The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

The latest research on therapeutic management of patients with relapsing-remitting multiple sclerosis (MS) presented at the European Committee for Treatment and Research in Multiple Sclerosis 2024 Congress is reported by Dr Patricia Coyle from Stony Brook University Hospital, in Stony Brook, New York. 

Dr Coyle first discusses a registry study looking at initiation of monoclonal antibody therapy for patients with pediatric-onset MS. Results showed a significant reduction in disability at age 23 and beyond when therapy was initiated in childhood.   

Next, Dr Coyle discusses a trial examining the safety and efficacy of frexalimab, a second-generation anti-CD40L antibody. In an open-label extension trial through 72 weeks, frexalimab provided a sustained reduction of disease activity, as measured by MRI, and was well tolerated. 

She then details a study looking at the effects of disease-modifying therapies (DMTs) on pregnancy outcomes in patients with MS. Using a German MS registry, researchers looked at 3722 pregnancies, 2885 with DMT exposure, and concluded that most pregnancy outcomes are unaffected by DMT exposure; however, the data showed the potential risk for reduced birth rates. 

Finally, Dr Coyle examines the efficacy of the Bruton tyrosine kinase (BTK) inhibitor tolebrutinib, as evidenced by the HERCULES trial and the two GEMINI trials. In HERCULES, the BTK inhibitor reduced 6-month disability progression by a significant 31% compared with placebo.  

--

Patricia K. Coyle, MD, Professor and Interim Chair, Department of Neurology; Director, MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, New York

Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: 
 
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Accordant; Amgen; Biogen; Bristol Myers Squibb; Eli Lilly & Company; EMD Serono; GSK; Genentech; Horizon; LabCorp; Mylan; Novartis; Sanofi Genzyme; Viatris 
Received research grant from: Celgene; CorEvitas LLC; Genentech/Roche; National Institute of Neurological Disorders and Stroke; Sanofi Genzyme

Summary:

In this segment, the speaker discusses how AI is revolutionizing the drug repurposing process. Previously, drug repurposing was limited by manual research on individual diseases and drugs. With AI, scientists can now analyze a vast array of drugs and diseases simultaneously, generating a ranking system based on the likelihood of success. The Center for Cytokine Storm Treatment and Laboratory, along with the platform Every Cure, uses AI to score 3000 drugs against 18,000 diseases. This platform dramatically reduces the time and resources required for drug repurposing, enabling predictions that can be tested in a fraction of the time.
 

Key Takeaways:

AI is accelerating the drug repurposing process, offering faster and more comprehensive analysis of possible drug-disease matches.

The AI-based platform assigns a likelihood score to each potential match, streamlining the process for testing and validation.

The ability to analyze global biomedical knowledge in 24 hours is unprecedented, reducing research costs and increasing the speed of drug discovery.
 

Our Editors Also Recommend: 

AI’s Drug Revolution, Part 1: Faster Trials and Approvals

From AI to Obesity Drugs to Soaring Costs: Medscape Hot Topics in the Medical Profession Report 2024

AI Voice Analysis for Diabetes Screening Shows Promise

To see the full event recording, click here.
 

A version of this article appeared on Medscape.com.

Summary:

In this segment, the speaker discusses how AI is revolutionizing the drug repurposing process. Previously, drug repurposing was limited by manual research on individual diseases and drugs. With AI, scientists can now analyze a vast array of drugs and diseases simultaneously, generating a ranking system based on the likelihood of success. The Center for Cytokine Storm Treatment and Laboratory, along with the platform Every Cure, uses AI to score 3000 drugs against 18,000 diseases. This platform dramatically reduces the time and resources required for drug repurposing, enabling predictions that can be tested in a fraction of the time.
 

Key Takeaways:

AI is accelerating the drug repurposing process, offering faster and more comprehensive analysis of possible drug-disease matches.

The AI-based platform assigns a likelihood score to each potential match, streamlining the process for testing and validation.

The ability to analyze global biomedical knowledge in 24 hours is unprecedented, reducing research costs and increasing the speed of drug discovery.
 

Our Editors Also Recommend: 

AI’s Drug Revolution, Part 1: Faster Trials and Approvals

From AI to Obesity Drugs to Soaring Costs: Medscape Hot Topics in the Medical Profession Report 2024

AI Voice Analysis for Diabetes Screening Shows Promise

To see the full event recording, click here.
 

A version of this article appeared on Medscape.com.

Summary:

In this segment, the speaker discusses how AI is revolutionizing the drug repurposing process. Previously, drug repurposing was limited by manual research on individual diseases and drugs. With AI, scientists can now analyze a vast array of drugs and diseases simultaneously, generating a ranking system based on the likelihood of success. The Center for Cytokine Storm Treatment and Laboratory, along with the platform Every Cure, uses AI to score 3000 drugs against 18,000 diseases. This platform dramatically reduces the time and resources required for drug repurposing, enabling predictions that can be tested in a fraction of the time.
 

Key Takeaways:

AI is accelerating the drug repurposing process, offering faster and more comprehensive analysis of possible drug-disease matches.

The AI-based platform assigns a likelihood score to each potential match, streamlining the process for testing and validation.

The ability to analyze global biomedical knowledge in 24 hours is unprecedented, reducing research costs and increasing the speed of drug discovery.
 

Our Editors Also Recommend: 

AI’s Drug Revolution, Part 1: Faster Trials and Approvals

From AI to Obesity Drugs to Soaring Costs: Medscape Hot Topics in the Medical Profession Report 2024

AI Voice Analysis for Diabetes Screening Shows Promise

To see the full event recording, click here.
 

A version of this article appeared on Medscape.com.

In 2024, the Royal Swedish Academy of Sciences is honoring two US researchers with the Nobel Prize in Medicine for the discovery of a fundamental principle of how gene activity is regulated. Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.

“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
 

Protein Expression 

Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.

Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.

Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.

In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood. 
 

Roundworm Research 

In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.

Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.

Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.

Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
 

Collaboration Yields Breakthrough

After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14. 

At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.

The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
 

Subdued Initial Response

The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.

In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.

In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.

The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
 

Small RNAs, Great Importance

Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.

From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2024, the Royal Swedish Academy of Sciences is honoring two US researchers with the Nobel Prize in Medicine for the discovery of a fundamental principle of how gene activity is regulated. Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.

“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
 

Protein Expression 

Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.

Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.

Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.

In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood. 
 

Roundworm Research 

In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.

Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.

Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.

Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
 

Collaboration Yields Breakthrough

After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14. 

At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.

The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
 

Subdued Initial Response

The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.

In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.

In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.

The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
 

Small RNAs, Great Importance

Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.

From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2024, the Royal Swedish Academy of Sciences is honoring two US researchers with the Nobel Prize in Medicine for the discovery of a fundamental principle of how gene activity is regulated. Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.

“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
 

Protein Expression 

Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.

Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.

Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.

In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood. 
 

Roundworm Research 

In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.

Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.

Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.

Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
 

Collaboration Yields Breakthrough

After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14. 

At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.

The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
 

Subdued Initial Response

The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.

In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.

In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.

The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
 

Small RNAs, Great Importance

Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.

From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A 1-year course of methotrexate (MTX) in clinically suspected arthralgia may prevent the development of rheumatoid arthritis (RA) in at-risk individuals who test negative for anti-citrullinated protein antibody (ACPA), according to 4-year results from the TREAT EARLIER study.

