manasa Alla, MD, a hepatologist from the Institute of Liver and Biliary Sciences (ILBS), New Delhi, said at the European Association for the Study of the Liver (EASL) 2023, where she presented the study findings.

Importantly, naltrexone was found to be safe for patients with compensated cirrhosis. “This fragile population of patients has limited drugs to help them quit alcohol. Naltrexone can be a valuable addition to their measures to reduce craving and on their journey to reach de-addiction and abstinence,” Dr. Alla said.

Hepatotoxicity with naltrexone is rare and data are limited. The Food and Drug Administration previously placed a warning on its use for patients with alcoholic liver disease and underlying cirrhosis.

As a clinician constantly challenged with treating patients with AUD and cirrhosis, Dr. Alla wanted to explore the safety of naltrexone and to test its suitability for these patients who struggle to quit alcohol.

“Here we aimed to primarily test the safety of naltrexone in achieving abstinence and reducing alcohol cravings in patients with alcohol-related cirrhosis,” she said, adding, “The FDA black box warning has been removed, but it has never been tested in an RCT in patients with cirrhosis, so this is exactly what we did here.

“Naltrexone is a very good anti-alcohol-craving drug. If we can establish its safety in cirrhotic patients, it may have very good potential in reducing AUD and reducing the related complications of continued alcohol intake,” Dr. Alla said.
 

Safety, abstinence, lapse, and relapse assessed

The prospective, double-blind, single-center study at the ILBS in New Delhi, enrolled 100 patients with alcohol dependence and cirrhosis between 2020 and 2022. Participants were randomly assigned in a 1:1 ratio to receive naltrexone (50 mg/d) or placebo for 12 weeks. All participants attended regular counseling sessions with the resident psychiatrist. At baseline, the biochemical and drinking-related assessment scores between active and placebo groups of patients with compensated cirrhosis were matched.

Abstinence from alcohol was assessed through self-reported mean number of standard drinks (12 g alcohol per day). Findings were corroborated through an interview with a family member. Serum ethyl glucuronide levels were measured in cases of discrepancy. A relapse was considered to be consumption of over four standard alcoholic drinks/month; a lapse was considered any other alcohol drinking event not classified as relapse.

The primary outcome was the proportion of patients who achieved and maintained alcohol abstinence at 12 weeks; secondary outcomes were the proportion of patients who took naltrexone without a liver-related adverse effect compared with placebo at 12 weeks, the number of relapses and lapses, the difference in craving scores on the Obsessive Compulsive Drinking Scale (OCDS) between groups at 4, 8, and 12 weeks and at 6 months and 12 months, and the proportion of patients who achieved and maintained alcohol abstinence at 6 months.
 

Abstinence at 3 months

After 3 months, abstinence was noted in 64% of the study population who received naltrexone, compared to 22% of those who received placebo (P < .001). At 6 months, a higher proportion of patients in the naltrexone group achieved abstinence (22% vs. 8% with placebo; P = .09).

“We still need to look at the longer-term effects of naltrexone,” Dr. Alla said. “Here we gave the drug plus counseling for 3 months only, so despite encouraging findings, we need further studies to understand more.”

The researchers analyzed the predictors of abstinence at 3 months. They found that patients who consumed fewer than 17 drinks per month at baseline were more likely to achieve abstinence (sensitivity, 81%).

“Our study showed that patients who are consuming less alcohol at baseline can quit alcohol if adequately motivated. We need the motivation, as well as the drug,” she said.

Patient counseling was also very important and was provided for the 3 months of the study. “Even in the placebo arm, we had some patients who became abstinent [11/50 patients], but this dropped at 6 months [to 4/50],” Dr. Alla said.

At 12 weeks, 28% in the naltrexone group experienced relapse, vs. 72% in the placebo group (P < .001). Regarding the secondary outcome of craving scores and how they were affected by naltrexone, the mean OCDS-O (obsessive element) scores were 6.63, compared with 9.29 in naltrexone and placebo, respectively (P < .01). The mean OCDS-C (compulsive element) scores were 6.34 and 9.02, respectively (P < .01).

“Most important, was the safety of naltrexone in this study,” she said. There were no significant adverse events in either arm, and only one patient discontinued the drug in the naltrexone arm. Three patients in the naltrexone group who continued alcohol consumption developed jaundice, “so the jaundice can be attributed to continuous alcohol intake and may not be secondary to the naltrexone per se. We concluded that naltrexone is safe in a compensated cirrhotic patient,” Dr. Alla said.

Regarding other adverse events, 13.7% of patients experienced gastritis with naltrexone, vs. 3.7% among patients who received placebo. Nausea was more common in the placebo group, at 11.1% compared with 6.8% among patients who received naltrexone. Vomiting was more common in the naltrexone arm, at 10.3% vs. 7.4% with placebo. None of these differences reached statistical significance.

A longer-term study and comparisons to other drugs would provide valuable insights going forward.

Moderator Aleksander Krag, MD, professor and head of hepatology at the University of Southern Denmark and Odense University Hospital, Denmark, said: “Any intervention that can reduce or stop alcohol use in patients with cirrhosis and more advanced cirrhosis will improve outcome as well as reduce complications and mortality.

“In some cases, alcohol rehabilitation can completely revert the damaged liver. We have lots of data that show that continuous alcohol use at the more advanced stages can be devastating and reduction [in alcohol use] improves outcome. Therefore, any intervention that can help us to achieve this on behalf of all patients is most welcome,” he said.

Naltrexone (ADDTREX) and identical placebos were supplied by Rusan Pharma. Dr. Alla has disclosed no relevant financial relationships. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience and has participated in advisory boards for Norgine and Siemens outside the submitted work. He receives royalties from Gyldendal and Echosens.
 

A version of this article appeared on Medscape.com.

VIENNA – Naltrexone can be safely administered to patients with alcohol use disorder (AUD) and compensated cirrhosis to help them achieve abstinence and decrease craving, results of the first randomized controlled trial (RCT) show.

After 3 months, 64% of patients who received naltrexone were abstinent from alcohol, compared with 22% of patients who received placebo, Manasa Alla, MD, a hepatologist from the Institute of Liver and Biliary Sciences (ILBS), New Delhi, said at the European Association for the Study of the Liver (EASL) 2023, where she presented the study findings.

Importantly, naltrexone was found to be safe for patients with compensated cirrhosis. “This fragile population of patients has limited drugs to help them quit alcohol. Naltrexone can be a valuable addition to their measures to reduce craving and on their journey to reach de-addiction and abstinence,” Dr. Alla said.

Hepatotoxicity with naltrexone is rare and data are limited. The Food and Drug Administration previously placed a warning on its use for patients with alcoholic liver disease and underlying cirrhosis.

As a clinician constantly challenged with treating patients with AUD and cirrhosis, Dr. Alla wanted to explore the safety of naltrexone and to test its suitability for these patients who struggle to quit alcohol.

“Here we aimed to primarily test the safety of naltrexone in achieving abstinence and reducing alcohol cravings in patients with alcohol-related cirrhosis,” she said, adding, “The FDA black box warning has been removed, but it has never been tested in an RCT in patients with cirrhosis, so this is exactly what we did here.

“Naltrexone is a very good anti-alcohol-craving drug. If we can establish its safety in cirrhotic patients, it may have very good potential in reducing AUD and reducing the related complications of continued alcohol intake,” Dr. Alla said.
 

Safety, abstinence, lapse, and relapse assessed

The prospective, double-blind, single-center study at the ILBS in New Delhi, enrolled 100 patients with alcohol dependence and cirrhosis between 2020 and 2022. Participants were randomly assigned in a 1:1 ratio to receive naltrexone (50 mg/d) or placebo for 12 weeks. All participants attended regular counseling sessions with the resident psychiatrist. At baseline, the biochemical and drinking-related assessment scores between active and placebo groups of patients with compensated cirrhosis were matched.

Abstinence from alcohol was assessed through self-reported mean number of standard drinks (12 g alcohol per day). Findings were corroborated through an interview with a family member. Serum ethyl glucuronide levels were measured in cases of discrepancy. A relapse was considered to be consumption of over four standard alcoholic drinks/month; a lapse was considered any other alcohol drinking event not classified as relapse.