While 2-year data did not show a preventive effect, researchers risk-stratified patients in this most recent data. The previous study also grouped all individuals together, while this new analysis separated patients by seropositivity.

“Heterogeneity in risk of rheumatoid arthritis development in ACPA–negative participants with clinically suspect arthralgia might have concealed a treatment effect due to dilution,” wrote senior author Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at Leiden University Medical Center, Leiden, the Netherlands, and colleagues. “Therefore, risk-stratified analyses are required to adequately assess the possibility of prevention of rheumatoid arthritis in people with clinically suspect arthralgia who are ACPA–negative.”

Leiden University

To qualify for the study, participants needed to have recent-onset joint pain that a treating rheumatologist suspected of progressing to RA. Second, participants had to have subclinical joint inflammation, detected via MRI.

These are “promising results” for a group where predicting risk for RA has been more difficult than for their ACPA–positive counterparts, said Kevin Deane, MD, PhD, a professor of medicine and rheumatologist at the University of Colorado School of Medicine, Aurora, who was not involved with the study. However, additional research is necessary to investigate these findings.

The clinical utility of this finding is also unclear, he noted, as it would be an “extensive process” for all ACPA–negative individuals with joint pain to undergo MRI screening, he continued.

“It’s hard to find people who would meet these criteria, and healthcare systems need to understand how ultimately this could be implemented in clinical care,” he said.
 

Adding Risk Stratification

The TREAT EARLIER trial included 236 participants; nearly two thirds were women, and 77% were ACPA–negative (specifically for anti-cyclic citrullinated peptide 2). Patients randomly assigned to active treatment received a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) upon inclusion and then completed a 1-year course of MTX. The comparator group received a single placebo injection at the beginning of the trial and a 1-year course of placebo tablets. All trial screenings and visits were conducted at the Leiden University Medical Center.

At the 2-year mark, there was no difference in the development of RA between the treatment and placebo groups, although there was improvement in joint pain, physical functioning, and MRI-detected joint inflammation in all at-risk groups given MTX — ACPA–positive patients and those at high risk for clinical arthritis development.

MTX delayed the onset of RA, with a statistically significant difference between treatment and placebo at 6 and 12 months, but not at 24 months.

For this 4-year analysis, published in The Lancet Rheumatology, authors stratified patients at their time of enrollment according to their risk of developing RA based on a published model for predicting inflammatory arthritis. Predictors included ACPA positivity (2 points), rheumatoid factor positivity (1 point), more than two locations of subclinical inflammation on MRI (2 points), and presence of metacarpophalangeal extensor tenosynovitis on MRI (1 point).

Patients with at least 4 points were classified as “high-risk,” with a 70% or higher predicted risk of developing RA. Participants with 2-3 points were at “increased risk” — translating to a 25%-70% higher likelihood of developing the condition. Low-risk patients, with 0-1 points, had < 25% chance of developing RA.

Of the 182 ACPA–negative participants in the study, none were considered high risk, 66 (36%) were at increased risk, and 116 (64%) were at low risk.
 

Decreased Rates of RA Development

Of these ACPA–negative patients stratified as increased risk, 3 of 35 (9%) in the treatment group developed RA, compared with 9 of 31 (29%) in the placebo arm (hazard ratio [HR], 0.27; P = .034).

All 54 ACPA–positive patients enrolled in the study were classified as either increased risk or high risk, but the treatment showed no difference in the rate of RA development in this group, and more than half (56%) developed RA during 4 years of follow-up. However, Dr. van der Helm-van Mil noted that the 2-year data showed treatment improved the severity of subclinical inflammation and symptoms over time in these patients.

The 5-year data from the trial, including physical function and other measures of disease burden, will be analyzed in 2025, she said, and will reveal whether ACPA–negative patients treated with MTX had sustained improvements in these measures.

Additional studies are needed to validate these findings, Dr. van der Helm-van Mil said, but the results indicate that ACPA–positive and ACPA–negative patients “are different populations, and we should evaluate them separately.”

Future RA prevention studies should also risk stratify patients before enrollment so that patients at low risk of developing the disease are not included in the interventions. “You can’t expect a treatment effect if there is no risk for disease,” she added.
 

Is It Cost-Effective?

In a separate analysis, published in Annals of the Rheumatic Diseases, Dr. van der Helm-van Mil and colleagues sought to investigate the cost-effectiveness of the TREAT EARLIER intervention at 2 years of follow-up.

“There is an ongoing debate whether people with arthralgia at risk for RA should be treated with DMARDs [disease-modifying antirheumatic drugs]; however, the economic effects of an intervention in the arthralgia at risk phase are unknown.”

The analysis calculated healthcare productivity and work productivity costs from enrollment to 2 years of follow-up. To demonstrate effect, they also calculated change in quality-adjusted life years (QALYs).

Over the course of 2 years, estimated costs for the treatment arm were €4809 lower (−$5304) than the placebo arm per patient. Lower productivity costs accounted for 97% of this difference.

The treatment arm also resulted in a small improvement (+0.041) in QALYs, compared with placebo.

“These data provide the first evidence that first-line treatment aiming at secondary prevention in arthralgia at-risk for RA is cost-effective,” the authors wrote.

Dr. van der Helm-van Mil emphasized that this cost analysis used only 2-year follow-up data (rather than the newly published 4-year data) and did not differentiate ACPA–negative patients. Despite including a greater heterogeneity of patients, the intervention was still cost-effective. A future analysis that includes 5-year follow-up data and stratifies patients by ACPA status and excludes low-risk individuals could demonstrate more cost benefits to a temporary MTX regimen, she said.

Considering the costs of these preventive interventions is important, added Dr. Deane, who agreed that future analyses should examine cost-effectiveness in groups at high risk of developing RA. (Dr. Deane noted that he had reviewed this article for publication.) However, this analysis did not include the costs of screening patients before enrollment in the study.

Richard Mark Kirkner/MDedge News

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

A 1-year course of methotrexate (MTX) in clinically suspected arthralgia may prevent the development of rheumatoid arthritis (RA) in at-risk individuals who test negative for anti-citrullinated protein antibody (ACPA), according to 4-year results from the TREAT EARLIER study.

While 2-year data did not show a preventive effect, researchers risk-stratified patients in this most recent data. The previous study also grouped all individuals together, while this new analysis separated patients by seropositivity.

“Heterogeneity in risk of rheumatoid arthritis development in ACPA–negative participants with clinically suspect arthralgia might have concealed a treatment effect due to dilution,” wrote senior author Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at Leiden University Medical Center, Leiden, the Netherlands, and colleagues. “Therefore, risk-stratified analyses are required to adequately assess the possibility of prevention of rheumatoid arthritis in people with clinically suspect arthralgia who are ACPA–negative.”

Leiden University

To qualify for the study, participants needed to have recent-onset joint pain that a treating rheumatologist suspected of progressing to RA. Second, participants had to have subclinical joint inflammation, detected via MRI.

These are “promising results” for a group where predicting risk for RA has been more difficult than for their ACPA–positive counterparts, said Kevin Deane, MD, PhD, a professor of medicine and rheumatologist at the University of Colorado School of Medicine, Aurora, who was not involved with the study. However, additional research is necessary to investigate these findings.

The clinical utility of this finding is also unclear, he noted, as it would be an “extensive process” for all ACPA–negative individuals with joint pain to undergo MRI screening, he continued.

“It’s hard to find people who would meet these criteria, and healthcare systems need to understand how ultimately this could be implemented in clinical care,” he said.
 

Adding Risk Stratification

The TREAT EARLIER trial included 236 participants; nearly two thirds were women, and 77% were ACPA–negative (specifically for anti-cyclic citrullinated peptide 2). Patients randomly assigned to active treatment received a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) upon inclusion and then completed a 1-year course of MTX. The comparator group received a single placebo injection at the beginning of the trial and a 1-year course of placebo tablets. All trial screenings and visits were conducted at the Leiden University Medical Center.

At the 2-year mark, there was no difference in the development of RA between the treatment and placebo groups, although there was improvement in joint pain, physical functioning, and MRI-detected joint inflammation in all at-risk groups given MTX — ACPA–positive patients and those at high risk for clinical arthritis development.

MTX delayed the onset of RA, with a statistically significant difference between treatment and placebo at 6 and 12 months, but not at 24 months.

For this 4-year analysis, published in The Lancet Rheumatology, authors stratified patients at their time of enrollment according to their risk of developing RA based on a published model for predicting inflammatory arthritis. Predictors included ACPA positivity (2 points), rheumatoid factor positivity (1 point), more than two locations of subclinical inflammation on MRI (2 points), and presence of metacarpophalangeal extensor tenosynovitis on MRI (1 point).

Patients with at least 4 points were classified as “high-risk,” with a 70% or higher predicted risk of developing RA. Participants with 2-3 points were at “increased risk” — translating to a 25%-70% higher likelihood of developing the condition. Low-risk patients, with 0-1 points, had < 25% chance of developing RA.

Of the 182 ACPA–negative participants in the study, none were considered high risk, 66 (36%) were at increased risk, and 116 (64%) were at low risk.
 

Decreased Rates of RA Development

Of these ACPA–negative patients stratified as increased risk, 3 of 35 (9%) in the treatment group developed RA, compared with 9 of 31 (29%) in the placebo arm (hazard ratio [HR], 0.27; P = .034).

All 54 ACPA–positive patients enrolled in the study were classified as either increased risk or high risk, but the treatment showed no difference in the rate of RA development in this group, and more than half (56%) developed RA during 4 years of follow-up. However, Dr. van der Helm-van Mil noted that the 2-year data showed treatment improved the severity of subclinical inflammation and symptoms over time in these patients.

The 5-year data from the trial, including physical function and other measures of disease burden, will be analyzed in 2025, she said, and will reveal whether ACPA–negative patients treated with MTX had sustained improvements in these measures.

Additional studies are needed to validate these findings, Dr. van der Helm-van Mil said, but the results indicate that ACPA–positive and ACPA–negative patients “are different populations, and we should evaluate them separately.”

Future RA prevention studies should also risk stratify patients before enrollment so that patients at low risk of developing the disease are not included in the interventions. “You can’t expect a treatment effect if there is no risk for disease,” she added.
 

Is It Cost-Effective?

In a separate analysis, published in Annals of the Rheumatic Diseases, Dr. van der Helm-van Mil and colleagues sought to investigate the cost-effectiveness of the TREAT EARLIER intervention at 2 years of follow-up.

“There is an ongoing debate whether people with arthralgia at risk for RA should be treated with DMARDs [disease-modifying antirheumatic drugs]; however, the economic effects of an intervention in the arthralgia at risk phase are unknown.”

The analysis calculated healthcare productivity and work productivity costs from enrollment to 2 years of follow-up. To demonstrate effect, they also calculated change in quality-adjusted life years (QALYs).

Over the course of 2 years, estimated costs for the treatment arm were €4809 lower (−$5304) than the placebo arm per patient. Lower productivity costs accounted for 97% of this difference.

The treatment arm also resulted in a small improvement (+0.041) in QALYs, compared with placebo.

“These data provide the first evidence that first-line treatment aiming at secondary prevention in arthralgia at-risk for RA is cost-effective,” the authors wrote.

Dr. van der Helm-van Mil emphasized that this cost analysis used only 2-year follow-up data (rather than the newly published 4-year data) and did not differentiate ACPA–negative patients. Despite including a greater heterogeneity of patients, the intervention was still cost-effective. A future analysis that includes 5-year follow-up data and stratifies patients by ACPA status and excludes low-risk individuals could demonstrate more cost benefits to a temporary MTX regimen, she said.

Considering the costs of these preventive interventions is important, added Dr. Deane, who agreed that future analyses should examine cost-effectiveness in groups at high risk of developing RA. (Dr. Deane noted that he had reviewed this article for publication.) However, this analysis did not include the costs of screening patients before enrollment in the study.

Richard Mark Kirkner/MDedge News

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

A 1-year course of methotrexate (MTX) in clinically suspected arthralgia may prevent the development of rheumatoid arthritis (RA) in at-risk individuals who test negative for anti-citrullinated protein antibody (ACPA), according to 4-year results from the TREAT EARLIER study.

While 2-year data did not show a preventive effect, researchers risk-stratified patients in this most recent data. The previous study also grouped all individuals together, while this new analysis separated patients by seropositivity.

“Heterogeneity in risk of rheumatoid arthritis development in ACPA–negative participants with clinically suspect arthralgia might have concealed a treatment effect due to dilution,” wrote senior author Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at Leiden University Medical Center, Leiden, the Netherlands, and colleagues. “Therefore, risk-stratified analyses are required to adequately assess the possibility of prevention of rheumatoid arthritis in people with clinically suspect arthralgia who are ACPA–negative.”

Leiden University

To qualify for the study, participants needed to have recent-onset joint pain that a treating rheumatologist suspected of progressing to RA. Second, participants had to have subclinical joint inflammation, detected via MRI.

These are “promising results” for a group where predicting risk for RA has been more difficult than for their ACPA–positive counterparts, said Kevin Deane, MD, PhD, a professor of medicine and rheumatologist at the University of Colorado School of Medicine, Aurora, who was not involved with the study. However, additional research is necessary to investigate these findings.

The clinical utility of this finding is also unclear, he noted, as it would be an “extensive process” for all ACPA–negative individuals with joint pain to undergo MRI screening, he continued.

“It’s hard to find people who would meet these criteria, and healthcare systems need to understand how ultimately this could be implemented in clinical care,” he said.
 

Adding Risk Stratification

The TREAT EARLIER trial included 236 participants; nearly two thirds were women, and 77% were ACPA–negative (specifically for anti-cyclic citrullinated peptide 2). Patients randomly assigned to active treatment received a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) upon inclusion and then completed a 1-year course of MTX. The comparator group received a single placebo injection at the beginning of the trial and a 1-year course of placebo tablets. All trial screenings and visits were conducted at the Leiden University Medical Center.

At the 2-year mark, there was no difference in the development of RA between the treatment and placebo groups, although there was improvement in joint pain, physical functioning, and MRI-detected joint inflammation in all at-risk groups given MTX — ACPA–positive patients and those at high risk for clinical arthritis development.

MTX delayed the onset of RA, with a statistically significant difference between treatment and placebo at 6 and 12 months, but not at 24 months.