The primary outcome was the proportion of patients who achieved and maintained alcohol abstinence at 12 weeks; secondary outcomes were the proportion of patients who took naltrexone without a liver-related adverse effect compared with placebo at 12 weeks, the number of relapses and lapses, the difference in craving scores on the Obsessive Compulsive Drinking Scale (OCDS) between groups at 4, 8, and 12 weeks and at 6 months and 12 months, and the proportion of patients who achieved and maintained alcohol abstinence at 6 months.
 

Abstinence at 3 months

After 3 months, abstinence was noted in 64% of the study population who received naltrexone, compared to 22% of those who received placebo (P < .001). At 6 months, a higher proportion of patients in the naltrexone group achieved abstinence (22% vs. 8% with placebo; P = .09).

“We still need to look at the longer-term effects of naltrexone,” Dr. Alla said. “Here we gave the drug plus counseling for 3 months only, so despite encouraging findings, we need further studies to understand more.”

The researchers analyzed the predictors of abstinence at 3 months. They found that patients who consumed fewer than 17 drinks per month at baseline were more likely to achieve abstinence (sensitivity, 81%).

“Our study showed that patients who are consuming less alcohol at baseline can quit alcohol if adequately motivated. We need the motivation, as well as the drug,” she said.

Patient counseling was also very important and was provided for the 3 months of the study. “Even in the placebo arm, we had some patients who became abstinent [11/50 patients], but this dropped at 6 months [to 4/50],” Dr. Alla said.

At 12 weeks, 28% in the naltrexone group experienced relapse, vs. 72% in the placebo group (P < .001). Regarding the secondary outcome of craving scores and how they were affected by naltrexone, the mean OCDS-O (obsessive element) scores were 6.63, compared with 9.29 in naltrexone and placebo, respectively (P < .01). The mean OCDS-C (compulsive element) scores were 6.34 and 9.02, respectively (P < .01).

“Most important, was the safety of naltrexone in this study,” she said. There were no significant adverse events in either arm, and only one patient discontinued the drug in the naltrexone arm. Three patients in the naltrexone group who continued alcohol consumption developed jaundice, “so the jaundice can be attributed to continuous alcohol intake and may not be secondary to the naltrexone per se. We concluded that naltrexone is safe in a compensated cirrhotic patient,” Dr. Alla said.

Regarding other adverse events, 13.7% of patients experienced gastritis with naltrexone, vs. 3.7% among patients who received placebo. Nausea was more common in the placebo group, at 11.1% compared with 6.8% among patients who received naltrexone. Vomiting was more common in the naltrexone arm, at 10.3% vs. 7.4% with placebo. None of these differences reached statistical significance.

A longer-term study and comparisons to other drugs would provide valuable insights going forward.

Moderator Aleksander Krag, MD, professor and head of hepatology at the University of Southern Denmark and Odense University Hospital, Denmark, said: “Any intervention that can reduce or stop alcohol use in patients with cirrhosis and more advanced cirrhosis will improve outcome as well as reduce complications and mortality.

“In some cases, alcohol rehabilitation can completely revert the damaged liver. We have lots of data that show that continuous alcohol use at the more advanced stages can be devastating and reduction [in alcohol use] improves outcome. Therefore, any intervention that can help us to achieve this on behalf of all patients is most welcome,” he said.

Naltrexone (ADDTREX) and identical placebos were supplied by Rusan Pharma. Dr. Alla has disclosed no relevant financial relationships. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience and has participated in advisory boards for Norgine and Siemens outside the submitted work. He receives royalties from Gyldendal and Echosens.
 

A version of this article appeared on Medscape.com.

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

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

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

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

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).

Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.

The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.

“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.

Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.

Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”

Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.

Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
 

Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics

Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.

Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.

But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”

This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).

“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”

Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”

Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.

Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”

Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
 

Lupus nephritis

Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.

Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).

“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”

He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.

“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”

Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.

Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.

Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
 

Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations

Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.

There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.

Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.

“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m²,” he remarked, completing his detailed discussion of the updated recommendations.

Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.

MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).

Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.

The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.

“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.

Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.

Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”

Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.

Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
 

Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics

Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.

Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.

But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”

This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).

“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”

Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”

Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.

Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”

Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
 

Lupus nephritis

Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.

Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).

“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”

He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.

“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”

Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.

Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.

Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
 

Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations

Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.

There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.

Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.

“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m²,” he remarked, completing his detailed discussion of the updated recommendations.

Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.

MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).

Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.

The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.

“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.

Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.

Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”

Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.

Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
 

Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics

Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.

Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.

But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”

This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).

“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”

Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”

Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.

Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”

Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
 

Lupus nephritis

Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.

Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).

“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”

He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.

“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”

Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.

Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.

Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
 

Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations

Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.

There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.

Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.

“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m²,” he remarked, completing his detailed discussion of the updated recommendations.

Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.

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 – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

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.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.

The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.

Becky McCall/MDedge News

Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.

Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”

The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).

A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).

The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.

When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”

Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”

“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”

Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”

The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.

DUBLIN – Changing the way food options and information is presented on food delivery apps, as well as default smaller portions, may encourage healthier selections, lowering the calorie intake by 4%-15%, show three new randomized trials from the United Kingdom.

The prominent positioning of low-calorie menu items, and restaurants with low-calorie main meals, on a food app emerged as the most promising approach to promote healthier eating, followed by preselecting smaller portions by default, and finally calorie labels, Anna Keleher, MPA, a behavioral scientist at Nesta, London, reported at the European Congress on Obesity (ECO) meeting.

“Many out-of-home meals have more calories than meals cooked in-home and using delivery apps is linked with a higher risk of becoming overweight or obese,” she remarked. “We’re interested in understanding more about delivery apps because they can be modified at scale easily and can reach millions of people with interventions to promote healthier and more nutritious options in these settings.”

Food delivery apps have surged in use in the United Kingdom with a 55% increase since 2015; examples include Uber Eats, Just Eat, and Deliveroo. “This trend is similar in the United States, with more and more consumers using delivery apps to buy food,” said Ms. Keleher, a senior adviser at the Behavioral Insights Team, New York. 

Emma Boyland, PhD, an obesity psychologist from Liverpool (England) University, said: “Apps are an increasingly popular way for people to buy food and the virtual food environment is becoming as prominent as the physical food environment in how we go about obtaining meals.”

She highlighted the need to understand more about how food apps change the way we purchase and eat, but noted that “the work presented today” showed that “moving the position of food choices and information, as well as the brand name and imagery, influences what people end up buying and consuming.

“I think there’s a place for interventions that challenge these things and improve dietary health,” said Dr. Boyland, who chaired the session during which Ms. Keleher presented her results. “However, as we’ve seen with calorie labeling, they don’t always have the biggest effect on their own, so as is often the case, we need to take multiple actions, incorporating all the elements of the environment to make a meaningful difference.”
 

Three trials changing displays on simulated food delivery apps

“Delivery apps could reach millions of people and help us select healthier food options, and yet there is very little research looking at what works to promote healthier and more nutritious options in these settings,” Filippo Bianchi, MD, a colleague working with Ms. Keleher, said in a press release issued by ECO.

So the research team carried out a proof-of-concept testing of health-promoting interventions by developing a simulated food delivery app and asking 23,783 adults who typically use such services to choose a meal for themselves as if it were a real-life food delivery order.

“As a first step, we developed a simulated online food delivery platform to generate evidence on the effectiveness of our interventions,” Ms. Keleher explained, noting that the simulated platform included 21 restaurants and almost 600 food and drink items to choose from.

The research evaluated 14 interventions across three randomized controlled trials, displaying various food-ordering options that promoted lower-calorie options against a control. The trials investigated default choices (promoting the selection of small portion sizes through defaults, n = 6,000); positioning (promoting the selection of less calorie-dense options through positioning, n = 9,003); and labeling (promoting the selection of less calorific options through calorie labels, n = 8,780).

The primary outcome was the total number of calories in the basket at checkout. The results were adjusted for potentially confounding factors, such as body mass index, age, gender, and income.