For this 4-year analysis, published in The Lancet Rheumatology, authors stratified patients at their time of enrollment according to their risk of developing RA based on a published model for predicting inflammatory arthritis. Predictors included ACPA positivity (2 points), rheumatoid factor positivity (1 point), more than two locations of subclinical inflammation on MRI (2 points), and presence of metacarpophalangeal extensor tenosynovitis on MRI (1 point).

Patients with at least 4 points were classified as “high-risk,” with a 70% or higher predicted risk of developing RA. Participants with 2-3 points were at “increased risk” — translating to a 25%-70% higher likelihood of developing the condition. Low-risk patients, with 0-1 points, had < 25% chance of developing RA.

Of the 182 ACPA–negative participants in the study, none were considered high risk, 66 (36%) were at increased risk, and 116 (64%) were at low risk.
 

Decreased Rates of RA Development

Of these ACPA–negative patients stratified as increased risk, 3 of 35 (9%) in the treatment group developed RA, compared with 9 of 31 (29%) in the placebo arm (hazard ratio [HR], 0.27; P = .034).

All 54 ACPA–positive patients enrolled in the study were classified as either increased risk or high risk, but the treatment showed no difference in the rate of RA development in this group, and more than half (56%) developed RA during 4 years of follow-up. However, Dr. van der Helm-van Mil noted that the 2-year data showed treatment improved the severity of subclinical inflammation and symptoms over time in these patients.

The 5-year data from the trial, including physical function and other measures of disease burden, will be analyzed in 2025, she said, and will reveal whether ACPA–negative patients treated with MTX had sustained improvements in these measures.

Additional studies are needed to validate these findings, Dr. van der Helm-van Mil said, but the results indicate that ACPA–positive and ACPA–negative patients “are different populations, and we should evaluate them separately.”

Future RA prevention studies should also risk stratify patients before enrollment so that patients at low risk of developing the disease are not included in the interventions. “You can’t expect a treatment effect if there is no risk for disease,” she added.
 

Is It Cost-Effective?

In a separate analysis, published in Annals of the Rheumatic Diseases, Dr. van der Helm-van Mil and colleagues sought to investigate the cost-effectiveness of the TREAT EARLIER intervention at 2 years of follow-up.

“There is an ongoing debate whether people with arthralgia at risk for RA should be treated with DMARDs [disease-modifying antirheumatic drugs]; however, the economic effects of an intervention in the arthralgia at risk phase are unknown.”

The analysis calculated healthcare productivity and work productivity costs from enrollment to 2 years of follow-up. To demonstrate effect, they also calculated change in quality-adjusted life years (QALYs).

Over the course of 2 years, estimated costs for the treatment arm were €4809 lower (−$5304) than the placebo arm per patient. Lower productivity costs accounted for 97% of this difference.

The treatment arm also resulted in a small improvement (+0.041) in QALYs, compared with placebo.

“These data provide the first evidence that first-line treatment aiming at secondary prevention in arthralgia at-risk for RA is cost-effective,” the authors wrote.

Dr. van der Helm-van Mil emphasized that this cost analysis used only 2-year follow-up data (rather than the newly published 4-year data) and did not differentiate ACPA–negative patients. Despite including a greater heterogeneity of patients, the intervention was still cost-effective. A future analysis that includes 5-year follow-up data and stratifies patients by ACPA status and excludes low-risk individuals could demonstrate more cost benefits to a temporary MTX regimen, she said.

Considering the costs of these preventive interventions is important, added Dr. Deane, who agreed that future analyses should examine cost-effectiveness in groups at high risk of developing RA. (Dr. Deane noted that he had reviewed this article for publication.) However, this analysis did not include the costs of screening patients before enrollment in the study.

Richard Mark Kirkner/MDedge News

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

TOPLINE:

Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
• They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
• Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
• Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
• The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.

TAKEAWAY:

• Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
• The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
• Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
• The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).

IN PRACTICE:

“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.

“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
 

SOURCE:

This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
• They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
• Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
• Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
• The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.

TAKEAWAY:

• Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
• The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
• Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
• The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).

IN PRACTICE:

“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.

“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
 

SOURCE:

This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
• They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
• Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
• Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
• The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.

TAKEAWAY:

• Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
• The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
• Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
• The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).

IN PRACTICE:

“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.

“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
 

SOURCE:

This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.

But they have long wondered why.

“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”

Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.

Dr. Curtis and colleagues found that, like fingers molding clay, the genes you’re born with can coax the immune system into shape. DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.

“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.

The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.

While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.

“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
 

‘We’re Basically Unearthing the Dark Matter of the Human Genome’

Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.

In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.

“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.

Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).

They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.

“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”

These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.

In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.

But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.

This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.

And that “critical juncture” may very well be the optimal time for intervention.
 

The Precancer Push

Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”

Many labs are trying to understand the biology of precancer and exploring possible vaccines.

The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.

Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.

At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.

Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.

In the years and decades to come, all of this could lead to a new era in cancer treatment.

“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”

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

Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.

But they have long wondered why.

“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”

Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.

Dr. Curtis and colleagues found that, like fingers molding clay, the genes you’re born with can coax the immune system into shape. DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.

“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.

The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.

While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.

“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
 

‘We’re Basically Unearthing the Dark Matter of the Human Genome’

Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.

In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.

“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.

Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).

They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.

“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”

These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.

In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.

But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.

This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.

And that “critical juncture” may very well be the optimal time for intervention.
 

The Precancer Push

Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”

Many labs are trying to understand the biology of precancer and exploring possible vaccines.

The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.

Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.

At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.

Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.

In the years and decades to come, all of this could lead to a new era in cancer treatment.

“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”

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

Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.

But they have long wondered why.

“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”

Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.

Dr. Curtis and colleagues found that, like fingers molding clay, the genes you’re born with can coax the immune system into shape. DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.

“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.

The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.

While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.

“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
 

‘We’re Basically Unearthing the Dark Matter of the Human Genome’

Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.

In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.

“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.

Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).

They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.

“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”

These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.

In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.

But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.

This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.

And that “critical juncture” may very well be the optimal time for intervention.
 

The Precancer Push

Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”

Many labs are trying to understand the biology of precancer and exploring possible vaccines.

The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.

Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.

At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.

Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.

In the years and decades to come, all of this could lead to a new era in cancer treatment.

“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”

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

This transcript has been edited for clarity. 

Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data. 

One of the things I picked up on was a nice mini-symposium on gastrointestinal cancer led by Sara Lonardi, who made an excellent presentation, picking out three abstracts. They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.

She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment. 

Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.

There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.

Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly. 

Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets. 

We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells. 

We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.

For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells. 

We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together. 

Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.

Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.

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

This transcript has been edited for clarity. 

Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data. 

One of the things I picked up on was a nice mini-symposium on gastrointestinal cancer led by Sara Lonardi, who made an excellent presentation, picking out three abstracts. They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.

She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment. 

Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.

There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.

Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly. 

Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets. 

We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells. 

We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.

For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells. 

We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together. 

Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.

Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.

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

This transcript has been edited for clarity. 

Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data. 

One of the things I picked up on was a nice mini-symposium on gastrointestinal cancer led by Sara Lonardi, who made an excellent presentation, picking out three abstracts. They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.

She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment. 

Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.

There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.

Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly. 

Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets. 

We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells. 

We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.

For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells. 

We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together. 

Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.

Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.

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

WASHINGTON — Combining short-term androgen deprivation therapy (ADT) with high-dose radiotherapy improves disease-free survival in men with intermediate-risk prostate cancer, compared with high-dose radiotherapy alone, according to results of the phase 3 GETUG 14 trial.

The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.

In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.

The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.

Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.

Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.

The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.

Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).

In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).

On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).

Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).

As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.

Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).

Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.

The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”

Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”

The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.

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

WASHINGTON — Combining short-term androgen deprivation therapy (ADT) with high-dose radiotherapy improves disease-free survival in men with intermediate-risk prostate cancer, compared with high-dose radiotherapy alone, according to results of the phase 3 GETUG 14 trial.

The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.

In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.

The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.

Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.

Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.

The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.

Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).

In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).

On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).

Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).

As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.

Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).

Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.

The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”

Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”

The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.

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

WASHINGTON — Combining short-term androgen deprivation therapy (ADT) with high-dose radiotherapy improves disease-free survival in men with intermediate-risk prostate cancer, compared with high-dose radiotherapy alone, according to results of the phase 3 GETUG 14 trial.

The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.

In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.

The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.

Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.

Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.

The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.

Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).

In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).

On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).

Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).

As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.

Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).

Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.

The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”

Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”

The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.

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

Black box warnings added to antidepressant medications on increased risk for suicidality were associated with a decline in mental health treatment and an increase in suicide attempts and deaths in young people, a new analysis suggests. 

Investigators said the totality of evidence supports “reevaluation and possible replacement” of the US Food and Drug Administration (FDA) black box warning with routine warnings in product labeling. 

“The sudden, simultaneous, and sweeping effects of these warnings — the reduction in depression treatment and increase in suicide — are documented across 14 years of strong research. The consistency in observed harms and absence of observed benefits after the black box warnings indicate this is not a coincidence,” lead author Stephen Soumerai, ScD, professor of population medicine, Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, said in a news release. 

The study was published online in Health Affairs. 
 

How Did We Get Here?

In October 2003, the FDA warned that antidepressants may be associated with suicidality among people younger than age 18 years soon after starting treatment. In January 2005, the FDA required a permanent black box warning of this risk on product labels and in television and print advertising for all antidepressant drugs. 

In May 2007, the FDA expanded the 2005 black box warning to include young adults through age 24, and this broader warning remains in effect today. 

Dr. Soumerai and colleagues evaluated the intended and unintended outcomes of the youth antidepressant warnings through a systematic review of “the most credible evidence in the field,” Dr. Soumerai said. 

Through an exhaustive literature search, the researchers identified 34 studies of depression and suicide-related outcomes published in peer-reviewed journals after the warnings were issued. 

Eleven of these studies measured abrupt changes in outcome trends following the warnings and were included in their analyses. These outcomes included monitoring for suicidality, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use and psychotropic drug poisonings (a proxy for suicide attempts), and suicide deaths. 
 

More Harms Than Benefits

Four studies, with more than 12 million patients, found “consistent evidence of sudden and substantial” long-term declines in doctor visits for depression and depression diagnoses after the FDA warnings, the study team noted.

These studies showed increases in physician visits for depression and depression diagnoses in the years before the warnings and abrupt, sustained declines, ranging from 20% to 45%, in visits and diagnoses after the warnings. “Some spillover occurred in comparison groups of adults, who were not targeted by the FDA warnings,” the study team said. 

Seven studies revealed evidence that the FDA warnings were followed by abrupt reductions in antidepressant treatment and use, ranging from 20% to 50%. Most of these studies showed increasing use of antidepressants in the years before the FDA warnings, followed by abrupt and sustained reductions in use afterward. 

Three studies found evidence of declining or flat trends in psychotropic drug poisonings and suicide deaths among pediatric patients before the warnings, followed by abrupt increases in these trends after the warnings were issued. 

The intent of the warnings was to increase physician monitoring of suicidality of patients treated with antidepressants, but the data suggest that this did not occur. 

Less than 5% of pediatric patients were monitored in accordance with FDA’s recommended contact schedule recommendations after the warnings were issued. This low rate was unchanged from the rate before the warnings. 

No study documented improvements in mental health care or declines in suicide attempts or suicides after the warnings went into effect. 

“The overwhelming evidence suggests that the ongoing use of these warnings may result in more harms than benefits,” the authors wrote. 
 

Concerning Data 

The results are “very concerning and provide reason to pause, rethink, and possibly recalibrate boxed warning recommendations as it relates to antidepressants in younger populations,” said Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit.

Dr. McIntyre, who wasn’t involved in the study, said the data “unfortunately” provide evidence suggesting that the boxed warning had the “unintended consequence of increasing the likelihood that persons would not receive adequate healthcare for their mental disorder, consequently resulting in unfavorable outcomes, including suicidality.”

He added, “Two decades have now passed with additional information available, which not only appears to recalibrate the initial risk assessment but provides an opportunity for us to reduce the externality of decreasing access to healthcare for people living with mental illness during their youth years.” 

A spokesperson for the FDA said that “generally, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

The study had no commercial funding. Disclosures for the authors are listed with the original article. Dr. McIntyre has received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, and Neurocrine.
 

A version of this article appeared on Medscape.com.

Black box warnings added to antidepressant medications on increased risk for suicidality were associated with a decline in mental health treatment and an increase in suicide attempts and deaths in young people, a new analysis suggests. 

Investigators said the totality of evidence supports “reevaluation and possible replacement” of the US Food and Drug Administration (FDA) black box warning with routine warnings in product labeling. 

“The sudden, simultaneous, and sweeping effects of these warnings — the reduction in depression treatment and increase in suicide — are documented across 14 years of strong research. The consistency in observed harms and absence of observed benefits after the black box warnings indicate this is not a coincidence,” lead author Stephen Soumerai, ScD, professor of population medicine, Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, said in a news release. 

The study was published online in Health Affairs. 
 

How Did We Get Here?

In October 2003, the FDA warned that antidepressants may be associated with suicidality among people younger than age 18 years soon after starting treatment. In January 2005, the FDA required a permanent black box warning of this risk on product labels and in television and print advertising for all antidepressant drugs. 

In May 2007, the FDA expanded the 2005 black box warning to include young adults through age 24, and this broader warning remains in effect today. 

Dr. Soumerai and colleagues evaluated the intended and unintended outcomes of the youth antidepressant warnings through a systematic review of “the most credible evidence in the field,” Dr. Soumerai said. 

Through an exhaustive literature search, the researchers identified 34 studies of depression and suicide-related outcomes published in peer-reviewed journals after the warnings were issued. 

Eleven of these studies measured abrupt changes in outcome trends following the warnings and were included in their analyses. These outcomes included monitoring for suicidality, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use and psychotropic drug poisonings (a proxy for suicide attempts), and suicide deaths. 
 

More Harms Than Benefits

Four studies, with more than 12 million patients, found “consistent evidence of sudden and substantial” long-term declines in doctor visits for depression and depression diagnoses after the FDA warnings, the study team noted.

These studies showed increases in physician visits for depression and depression diagnoses in the years before the warnings and abrupt, sustained declines, ranging from 20% to 45%, in visits and diagnoses after the warnings. “Some spillover occurred in comparison groups of adults, who were not targeted by the FDA warnings,” the study team said. 

Seven studies revealed evidence that the FDA warnings were followed by abrupt reductions in antidepressant treatment and use, ranging from 20% to 50%. Most of these studies showed increasing use of antidepressants in the years before the FDA warnings, followed by abrupt and sustained reductions in use afterward. 