For the trial that promoted smaller portions by default, “all of our interventions significantly reduced calorie purchases, with each additional intervention element increasing the effect sizes, which ranged from a 6% to 13% reduction in calories [–5.5% to –12.5% kcal/order; P < .05],” reported Ms. Keleher.

The second trial varied the position of both items on the menu and the order of restaurants – effectively, lower-calorie menu options were more prominent, and restaurant options with lower-calorie main meals were placed at the top of the restaurant selection page.

Ms. Keleher noted that there have been some concerns about whether this strategy would negatively affect restaurant business, so the research team counteracted this by also incorporating an option where low-calorie but high-price options were placed near the top of the display to promote healthier options but without loss of income for participating restaurants. This last intervention with low-calorie/high-price options placed near the top also led to reduced calorie intake.

“This showed that promoting low-calorie options does not necessarily mean damaging business revenue,” she said. “We hope that the industry can evolve to meet the widely recognized needs of society and consumers.”

Repositioning restaurants emerged as more effective than repositioning foods on the menu, while all interventions significantly reduced calorie purchases. “Effect sizes ranged from 6% to 15% reductions in calories purchased per order [P < .05],” reported Ms. Keleher.

The last trial tested seven calorie labels: four that changed the font size and location of the label, two that added a switch on/off filter for calorie label display, and one that was a calorie summary at checkout.

“All these standard calorie labels directionally reduced the number of excess calories with two [options] reaching statistical significance. Five out of seven labels significantly reduced calorie purchases with effect sizes ranging from 4.3% to –7.8% kcal/order (P < .05),” reported Ms. Keleher.

“This research is important for policymakers so they can understand the best way for companies to display calorie labels and what to include in regulations and guidelines,” she summarized.
 

Qualitative think-aloud study explored views around food delivery apps

Another piece of research, the think-aloud study, by the same authors, was presented at ECO, and explored how best to enhance the effectiveness and acceptability of calorie labels in food delivery apps in consultation with 20 adult delivery app users in the United Kingdom.

Researchers tried to document the range of views people have about calorie labels, including variation both between people and within an individual.

“For example, on a weekend, people might not want to engage with calories at all because they are more concerned to treat themselves, whereas at a mid-week lunch that same person might really want the ability to check the calorie content of their food,” Ms. Keleher reported.

She said that considerations varied significantly between people such that they described different ways in which calorie labeling impacted their food-ordering experience.

“Some people felt labels supported their existing intentions, whereas others felt labels built their knowledge. Still others felt calorie labels were insufficient to support their health and wanted more information, such as on macronutrients,” said Ms. Keleher, quoting one participant: “There’s no situation in which I would look at [calories]. I look at nutrients. I prefer the traffic light system [color-coding salt, fat, and sugar content],” she relayed.   

The key recommendations based on the think-aloud study included providing a filter that allows users to switch calorie labels on and off; communicating recommended energy intake per meal (that is, 600 kcal) and not just per day (that is, 2,000 kcal); and avoiding framing calorie label messaging or formatting as judgmental (for example, red fonts).

“These studies provide encouraging proof-of-concept evidence that small tweaks in delivery apps could help many people to identify and select healthier foods. Testing similar initiatives with real restaurants and delivery apps will be important to assess the long-term impact of these interventions in the real world. Further research should also explore the best way to balance desired health impacts while minimizing effects on businesses and on cost-of-living concerns for consumers,” concluded Dr. Bianchi.
 

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

DUBLIN – Changing the way food options and information is presented on food delivery apps, as well as default smaller portions, may encourage healthier selections, lowering the calorie intake by 4%-15%, show three new randomized trials from the United Kingdom.

The prominent positioning of low-calorie menu items, and restaurants with low-calorie main meals, on a food app emerged as the most promising approach to promote healthier eating, followed by preselecting smaller portions by default, and finally calorie labels, Anna Keleher, MPA, a behavioral scientist at Nesta, London, reported at the European Congress on Obesity (ECO) meeting.

“Many out-of-home meals have more calories than meals cooked in-home and using delivery apps is linked with a higher risk of becoming overweight or obese,” she remarked. “We’re interested in understanding more about delivery apps because they can be modified at scale easily and can reach millions of people with interventions to promote healthier and more nutritious options in these settings.”