Three studies found evidence of declining or flat trends in psychotropic drug poisonings and suicide deaths among pediatric patients before the warnings, followed by abrupt increases in these trends after the warnings were issued. 

The intent of the warnings was to increase physician monitoring of suicidality of patients treated with antidepressants, but the data suggest that this did not occur. 

Less than 5% of pediatric patients were monitored in accordance with FDA’s recommended contact schedule recommendations after the warnings were issued. This low rate was unchanged from the rate before the warnings. 

No study documented improvements in mental health care or declines in suicide attempts or suicides after the warnings went into effect. 

“The overwhelming evidence suggests that the ongoing use of these warnings may result in more harms than benefits,” the authors wrote. 
 

Concerning Data 

The results are “very concerning and provide reason to pause, rethink, and possibly recalibrate boxed warning recommendations as it relates to antidepressants in younger populations,” said Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit.

Dr. McIntyre, who wasn’t involved in the study, said the data “unfortunately” provide evidence suggesting that the boxed warning had the “unintended consequence of increasing the likelihood that persons would not receive adequate healthcare for their mental disorder, consequently resulting in unfavorable outcomes, including suicidality.”

He added, “Two decades have now passed with additional information available, which not only appears to recalibrate the initial risk assessment but provides an opportunity for us to reduce the externality of decreasing access to healthcare for people living with mental illness during their youth years.” 

A spokesperson for the FDA said that “generally, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

The study had no commercial funding. Disclosures for the authors are listed with the original article. Dr. McIntyre has received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, and Neurocrine.
 

A version of this article appeared on Medscape.com.

Black box warnings added to antidepressant medications on increased risk for suicidality were associated with a decline in mental health treatment and an increase in suicide attempts and deaths in young people, a new analysis suggests. 

Investigators said the totality of evidence supports “reevaluation and possible replacement” of the US Food and Drug Administration (FDA) black box warning with routine warnings in product labeling. 

“The sudden, simultaneous, and sweeping effects of these warnings — the reduction in depression treatment and increase in suicide — are documented across 14 years of strong research. The consistency in observed harms and absence of observed benefits after the black box warnings indicate this is not a coincidence,” lead author Stephen Soumerai, ScD, professor of population medicine, Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, said in a news release. 

The study was published online in Health Affairs. 
 

How Did We Get Here?

In October 2003, the FDA warned that antidepressants may be associated with suicidality among people younger than age 18 years soon after starting treatment. In January 2005, the FDA required a permanent black box warning of this risk on product labels and in television and print advertising for all antidepressant drugs. 

In May 2007, the FDA expanded the 2005 black box warning to include young adults through age 24, and this broader warning remains in effect today. 

Dr. Soumerai and colleagues evaluated the intended and unintended outcomes of the youth antidepressant warnings through a systematic review of “the most credible evidence in the field,” Dr. Soumerai said. 

Through an exhaustive literature search, the researchers identified 34 studies of depression and suicide-related outcomes published in peer-reviewed journals after the warnings were issued. 

Eleven of these studies measured abrupt changes in outcome trends following the warnings and were included in their analyses. These outcomes included monitoring for suicidality, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use and psychotropic drug poisonings (a proxy for suicide attempts), and suicide deaths. 
 

More Harms Than Benefits

Four studies, with more than 12 million patients, found “consistent evidence of sudden and substantial” long-term declines in doctor visits for depression and depression diagnoses after the FDA warnings, the study team noted.

These studies showed increases in physician visits for depression and depression diagnoses in the years before the warnings and abrupt, sustained declines, ranging from 20% to 45%, in visits and diagnoses after the warnings. “Some spillover occurred in comparison groups of adults, who were not targeted by the FDA warnings,” the study team said. 

Seven studies revealed evidence that the FDA warnings were followed by abrupt reductions in antidepressant treatment and use, ranging from 20% to 50%. Most of these studies showed increasing use of antidepressants in the years before the FDA warnings, followed by abrupt and sustained reductions in use afterward. 

Three studies found evidence of declining or flat trends in psychotropic drug poisonings and suicide deaths among pediatric patients before the warnings, followed by abrupt increases in these trends after the warnings were issued. 

The intent of the warnings was to increase physician monitoring of suicidality of patients treated with antidepressants, but the data suggest that this did not occur. 

Less than 5% of pediatric patients were monitored in accordance with FDA’s recommended contact schedule recommendations after the warnings were issued. This low rate was unchanged from the rate before the warnings. 

No study documented improvements in mental health care or declines in suicide attempts or suicides after the warnings went into effect. 

“The overwhelming evidence suggests that the ongoing use of these warnings may result in more harms than benefits,” the authors wrote. 
 

Concerning Data 

The results are “very concerning and provide reason to pause, rethink, and possibly recalibrate boxed warning recommendations as it relates to antidepressants in younger populations,” said Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit.

Dr. McIntyre, who wasn’t involved in the study, said the data “unfortunately” provide evidence suggesting that the boxed warning had the “unintended consequence of increasing the likelihood that persons would not receive adequate healthcare for their mental disorder, consequently resulting in unfavorable outcomes, including suicidality.”

He added, “Two decades have now passed with additional information available, which not only appears to recalibrate the initial risk assessment but provides an opportunity for us to reduce the externality of decreasing access to healthcare for people living with mental illness during their youth years.” 

A spokesperson for the FDA said that “generally, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

The study had no commercial funding. Disclosures for the authors are listed with the original article. Dr. McIntyre has received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, and Neurocrine.
 

A version of this article appeared on Medscape.com.

HUNTINGTON BEACH, CALIFORNIA — When patients of Aaron Mangold, MD, first learn they have mycosis fungoides (MF), the most common form of primary cutaneous T-cell lymphoma (CTCL), some are concerned about whether the diagnosis means a shortened life expectancy.

“In most cases, mycosis fungoides will not shorten one’s life, but it can cause significant symptoms,” Dr. Mangold, codirector of the multidisciplinary cutaneous lymphoma clinic at Mayo Clinic, Scottsdale, Arizona, said at the annual meeting of the Pacific Dermatologic Association. “For early-stage disease, I think of it more like diabetes; this is really a chronic disease” that unlikely will be fatal but may be associated with increased morbidity as the disease progresses, and “the overall goal of therapy should be disease control to increase quality of life.”

courtesy Dr. Aaron Mangold

Patient- and lymphoma-specific factors drive the choice of therapy. The focus for patients with early-stage disease, Dr. Mangold said, is to treat comorbidities and symptoms, such as itch or skin pain, maximize their quality of life, and consider the potential for associated toxicities of therapy as the disease progresses. Start with the least toxic, targeted, nonimmunosuppressive therapy, “then work toward more toxic immunosuppressive therapies,” he advised. “Use toxic agents just long enough to control the disease, then transition to a maintenance regimen with less toxic immunosuppressive agents.”
 

When Close Follow-Up Is Advised

According to unpublished data from PROCLIPI (the Prospective Cutaneous Lymphoma International Prognostic Index) study presented at the fifth World Congress of Cutaneous Lymphomas earlier in 2024, the following factors warrant consideration for close follow-up and more aggressive treatment: Nodal enlargement greater than 15 mm, age over 60 years, presence of plaques, and large-cell transformation in skin. “These are some of the stigmata in early disease that might guide you toward referring” a patient to a CTCL expert, Dr. Mangold said. (Consensus-based recommendations on the management of MF in children were published in August of 2024.)