Food delivery apps have surged in use in the United Kingdom with a 55% increase since 2015; examples include Uber Eats, Just Eat, and Deliveroo. “This trend is similar in the United States, with more and more consumers using delivery apps to buy food,” said Ms. Keleher, a senior adviser at the Behavioral Insights Team, New York. 

Emma Boyland, PhD, an obesity psychologist from Liverpool (England) University, said: “Apps are an increasingly popular way for people to buy food and the virtual food environment is becoming as prominent as the physical food environment in how we go about obtaining meals.”

She highlighted the need to understand more about how food apps change the way we purchase and eat, but noted that “the work presented today” showed that “moving the position of food choices and information, as well as the brand name and imagery, influences what people end up buying and consuming.

“I think there’s a place for interventions that challenge these things and improve dietary health,” said Dr. Boyland, who chaired the session during which Ms. Keleher presented her results. “However, as we’ve seen with calorie labeling, they don’t always have the biggest effect on their own, so as is often the case, we need to take multiple actions, incorporating all the elements of the environment to make a meaningful difference.”
 

Three trials changing displays on simulated food delivery apps

“Delivery apps could reach millions of people and help us select healthier food options, and yet there is very little research looking at what works to promote healthier and more nutritious options in these settings,” Filippo Bianchi, MD, a colleague working with Ms. Keleher, said in a press release issued by ECO.

So the research team carried out a proof-of-concept testing of health-promoting interventions by developing a simulated food delivery app and asking 23,783 adults who typically use such services to choose a meal for themselves as if it were a real-life food delivery order.

“As a first step, we developed a simulated online food delivery platform to generate evidence on the effectiveness of our interventions,” Ms. Keleher explained, noting that the simulated platform included 21 restaurants and almost 600 food and drink items to choose from.

The research evaluated 14 interventions across three randomized controlled trials, displaying various food-ordering options that promoted lower-calorie options against a control. The trials investigated default choices (promoting the selection of small portion sizes through defaults, n = 6,000); positioning (promoting the selection of less calorie-dense options through positioning, n = 9,003); and labeling (promoting the selection of less calorific options through calorie labels, n = 8,780).

The primary outcome was the total number of calories in the basket at checkout. The results were adjusted for potentially confounding factors, such as body mass index, age, gender, and income.

For the trial that promoted smaller portions by default, “all of our interventions significantly reduced calorie purchases, with each additional intervention element increasing the effect sizes, which ranged from a 6% to 13% reduction in calories [–5.5% to –12.5% kcal/order; P < .05],” reported Ms. Keleher.

The second trial varied the position of both items on the menu and the order of restaurants – effectively, lower-calorie menu options were more prominent, and restaurant options with lower-calorie main meals were placed at the top of the restaurant selection page.

Ms. Keleher noted that there have been some concerns about whether this strategy would negatively affect restaurant business, so the research team counteracted this by also incorporating an option where low-calorie but high-price options were placed near the top of the display to promote healthier options but without loss of income for participating restaurants. This last intervention with low-calorie/high-price options placed near the top also led to reduced calorie intake.

“This showed that promoting low-calorie options does not necessarily mean damaging business revenue,” she said. “We hope that the industry can evolve to meet the widely recognized needs of society and consumers.”

Repositioning restaurants emerged as more effective than repositioning foods on the menu, while all interventions significantly reduced calorie purchases. “Effect sizes ranged from 6% to 15% reductions in calories purchased per order [P < .05],” reported Ms. Keleher.

The last trial tested seven calorie labels: four that changed the font size and location of the label, two that added a switch on/off filter for calorie label display, and one that was a calorie summary at checkout.

“All these standard calorie labels directionally reduced the number of excess calories with two [options] reaching statistical significance. Five out of seven labels significantly reduced calorie purchases with effect sizes ranging from 4.3% to –7.8% kcal/order (P < .05),” reported Ms. Keleher.

“This research is important for policymakers so they can understand the best way for companies to display calorie labels and what to include in regulations and guidelines,” she summarized.
 