According to Dr. Mangold, topical/skin-directed therapies are best for early-stage disease or in combination with systemic therapies in advanced disease. For early-stage disease, one of his preferred options is daily application of a skin moisturizer plus a topical corticosteroid such as clobetasol, halobetasol, or augmented betamethasone, then evaluating the response at 3 months. “This is a cheap option, and we see response rates as high as 90%,” he said. “I don’t often see steroid atrophy when treating patients with active MF. There’s a tendency to think, ‘I don’t want to overtreat.’ I think you can be aggressive. If you look in the literature, people typically pulse twice daily for a couple of weeks with a 1-week break.”

Mechlorethamine, a topical alkylating gel approved in 2013 for the treatment of early-stage MF, is an option when patients fail to respond to topical steroids, prefer to avoid steroids, or have thick, plaque-like disease. With mechlorethamine, it is important to “start slow and be patient,” Dr. Mangold said. “Real-world data shows that it takes 12-18 months to get a good response. Counsel patients that they are likely to get a rash, and that the risk of rash is dose dependent.”

Other treatment options to consider include imiquimod, which can be used for single refractory spots. He typically recommends application 5 days per week with titration up to daily if tolerated for up to 3 months. “Treat until you get a brisk immune response,” he said. “We’ve seen patients with durable, long-term responses.”
 

UVB Phototherapy Effective

For patients with stage IB disease, topical therapies are less practical and may be focused on refractory areas of disease. Narrow-band UVB phototherapy is the most practical and cost-effective treatment, Dr. Mangold said. Earlier-stage patch disease responds to phototherapy in up to 80% of cases, while plaque-stage disease responds in up to half of cases. “More frequent use of phototherapy may decrease time to clearance, but overall response is similar.”

Dr. Mangold recommends phototherapy 2-3 days per week, titrating up to a maximal response dose, and maintaining that dose for about 3 months. Maintenance involves tapering the phototherapy dose to a minimal dose with continued response. “The goal is to prevent relapse,” he said.

For patients with MF of stage IIB and higher, he considers total skin electron beam therapy, an oral retinoid with phototherapy, systemic agents, and focal radiation with systemic treatment. One of his go-to systemic options is bexarotene, which he uses for early-stage disease refractory to treatment or for less aggressive advanced disease. “We typically use a low dose ... and about half of patients respond,” Dr. Mangold said. The time to response is about 6 months. Bexarotene causes elevated lipids and low thyroid function, so he initiates patients on fenofibrate and levothyroxine at baseline.

Another systemic option is brentuximab vedotin, a monoclonal antibody that targets cells with CD30 expression, which is typically administered in a specialty center every 3 weeks for up to 16 cycles. “In practice, we often use six to eight cycles to avoid neuropathy,” he said. “It’s a good debulking agent, the time to response is 6-9 weeks, and it has a sustained response of 60%.” Neuropathy can occur with treatment, but improves over time.

Other systemic options for MF include romidepsin, mogamulizumab, and extracorporeal photopheresis used in erythrodermic disease.
 

Radiation An Option in Some Cases

Dr. Mangold noted that low doses of radiation therapy can effectively treat MF lesions in as little as one dose. “We can use it as a cure for a single spot or to temporarily treat the disease while other therapies are being started,” he said. Long-term side effects need to be considered when using radiation. “The more radiation, the more side effects.”

Dr. Mangold disclosed that he is an investigator for Sun Pharmaceutical, Solagenix, Elorac, miRagen, Kyowa Kirin, the National Clinical Trials Network, and CRISPR Therapeutics. He has also received consulting fees/honoraria from Kirin and Solagenix.

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

HUNTINGTON BEACH, CALIFORNIA — When patients of Aaron Mangold, MD, first learn they have mycosis fungoides (MF), the most common form of primary cutaneous T-cell lymphoma (CTCL), some are concerned about whether the diagnosis means a shortened life expectancy.

“In most cases, mycosis fungoides will not shorten one’s life, but it can cause significant symptoms,” Dr. Mangold, codirector of the multidisciplinary cutaneous lymphoma clinic at Mayo Clinic, Scottsdale, Arizona, said at the annual meeting of the Pacific Dermatologic Association. “For early-stage disease, I think of it more like diabetes; this is really a chronic disease” that unlikely will be fatal but may be associated with increased morbidity as the disease progresses, and “the overall goal of therapy should be disease control to increase quality of life.”

courtesy Dr. Aaron Mangold

Patient- and lymphoma-specific factors drive the choice of therapy. The focus for patients with early-stage disease, Dr. Mangold said, is to treat comorbidities and symptoms, such as itch or skin pain, maximize their quality of life, and consider the potential for associated toxicities of therapy as the disease progresses. Start with the least toxic, targeted, nonimmunosuppressive therapy, “then work toward more toxic immunosuppressive therapies,” he advised. “Use toxic agents just long enough to control the disease, then transition to a maintenance regimen with less toxic immunosuppressive agents.”
 

When Close Follow-Up Is Advised

According to unpublished data from PROCLIPI (the Prospective Cutaneous Lymphoma International Prognostic Index) study presented at the fifth World Congress of Cutaneous Lymphomas earlier in 2024, the following factors warrant consideration for close follow-up and more aggressive treatment: Nodal enlargement greater than 15 mm, age over 60 years, presence of plaques, and large-cell transformation in skin. “These are some of the stigmata in early disease that might guide you toward referring” a patient to a CTCL expert, Dr. Mangold said. (Consensus-based recommendations on the management of MF in children were published in August of 2024.)

According to Dr. Mangold, topical/skin-directed therapies are best for early-stage disease or in combination with systemic therapies in advanced disease. For early-stage disease, one of his preferred options is daily application of a skin moisturizer plus a topical corticosteroid such as clobetasol, halobetasol, or augmented betamethasone, then evaluating the response at 3 months. “This is a cheap option, and we see response rates as high as 90%,” he said. “I don’t often see steroid atrophy when treating patients with active MF. There’s a tendency to think, ‘I don’t want to overtreat.’ I think you can be aggressive. If you look in the literature, people typically pulse twice daily for a couple of weeks with a 1-week break.”

Mechlorethamine, a topical alkylating gel approved in 2013 for the treatment of early-stage MF, is an option when patients fail to respond to topical steroids, prefer to avoid steroids, or have thick, plaque-like disease. With mechlorethamine, it is important to “start slow and be patient,” Dr. Mangold said. “Real-world data shows that it takes 12-18 months to get a good response. Counsel patients that they are likely to get a rash, and that the risk of rash is dose dependent.”

Other treatment options to consider include imiquimod, which can be used for single refractory spots. He typically recommends application 5 days per week with titration up to daily if tolerated for up to 3 months. “Treat until you get a brisk immune response,” he said. “We’ve seen patients with durable, long-term responses.”
 

UVB Phototherapy Effective

For patients with stage IB disease, topical therapies are less practical and may be focused on refractory areas of disease. Narrow-band UVB phototherapy is the most practical and cost-effective treatment, Dr. Mangold said. Earlier-stage patch disease responds to phototherapy in up to 80% of cases, while plaque-stage disease responds in up to half of cases. “More frequent use of phototherapy may decrease time to clearance, but overall response is similar.”