Qualitative think-aloud study explored views around food delivery apps

Another piece of research, the think-aloud study, by the same authors, was presented at ECO, and explored how best to enhance the effectiveness and acceptability of calorie labels in food delivery apps in consultation with 20 adult delivery app users in the United Kingdom.

Researchers tried to document the range of views people have about calorie labels, including variation both between people and within an individual.

“For example, on a weekend, people might not want to engage with calories at all because they are more concerned to treat themselves, whereas at a mid-week lunch that same person might really want the ability to check the calorie content of their food,” Ms. Keleher reported.

She said that considerations varied significantly between people such that they described different ways in which calorie labeling impacted their food-ordering experience.

“Some people felt labels supported their existing intentions, whereas others felt labels built their knowledge. Still others felt calorie labels were insufficient to support their health and wanted more information, such as on macronutrients,” said Ms. Keleher, quoting one participant: “There’s no situation in which I would look at [calories]. I look at nutrients. I prefer the traffic light system [color-coding salt, fat, and sugar content],” she relayed.   

The key recommendations based on the think-aloud study included providing a filter that allows users to switch calorie labels on and off; communicating recommended energy intake per meal (that is, 600 kcal) and not just per day (that is, 2,000 kcal); and avoiding framing calorie label messaging or formatting as judgmental (for example, red fonts).

“These studies provide encouraging proof-of-concept evidence that small tweaks in delivery apps could help many people to identify and select healthier foods. Testing similar initiatives with real restaurants and delivery apps will be important to assess the long-term impact of these interventions in the real world. Further research should also explore the best way to balance desired health impacts while minimizing effects on businesses and on cost-of-living concerns for consumers,” concluded Dr. Bianchi.
 

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

DUBLIN – Changing the way food options and information is presented on food delivery apps, as well as default smaller portions, may encourage healthier selections, lowering the calorie intake by 4%-15%, show three new randomized trials from the United Kingdom.

The prominent positioning of low-calorie menu items, and restaurants with low-calorie main meals, on a food app emerged as the most promising approach to promote healthier eating, followed by preselecting smaller portions by default, and finally calorie labels, Anna Keleher, MPA, a behavioral scientist at Nesta, London, reported at the European Congress on Obesity (ECO) meeting.

“Many out-of-home meals have more calories than meals cooked in-home and using delivery apps is linked with a higher risk of becoming overweight or obese,” she remarked. “We’re interested in understanding more about delivery apps because they can be modified at scale easily and can reach millions of people with interventions to promote healthier and more nutritious options in these settings.”

Food delivery apps have surged in use in the United Kingdom with a 55% increase since 2015; examples include Uber Eats, Just Eat, and Deliveroo. “This trend is similar in the United States, with more and more consumers using delivery apps to buy food,” said Ms. Keleher, a senior adviser at the Behavioral Insights Team, New York. 

Emma Boyland, PhD, an obesity psychologist from Liverpool (England) University, said: “Apps are an increasingly popular way for people to buy food and the virtual food environment is becoming as prominent as the physical food environment in how we go about obtaining meals.”

She highlighted the need to understand more about how food apps change the way we purchase and eat, but noted that “the work presented today” showed that “moving the position of food choices and information, as well as the brand name and imagery, influences what people end up buying and consuming.

“I think there’s a place for interventions that challenge these things and improve dietary health,” said Dr. Boyland, who chaired the session during which Ms. Keleher presented her results. “However, as we’ve seen with calorie labeling, they don’t always have the biggest effect on their own, so as is often the case, we need to take multiple actions, incorporating all the elements of the environment to make a meaningful difference.”
 

Three trials changing displays on simulated food delivery apps

“Delivery apps could reach millions of people and help us select healthier food options, and yet there is very little research looking at what works to promote healthier and more nutritious options in these settings,” Filippo Bianchi, MD, a colleague working with Ms. Keleher, said in a press release issued by ECO.

So the research team carried out a proof-of-concept testing of health-promoting interventions by developing a simulated food delivery app and asking 23,783 adults who typically use such services to choose a meal for themselves as if it were a real-life food delivery order.