Dr. Mangold recommends phototherapy 2-3 days per week, titrating up to a maximal response dose, and maintaining that dose for about 3 months. Maintenance involves tapering the phototherapy dose to a minimal dose with continued response. “The goal is to prevent relapse,” he said.

For patients with MF of stage IIB and higher, he considers total skin electron beam therapy, an oral retinoid with phototherapy, systemic agents, and focal radiation with systemic treatment. One of his go-to systemic options is bexarotene, which he uses for early-stage disease refractory to treatment or for less aggressive advanced disease. “We typically use a low dose ... and about half of patients respond,” Dr. Mangold said. The time to response is about 6 months. Bexarotene causes elevated lipids and low thyroid function, so he initiates patients on fenofibrate and levothyroxine at baseline.

Another systemic option is brentuximab vedotin, a monoclonal antibody that targets cells with CD30 expression, which is typically administered in a specialty center every 3 weeks for up to 16 cycles. “In practice, we often use six to eight cycles to avoid neuropathy,” he said. “It’s a good debulking agent, the time to response is 6-9 weeks, and it has a sustained response of 60%.” Neuropathy can occur with treatment, but improves over time.

Other systemic options for MF include romidepsin, mogamulizumab, and extracorporeal photopheresis used in erythrodermic disease.
 

Radiation An Option in Some Cases

Dr. Mangold noted that low doses of radiation therapy can effectively treat MF lesions in as little as one dose. “We can use it as a cure for a single spot or to temporarily treat the disease while other therapies are being started,” he said. Long-term side effects need to be considered when using radiation. “The more radiation, the more side effects.”

Dr. Mangold disclosed that he is an investigator for Sun Pharmaceutical, Solagenix, Elorac, miRagen, Kyowa Kirin, the National Clinical Trials Network, and CRISPR Therapeutics. He has also received consulting fees/honoraria from Kirin and Solagenix.

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

HUNTINGTON BEACH, CALIFORNIA — When patients of Aaron Mangold, MD, first learn they have mycosis fungoides (MF), the most common form of primary cutaneous T-cell lymphoma (CTCL), some are concerned about whether the diagnosis means a shortened life expectancy.

“In most cases, mycosis fungoides will not shorten one’s life, but it can cause significant symptoms,” Dr. Mangold, codirector of the multidisciplinary cutaneous lymphoma clinic at Mayo Clinic, Scottsdale, Arizona, said at the annual meeting of the Pacific Dermatologic Association. “For early-stage disease, I think of it more like diabetes; this is really a chronic disease” that unlikely will be fatal but may be associated with increased morbidity as the disease progresses, and “the overall goal of therapy should be disease control to increase quality of life.”

courtesy Dr. Aaron Mangold

Patient- and lymphoma-specific factors drive the choice of therapy. The focus for patients with early-stage disease, Dr. Mangold said, is to treat comorbidities and symptoms, such as itch or skin pain, maximize their quality of life, and consider the potential for associated toxicities of therapy as the disease progresses. Start with the least toxic, targeted, nonimmunosuppressive therapy, “then work toward more toxic immunosuppressive therapies,” he advised. “Use toxic agents just long enough to control the disease, then transition to a maintenance regimen with less toxic immunosuppressive agents.”
 

When Close Follow-Up Is Advised

According to unpublished data from PROCLIPI (the Prospective Cutaneous Lymphoma International Prognostic Index) study presented at the fifth World Congress of Cutaneous Lymphomas earlier in 2024, the following factors warrant consideration for close follow-up and more aggressive treatment: Nodal enlargement greater than 15 mm, age over 60 years, presence of plaques, and large-cell transformation in skin. “These are some of the stigmata in early disease that might guide you toward referring” a patient to a CTCL expert, Dr. Mangold said. (Consensus-based recommendations on the management of MF in children were published in August of 2024.)

According to Dr. Mangold, topical/skin-directed therapies are best for early-stage disease or in combination with systemic therapies in advanced disease. For early-stage disease, one of his preferred options is daily application of a skin moisturizer plus a topical corticosteroid such as clobetasol, halobetasol, or augmented betamethasone, then evaluating the response at 3 months. “This is a cheap option, and we see response rates as high as 90%,” he said. “I don’t often see steroid atrophy when treating patients with active MF. There’s a tendency to think, ‘I don’t want to overtreat.’ I think you can be aggressive. If you look in the literature, people typically pulse twice daily for a couple of weeks with a 1-week break.”

Mechlorethamine, a topical alkylating gel approved in 2013 for the treatment of early-stage MF, is an option when patients fail to respond to topical steroids, prefer to avoid steroids, or have thick, plaque-like disease. With mechlorethamine, it is important to “start slow and be patient,” Dr. Mangold said. “Real-world data shows that it takes 12-18 months to get a good response. Counsel patients that they are likely to get a rash, and that the risk of rash is dose dependent.”

Other treatment options to consider include imiquimod, which can be used for single refractory spots. He typically recommends application 5 days per week with titration up to daily if tolerated for up to 3 months. “Treat until you get a brisk immune response,” he said. “We’ve seen patients with durable, long-term responses.”
 

UVB Phototherapy Effective

For patients with stage IB disease, topical therapies are less practical and may be focused on refractory areas of disease. Narrow-band UVB phototherapy is the most practical and cost-effective treatment, Dr. Mangold said. Earlier-stage patch disease responds to phototherapy in up to 80% of cases, while plaque-stage disease responds in up to half of cases. “More frequent use of phototherapy may decrease time to clearance, but overall response is similar.”

Dr. Mangold recommends phototherapy 2-3 days per week, titrating up to a maximal response dose, and maintaining that dose for about 3 months. Maintenance involves tapering the phototherapy dose to a minimal dose with continued response. “The goal is to prevent relapse,” he said.

For patients with MF of stage IIB and higher, he considers total skin electron beam therapy, an oral retinoid with phototherapy, systemic agents, and focal radiation with systemic treatment. One of his go-to systemic options is bexarotene, which he uses for early-stage disease refractory to treatment or for less aggressive advanced disease. “We typically use a low dose ... and about half of patients respond,” Dr. Mangold said. The time to response is about 6 months. Bexarotene causes elevated lipids and low thyroid function, so he initiates patients on fenofibrate and levothyroxine at baseline.

Another systemic option is brentuximab vedotin, a monoclonal antibody that targets cells with CD30 expression, which is typically administered in a specialty center every 3 weeks for up to 16 cycles. “In practice, we often use six to eight cycles to avoid neuropathy,” he said. “It’s a good debulking agent, the time to response is 6-9 weeks, and it has a sustained response of 60%.” Neuropathy can occur with treatment, but improves over time.

Other systemic options for MF include romidepsin, mogamulizumab, and extracorporeal photopheresis used in erythrodermic disease.
 

Radiation An Option in Some Cases

Dr. Mangold noted that low doses of radiation therapy can effectively treat MF lesions in as little as one dose. “We can use it as a cure for a single spot or to temporarily treat the disease while other therapies are being started,” he said. Long-term side effects need to be considered when using radiation. “The more radiation, the more side effects.”

Dr. Mangold disclosed that he is an investigator for Sun Pharmaceutical, Solagenix, Elorac, miRagen, Kyowa Kirin, the National Clinical Trials Network, and CRISPR Therapeutics. He has also received consulting fees/honoraria from Kirin and Solagenix.

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