“As a first step, we developed a simulated online food delivery platform to generate evidence on the effectiveness of our interventions,” Ms. Keleher explained, noting that the simulated platform included 21 restaurants and almost 600 food and drink items to choose from.

The research evaluated 14 interventions across three randomized controlled trials, displaying various food-ordering options that promoted lower-calorie options against a control. The trials investigated default choices (promoting the selection of small portion sizes through defaults, n = 6,000); positioning (promoting the selection of less calorie-dense options through positioning, n = 9,003); and labeling (promoting the selection of less calorific options through calorie labels, n = 8,780).

The primary outcome was the total number of calories in the basket at checkout. The results were adjusted for potentially confounding factors, such as body mass index, age, gender, and income.

For the trial that promoted smaller portions by default, “all of our interventions significantly reduced calorie purchases, with each additional intervention element increasing the effect sizes, which ranged from a 6% to 13% reduction in calories [–5.5% to –12.5% kcal/order; P < .05],” reported Ms. Keleher.

The second trial varied the position of both items on the menu and the order of restaurants – effectively, lower-calorie menu options were more prominent, and restaurant options with lower-calorie main meals were placed at the top of the restaurant selection page.

Ms. Keleher noted that there have been some concerns about whether this strategy would negatively affect restaurant business, so the research team counteracted this by also incorporating an option where low-calorie but high-price options were placed near the top of the display to promote healthier options but without loss of income for participating restaurants. This last intervention with low-calorie/high-price options placed near the top also led to reduced calorie intake.

“This showed that promoting low-calorie options does not necessarily mean damaging business revenue,” she said. “We hope that the industry can evolve to meet the widely recognized needs of society and consumers.”

Repositioning restaurants emerged as more effective than repositioning foods on the menu, while all interventions significantly reduced calorie purchases. “Effect sizes ranged from 6% to 15% reductions in calories purchased per order [P < .05],” reported Ms. Keleher.

The last trial tested seven calorie labels: four that changed the font size and location of the label, two that added a switch on/off filter for calorie label display, and one that was a calorie summary at checkout.

“All these standard calorie labels directionally reduced the number of excess calories with two [options] reaching statistical significance. Five out of seven labels significantly reduced calorie purchases with effect sizes ranging from 4.3% to –7.8% kcal/order (P < .05),” reported Ms. Keleher.

“This research is important for policymakers so they can understand the best way for companies to display calorie labels and what to include in regulations and guidelines,” she summarized.
 

Qualitative think-aloud study explored views around food delivery apps

Another piece of research, the think-aloud study, by the same authors, was presented at ECO, and explored how best to enhance the effectiveness and acceptability of calorie labels in food delivery apps in consultation with 20 adult delivery app users in the United Kingdom.

Researchers tried to document the range of views people have about calorie labels, including variation both between people and within an individual.

“For example, on a weekend, people might not want to engage with calories at all because they are more concerned to treat themselves, whereas at a mid-week lunch that same person might really want the ability to check the calorie content of their food,” Ms. Keleher reported.

She said that considerations varied significantly between people such that they described different ways in which calorie labeling impacted their food-ordering experience.

“Some people felt labels supported their existing intentions, whereas others felt labels built their knowledge. Still others felt calorie labels were insufficient to support their health and wanted more information, such as on macronutrients,” said Ms. Keleher, quoting one participant: “There’s no situation in which I would look at [calories]. I look at nutrients. I prefer the traffic light system [color-coding salt, fat, and sugar content],” she relayed.   

The key recommendations based on the think-aloud study included providing a filter that allows users to switch calorie labels on and off; communicating recommended energy intake per meal (that is, 600 kcal) and not just per day (that is, 2,000 kcal); and avoiding framing calorie label messaging or formatting as judgmental (for example, red fonts).

“These studies provide encouraging proof-of-concept evidence that small tweaks in delivery apps could help many people to identify and select healthier foods. Testing similar initiatives with real restaurants and delivery apps will be important to assess the long-term impact of these interventions in the real world. Further research should also explore the best way to balance desired health impacts while minimizing effects on businesses and on cost-of-living concerns for consumers,” concluded Dr. Bianchi.
 

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